Using ncRNAs as Tools in Cancer Diagnosis and Treatment-The Way towards Personalized Medicine to Improve Patients' Health.

1. Introduction—Filling the Protein World with RNA

Some decades ago, it was assumed that the biological needs of cells were essentially met through the actions of proteins. This assumption came basically from the experiments of Beadle and Tatum, who ca. 80 years ago for the first time showed the direct link between genes and enzymatic reactions in the organism Neurospora crassa [ 1 ]—the so called one gene , one enzyme hypothesis—whose discovery earned them the Nobel Prize in Physiology or Medicine in 1958, together with Lederberg. This concept was further expanded thanks to Vernom Ingram’s work in 1956, with the statement one gene , one polypeptide , when by studying the sickle cell hemoglobin he found that genetic variations in proteins could affect only a single polypeptide chain inside a multimeric protein complex [ 2 ]. The discovery of the DNA structure [ 3 ] and the cracking of the genetic code in the following years [ 4 ] set the basis for the formulation of the central dogma of molecular biology, first formulated in 1956 [ 5 ] in the following form: “once information has got into a protein it cannot get out again”. Beyond the obvious consequence of information not travelling back from proteins to nucleic acids, the central dogma indirectly tells us two additional things: (1) the flux of information cannot go beyond the protein level, which means that once the information arrives at a protein, the protein performs the cellular job; (2) however, nothing prevents information from stopping “before” reaching a protein, which in turn means that the information can be used by other molecules, i.e., DNA and RNA. As for the DNA, there are portions of the genome that store information that is strictly connected to the DNA; indeed, this part of the genome is normally not transcribed at all—for example, in centromeres and telomeres, in which (i) the information is stored in the DNA sequence itself; (ii) the cellular jobs are essentially chromosome segregation and integrity, respectively [ 6 ]; and (iii) their maintenance is epigenetically regulated [ 7 ]. As for the RNA, the first identification of tRNA (transfer RNA) dates back to 1958 [ 8 ], and in the same year the ribosome components started to be identified [ 9 ], including ribosomal RNA (rRNA). Together, the tRNAs and rRNAs represent more than 95% of the total mass of the RNA inside a cell [ 10 ]; rRNAs derive from approximately 300–400 gene repeats organized in 5 clusters per human haploid genome [ 11 ], producing millions of rRNA molecules per cell, while tRNAs are transcribed by ca. 500 genes in H. sapiens [ 12 ], producing a few million transcripts.

Interestingly, “non-coding” RNAs were discovered before the coding ones, i.e., mRNAs (messenger RNAs), the molecules physically conveying information between DNA and proteins, whose identification occurred in 1961 [ 13 , 14 , 15 ]. Starting from the 1970s in the twentieth century, several additional non-coding RNAs (ncRNAs) were identified, either as single molecules performing a specific task (such as Xist , TERRA ) or entire categories performing similar tasks and sharing common structural characteristics; an incomplete list of these molecules includes the following (in parentheses is the abbreviated name if present and the approximate year(s) of first discovery): small nuclear RNA (snRNA, 1977), transfer RNA-derived small RNA (tsRNA, 1977-79), ribozymes (1980), Y RNA (1981), antisense RNA (1981-86), interfering RNA (1990), Xist (1992), small nucleolar RNA (snoRNA, 1992), microRNA (miRNA, 1993), Tsix (1999), riboswitches (2002), Piwi-associated RNA (piRNA, 2006), TERC (2007), TERRA (2010), enhancer RNA (eRNA, 2010), circular RNA (circRNA, 2012), and ribosome-associated non-coding RNA (rancRNA, 2012) (reviewed in [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]). It is now clear that the transcriptome largely outsizes the proteome in terms of the number of different molecules: a large part of the human genome is transcribed into RNAs, but the protein-coding loci account for just 3% of it [ 24 ]. To further complicate this scenario, in recent years even the dichotomy of coding vs. non-coding RNAs has been weakening, due to the discovery of bi-functional RNAs [ 25 ], which are RNA molecules that have an open reading frame (ORF) but at the same time can also fulfill other cellular functions without being translated.

2. Overview of Non-Coding RNAs: Abundance, Types and Classification

In the easiest scenario, non-coding RNAs (ncRNAs) are generally defined by the absence of an ORF in their sequence. This class of RNAs is largely the most abundant in the cell, exonic sequences covering a mere 1% of the total human genome [ 26 ]. Since the first human genome draft [ 27 ], it has been clear that for the most part such RNAs could not be just a background of the ORF transcription; in fact, the human genome contains approximately 20,000 protein coding genes, while transcripts come from the activity of ca. 93% of the human genome, with 53% of them coming from regions outside the gene boundaries (intergenic sequences), thereby exceeding the 120,000 non-coding transcriptional units [ 26 , 28 ]. However, an exact estimate of their number is extremely hard to obtain because a locus may encode for more than one ncRNA (up to dozens in a row in the case of microRNAs), but not all have a biological function. For example, miRs derive from a precursor double-stranded RNA, but while in some cases only one strand is biologically active, in other cases both strands are retained in the cell and perform different functions. Moreover, it is also likely that a significant portion of them are devoid of any biologically relevant function, and indeed are mere byproducts of the transcription of nearby sequences [ 10 ].

The ncRNAs represent a highly heterogeneous group ( Figure 1 ). Because of this, they are arbitrarily classified into two broad categories according to their length, with a threshold of approximately 200 nucleotides (nt). Those below the threshold are called short ncRNAs (sncRNAs), and in most cases their length is below 30 nt; those above the threshold are named long ncRNAs (lncRNAs), and may be as long as several kilobases [ 29 ]. The sncRNA group includes subgroups such as microRNAs (miRs or miRNAs), which recognize and bind partially complementary sequences located in other RNAs, either coding or non-coding, altering protein expression; Piwi-interacting RNAs (piRNAs), which function mainly in the germ line and inhibit the transcription and movement of retrotransposons, retroviruses, repetitive sequences, and other mobile elements; small interfering RNAs (or short interfering RNAs, siRNAs), double-stranded RNA molecules that promote target mRNA degradation but also play a role in antiviral activity and chromatin remodeling; small nuclear RNAs (snRNAs), involved in pre-mRNA splicing; and small nucleolar RNAs (snoRNAs), involved in RNA modification [ 30 , 31 ]. A comparable classification for lncRNAs is not possible, due to their ample variability in terms of their genome position (intragenic, intergenic), direction of transcription (sense, antisense), length (starting at around 200 nt and up to several kb), function (acting as transcriptional or translational regulators, chromatin modifiers, enhancers, decoys, ceRNAs, micropeptide templates, etc.), structure (linear, circular), cellular localization (nucleus, cytoplasm), and so on [ 28 , 32 ].

3. Competing Endogenous RNA Networks (ceRNETs): When lncRNAs and sncRNAs Interact

Other than the abovementioned classification, in recent years a new category of ncRNAs has been identified based on functional assays. It has been repeatedly shown that miRs are able to interact not only with their target mRNA, but also with lncRNAs ( Figure 2 ). In other words, the mRNA and lncRNA “compete” for the binding of the miR. On this basis, competing endogenous RNAs (ceRNAs) have been named to indicate this interaction. In this scenario, the lncRNA acts as a sponge for the miR and prevents its action on the mRNA, allowing its expression at the protein level. The deregulation of such interactions may cause alterations in cell homeostasis and be a cause of disease with an epigenetic basis. This deregulation has been found in several human diseases, including cardiovascular anomalies [ 33 ], neurodegenerative disorders [ 34 , 35 ], and various types of cancer [ 36 , 37 , 38 ], such as those of the urogenital apparatus [ 39 , 40 , 41 , 42 ]. This has a deep effect in cancer; in fact, if the target mRNA encodes for an oncosuppressor, the miR that targets it acts as an oncogene (because it inhibits the expression of an oncosuppressor), and in turn the lncRNA that sponges the miR acts as an anti-oncogene (and functionally as an oncosuppressor as well); the same logic but with opposite effects applies if the mRNA is an oncogene. This represents a further step in gene expression control at the translational level in eukaryotic cells.

The binding of the miR onto the mRNA occurs at the 3′UTR of the messenger, while the interaction between miRs and lncRNAs may also occur in other regions [ 43 ]. This creates a circuit in which the increase in cellular concentration of an miR represses the translation—and hence, the expression—of its target mRNA; instead, the increase in concentration of the competing lncRNA allows this molecule to act as a sponge for the miR, decreasing the miR–mRNA interaction, and in turn promoting mRNA translation, i.e., protein expression. However, things are more complex than this. In fact, any given miR may have several target mRNAs, an mRNA may be bound by more than one miR, and a given lncRNA may sponge several different miRs. As a consequence, metabolic pathways under ceRNA control are usually very complex and ceRNAs create a complex system of crossed interactions called ceRNA networks (ceRNETs) [ 44 , 45 ]. Thus, a ceRNET may be represented as a network composed of several subnetworks, where nodes are ceRNAs (lncRNAs and mRNAs), while miRs represent their connections [ 46 , 47 ]. This complex organization allows the cell to fine tune the mRNA expression due to these intricate relations, and at the same time the deregulation of even one of the actors in this network may impair the function of several target molecules, causing disease. In physiological conditions, the optimal control and best tuning of ceRNETs occur when the miR and interacting lncRNA are at equimolar concentrations [ 48 ], so small differences in their amounts may drive cell metabolism; instead, an evident imbalance of this equilibrium is typical of disease when one of the two mRNA controllers (either the miR or lncRNA) is over-expressed or depleted. It is then reasonable to assume that such networks can be influenced in order to diagnose and treat human conditions.

4. Effects of Lifestyle on ncRNA Expression and Cancer

The efforts aimed at identifying the genetic and epigenetic causes of cancer are enormous, yet it should be borne in mind that the human genome can be considered the main cause of this disease only in a minority of cases. Internal factors, such as mutations in genes, hormone imbalances, or immune system-related conditions can account for only 5–10% of cancer cases; the remaining can be directly related to external factors, such as tobacco or alcohol consumption, dietary factors, infections, and how these factors interact with the genetic and epigenetic variability of humans [ 49 ]. In this perspective, understanding the genetic background of a patient, and placing this into the environmental context in which they live, is crucial for switching from traditional to personalized medicine.

4.1. Tobacco and Alcohol

Tobacco smoking has long been associated with several types of cancer, either due to direct contact of the tissues with the over 70 carcinogenic chemicals produced [ 50 ] (oral, head and neck, esophagus, and lung cancers) or after their penetration into the blood stream, mainly through the lungs (liver, bladder, pancreas, stomach, bowel, cervix and ovary cancers, leukemia). Despite the advent of smokeless tobacco and e-cigarettes, the situation has not significantly improved, since most carcinogens are still present in these products [ 51 , 52 ]. For example, it has been shown that e-cigarettes can alter the user’s epigenome [ 51 ] and their aerosol exposure could lead to the dysregulation of hundreds of miRNAs, such as miR-126 [ 52 ]. Moreover, the chemicals contained in the liquid—especially nicotine and its derivatives—have been associated with the dysregulation of several other sncRNAs and of their target mRNAs, including miR-33, miR-330, and miR-10b [ 53 ], miR-506 [ 54 ], miR-9 and miR-101 [ 55 ], miR-622 [ 56 ], miR-133b and miR-206 [ 57 ], miR-21 [ 58 ], miR-200c [ 59 ], and miR-30a and miR-379 [ 60 ]. Notably, all of them have been linked to neoplastic transformation or tumor progression in various human cancers. Several other chemicals present in e-cigarettes may potentially alter the miR expression as well [ 51 ]; however, the direct evidence of their action through this method of administration needs further investigation. Similarly, the evidence is growing regarding the role of the smoke-related dysregulation of lncRNAs, such as CCAT1 [ 61 ], linc-RoR [ 62 ], linc00152 [ 62 ], linc00460 [ 63 ], LCPAT1 [ 64 ], linc00673 [ 65 ], H19 [ 66 ], and lncAC007255.8 [ 67 ]. In addition to smoking, alcohol consumption, another well-established cause of cancer, has been reported in a relatively high number of patients [ 68 ]. Chronic alcohol abuse has been linked to cancer in various organs, either by direct interactions with the upper aerial and digestive ways (oral cavity, pharynx, hypopharynx, larynx, and esophagus) and lower digestive tract (stomach, bowel) or by indirect effects on more distant organs, such as the liver, pancreas, and breast. Also in the latter case, several ncRNAs, either long [ 69 , 70 , 71 ] or short [ 72 , 73 ], have been found to be altered. Specific research on individual lncRNAs has found a correlation between drinking habits and cancer; examples include linc01133 [ 74 ] and AC012456.4 [ 75 ]. Notably, some studies are specifically focused on ceRNETs. For example, Du and collaborators recently published a study, performed in silico on data available in public databases, aimed at identifying deregulated ceRNETs in esophageal cancer (EC) [ 76 ]. They found at least four possible candidate gene modules deemed to be closely related to EC progression. Although these are only predictions, they provide a compelling framework for the further analysis of these mechanisms in lifestyle-related cancer formation. Other than alcohol, diet has long been known as a major factor in cancer [ 76 ]. In fact, it is estimated that up to 35% of cancers deaths in USA are caused by dietary factors, although such an estimation varies considerably among different countries and cultures [ 77 ]. Several chemicals can reportedly cause such effects, including nitrates, nitrosamines, pesticides, and dioxins, either ingested accidentally or being part of food additives. Because of their extremely high heterogeneity in their composition, method of action, and routes of intake (air, water, food, skin contact) [ 78 , 79 , 80 ], such aspects fall beyond the scope of this review here. Looking at the relationship among food, cancer, and epigenetics, numerous interesting findings collected over the years show the importance of food intake and eating habits in preventing cancer [ 81 , 82 ]. The importance and beneficial potential of some plant-based foods and compounds in cancer prevention has in fact long been researched and documented.

4.2. Phytochemicals

4.2.1. Curcumin

Curcumin is a molecule belonging to the family of phenols; it comes from the rhizomes of turmeric ( Curcuma longa ). It has widely been used as a spice for Asian recipes and as a drug in traditional Indian (Ayurveda) and Chinese (TCM) medicine for centuries. Its properties include the inhibition of cell proliferation, invasion, migration, angiogenesis, and inflammation; in addition, it also promotes cell cycle arrest and apoptosis on various cancers, such as breast, cervical, oral, gastric, melanoma, pancreatic, colon, and prostate cancers [ 83 ]. Moreover, curcumin has been shown to exert its functions through the regulation of miR expression. In breast cancer, it acts by upregulating miR-34a [ 83 ], miR-132 and miR-502c [ 84 ], miR-181b, miR-34a, miR-16, miR-15a, and miR-146b-5p, and by downregulating miR-19a and miR-19b [ 85 ], while in recent studies several other miRs were added to the list, either involving curcumin or its synthetic analogs [ 86 , 87 , 88 ]. In gastric cancer cells, similarly to breast cancer, curcumin enhances miR-34a expression [ 89 ] but inhibits miR-21 [ 90 ], which has also been reported in other cancer types (see below); in lung cancer it downregulates miR-186 [ 91 ] and circ-PRKCA [ 92 ] but upregulates miR-142-5p [ 93 ], miR-206 [ 94 ], and miR-192-5p [ 95 ]; in chronic myelogenous leukemia curcumin induces the miR-21-mediated modulation of the PTEN/AKT pathway, causing the inhibition of leukemic cell growth, both in vitro and in vivo [ 96 ], while in acute myeloid leukemia it inhibits the expression of the lncRNA HOTAIR and enhances the expression of miR-20a-5p [ 97 ]; in multiple myeloma it upregulates miR-101, thereby inhibiting EZH2 expression [ 98 ]; in colon cancer it downregulates both miR-130a [ 99 ] and miR-491 [ 100 ] but upregulates miR-137 [ 101 ], miR-200c [ 102 ], and miR-409-3p [ 103 ]; in melanoma it enhances the expression of miR-222-3p [ 104 ]; in pancreas cancer cells curcumin downregulates miR-199a and upregulates miR-22 [ 105 ]; in human prostate cancer stem cells, curcumin influences the expression of both miR-143 and miR-145 [ 106 , 107 ], and similarly to breast and gastric cancer it upregulates miR-34a [ 108 ]; in ovarian cancer, a curcumin derivative (ST09) deregulated the miR-199a-5p/DDR1 axis [ 109 ], while curcumin itself upregulates the lncRNA circ-PLEKHM3, promoting the intracellular depletion of miR-320a and suppressing cell proliferation and enhancing apoptosis [ 110 ]; in hepatocellular carcinoma it downregulates the expression of circ_0078710 (and consequently enhances miR-378b expression) [ 111 ] and downregulates miR-21-5p [ 112 ] and miR-21 [ 113 ]; in renal carcinoma, curcumin acts on the circ-FNDC3B/miR-138-5p/IGF2 axis [ 114 ]; in lymphoma, miR-28-5p is upregulated by curcumin treatment [ 115 ] while miR-21 is repressed [ 116 ]; in nasopharyngeal carcinoma, curcumin regulates the circRNA_102115/miR-335-3p/MAPK1 pathway [ 117 ], and other circRNAs have been identified as well [ 118 ]; in osteosarcoma it downregulates miR-21 [ 119 ]; in glioma, curcumin regulates the intracellular amounts of both the lncRNA H19 and miR-675 [ 120 ]; in bladder cancer it downregulates miR-1246 [ 121 ]. All together, these data show the enormous potential of curcumin as an anticancer agent, also thanks to the multiple ncRNA targets and the wide array of potentially treatable cancers.

4.2.2. Garcinol

Another phenolic compound and Ayurveda medical component of vegetable origin is garcinol (camboginol), another Indian spice isolated from the kokum tree ( Garcinia indica ) and used in food consumption. The first relationship among garcinol, human cancer treatment, and ncRNA was identified in relatively recent times—10 years ago—meaning the data, although promising, still require further validation. In breast cancer, garcinol reverses the epithelial-to-mesenchymal transition (EMT) through its action on miR-200b, miR200c, and let-7 [ 122 ]; in pancreatic cancer, garcinol enhances the efficiency of gemcitabine treatment by modulating a number of miRs (miR-21, miR-196a, miR-495, miR-605, miR-638, and miR-453) and promoting apoptosis [ 123 ], and similarly to what happens in breast cancer, it upregulates several miRs, including miR-200c [ 124 ]; in lung cancer it inhibits the EMT through the upregulation of various miRNAs, such as miR-200b, miR-205, miR-218, and let-7c [ 125 ]; in glioblastoma, garcinol suppresses the actions of STAT3 and STAT5A thanks to the upregulation of miR-181d [ 126 ].

4.2.3. Genistein

Genistein (prunetol) is a flavonoid compound and a phytoestrogen extracted from the dyer’s broom, Genista tinctoria ; it is present in several foods of vegetable origin, including lupin, fava beans, soybeans, kudzu, psoralea, and coffee. Also in this case, in the last years several connections have been found linking cancer, ncRNA expression, and genistein assumption. In kidney cancer cells, genistein lowers miR-21 [ 127 ], miR-23b-3p [ 128 ], and miR-1260b [ 129 ] expression. A similar action on miR-1260b is exerted also in prostate cancer [ 130 ], where genistein also downregulates miR-151 [ 131 ], miR-221, miR-222 [ 132 ], and miR-223 [ 133 ] but upregulates miR-34a, miR-574-3p, and miR-1296 [ 134 , 135 , 136 ] and enhances the expression of miR-200c and miR-141 by promoting the demethylation of the CpG sites closest to the miR-200c/miR-141 loci [ 137 ]; miR-27a downregulation by genistein is a hallmark in uveal melanoma (C918) [ 138 ], pancreatic cancer [ 139 ], lung cancer [ 140 ], and ovarian cancer (SKOV3) cells [ 141 ]. In breast cancer cells, genistein suppresses miR-155 expression and acts as an antiproliferative and pro-apoptotic molecule [ 142 ] but promotes the expression of miR-23b, causing a similar effect on cells [ 143 ]; in lung cancer it regulates the circ_0031250/miR-873-5p/FOXM1 axis [ 144 ]; in head and neck cancer, it can block the EMT by activating the miR-34a/RTCB axis [ 145 ]; in retinoblastoma cells, genistein promotes apoptosis by upregulating miR-145 [ 146 ]; in multiple myeloma cells, it upregulates miR-29b, thereby halting cell proliferation [ 147 ]; in pancreas cancer cells, it upregulates miR-34a [ 148 ], miR-200, let-7 [ 149 ], and miR-146a [ 150 ]. Genistein has been also tested in isoflavone mixtures, showing that the G2535 mixture (70.54% genistein, 26.34% daidzein, 0.31% glycitein) downregulates miR-221 in pancreas cancer cells [ 151 ].

4.2.4. Epigallocatechin-3-Gallate (EGCG)

EGCG is the major polyphenol compound present in green tea. In hepatoma, EGCG enhances the cancer cell sensitivity to ionizing radiation treatment via miR-34a/Sirt1/p53 signaling pathway regulation [ 152 ]; in hepatocellular carcinoma, the tumor suppressors let-7a and miR-34a are upregulated [ 153 ], and in HepG2 cells it has been shown that this molecule acts on several miRs, causing either their up- (13 miR) or down- (48 miR) regulation [ 154 ]. A similar situation occurs both in neuroblastoma cells, where oncogenic miRs are downregulated and oncosuppressor miRs are upregulated [ 155 ], as well as in nasopharyngeal carcinoma CNE2 cells, where a total of 66 signaling pathways, primarily involved in cancer development and lipid and glucose metabolism, were shown to be regulated by EGCG-specific miRNAs [ 156 ]; in oral squamous cell carcinoma cells, EGCG significantly inhibits the proliferation rate and self-renewal capacity by upregulating miR-204 [ 157 ]; in lung cancer cells, EGCG downregulates miR-98-5p and miR-125a-3p, thereby promoting apoptosis via the enhancement of the effects of cisplatin [ 158 ]; in prostate cancer cells it increases miR-330 (an oncosuppressor) and contemporarily inhibits miR21 (an oncomir) [ 159 ]; in gastric cancer it regulates the LINC00511/miR-29b/KDM2A axis [ 160 ]; in breast cancer it promotes apoptosis by downregulating miR-25 [ 161 ]; in colorectal cancer cells, EGCG enhances the sensitivity to 5-FU by inhibiting the GRP78/NF-κB/miR-155-5p/MDR1 pathway [ 162 ]; in lung cancer it inhibits cancer stem cell-like properties by targeting mir-485-5p/RXRα [ 163 ].

4.2.5. Resveratrol

Resveratrol (3,5,4-trihydroxystilbene) is a phenol produced by several plants in response to injury or infection; in food, it can be found in the skins of grapes, blueberries, raspberries, mulberries, and peanuts. It mainly acts as a strong antioxidant, and in general it promotes or enhances apoptosis in several types of cancer. Several papers exist linking this molecule to ncRNA expression and cancer. In the lung cancer A549 cell line, it has been shown that resveratrol influences the regulation of tens of miR [ 164 ], and comparable numeric results were obtained in colon and prostate cancer cells [ 165 ]. Venkatadri and collaborators found the upregulation of miR-122-5p, miR-542-3p, miR-16, miR-141, miR-143, and miR-200c in breast cancer [ 166 ]; miR-21 downregulation characterizes resveratrol’s effects in pancreatic cancer cells [ 167 ], as it blocks the malignant behavior of gastric cancer cells by downregulating miR-155-5p [ 168 ] and altering the expression of several lncRNAs, including MEG3, PTTG3P, GAS5, BISPR, MALAT1 and H19 [ 169 ]. The lncRNAs are also targets in HT-29 colon adenocarcinoma cells, where it has been found that the downregulation of CCAT1, CRNDE, HOTAIR, PCAT1, PVT1, and SNHG16 occurs [ 170 ], which lowers the levels of miR-3687 and miR-301a-3p while upregulating miR-3612 in TGF-β-induced HT-29 cells [ 171 ]. In liver cancer, it is able to suppress several malignant phenotypes through miR-185-5p upregulation [ 172 ]. Beyond the other compounds described here, resveratrol is able to upregulate miR-34a to suppress the proliferation, induce the apoptosis, and inhibit the invasion and migration of OV-90 and SKOV-3 ovarian cancer cell lines [ 173 ]; in skin squamous cell carcinoma, resveratrol inhibits proliferation, migration, and invasion through upregulating miR-126 [ 174 ]; in malignant melanoma cells, resveratrol induces apoptosis by regulating the miR-492/CD147 pathway [ 175 ]; in osteosarcoma, resveratrol blocks the tumor progression via miR-139-mediated NOTCH1 regulation [ 176 ].

4.2.6. Quercetin

Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a bioflavonoid found in fruits (mainly citrus), plant seeds, grains, olive oil, apples, kale, capers, and onions; variable amounts can also be found in beverages and seasonings, such as beer, wine, and vinegar. In pancreatic cancer cells, quercetin upregulates let-7c, thereby inhibiting cancer progression [ 177 ]; in gastric cancer cells, quercetin upregulates miR-143 [ 178 ]; in lung cancer cells, quercetin upregulates miR-16 [ 179 ] and promotes radio-sensitivity through the overexpression of miR-16-5p [ 180 ]; in ovarian carcinoma cells it acts by upregulating the expression of microRNA-145 [ 181 ]; in breast cancer cells it inhibits proliferation and invasion by upregulating miR-146a [ 182 ]; in hepatocellular carcinoma cells, quercetin promotes apoptosis by activating the p53/miR-34a/SIRT1 signal feedback loop [ 183 ]; in osteosarcoma cells, quercetin enhances the toxic effects of methotrexate by decreasing, among others, the anti-apoptotic miR-223 [ 184 ]; in triple negative breast cancer cells, a methoxylated quercetin glycoside isolated from Cleome droserifolia is able to repress the cellular proliferation, colony-forming ability, migration, and invasion capacities by modulating a ceRNA network, where it reduces the oncogenic lncRNA MALAT-1 and induces TP53 and its downstream miRNAs, miR-155 and miR-146a [ 185 ]. Interestingly, the same substance from this plant is also able to limit the cellular viability and anchorage-independent growth of hepatocellular carcinoma cells in a TP53/miR-15/miR-16-dependent manner [ 186 ]. In esophagus cancer cells, quercetin inhibits growth and metastasis by modulating the miR-1-3p/TAGLN2 pathway [ 187 ]; in lung cancer, quercetin inhibits the survival, proliferation, migration, and invasion of NSCLC cells and enhances their apoptosis by targeting the lncRNA SNHG7/miR-34a-5p pathway [ 188 ]; in oral squamous cell carcinoma it significantly suppresses the proliferation and invasion of CAL-27 cells in a dose-dependent manner, while upregulating the miR-1254/CD36 cascade [ 189 ]; in HBL-52 meningioma cells, quercetin promotes apoptosis by over-expressing miR-197 [ 190 ].

4.2.7. Other Compounds

Tens of other natural substances have been studied over time for their action on ncRNA expression in cancer, but to date there are limited data available as to their method of action. Readers interested in broadening their knowledge of such correlations can draw upon the currently available specific research studies [ 191 , 192 , 193 , 194 , 195 ].

4.3. Obesity

Obesity is a complex, multifactorial condition that is caused by the interaction of genetic, metabolic, social, behavioral, and cultural factors. Obesity has a significant impact on health, psychosocial well-being, life expectancy, and quality of life. The multiple components of this condition do not allow one to group patients together, beyond the common BMI (body mass index, kg/m 2 ) being over a set threshold, which is, however, a very limited criterion [ 196 ]. For this, subclassifications of obesity exist to reflect its complexity [ 197 ]. The spectrum of diseases linked to obesity are equally complex, and frequently associated with specific geographic regions [ 198 ]. The most common conditions associated with obesity are diabetes, hepatic steatosis, cardiovascular diseases, stroke, dyslipidemia, hypertension, gallbladder problems, osteoarthritis, sleep apnea, and other breathing problems; in addition, obese people also show an increased risk of getting some types of cancer, such as endometrial, breast, ovary, prostate, liver, gallbladder, kidney, and colon cancers [ 197 ]. It is widely accepted that this increased risk is linked to chronic inflammation caused by excessive weight [ 199 ], although several other links can be drawn, such as microbiome alterations, diabetes, and an altered steroid metabolism [ 200 ]. Losing weight and keeping it off, through a diet with nuts, fruits, vegetables, and olive oil; increasing physical exercise; and cutting down on alcohol consumption are all known to enhance life quality, reduce cancer risk, and improve health overall [ 201 ]. Several lncRNA have been shown to be involved in adipogenesis and lipid homeostasis [ 202 , 203 ]. In mice, a specific regulation of lncRNAs by nutrients, hormones, and transcription factors in vitro has been highlighted [ 204 ], and circulating lncRNAs in obese patients are different from those in controls [ 205 ]. Interestingly, some of these lncRNAs (such as ANRIL, H19, and HOTAIR) are also dysregulated in cancer, creating a link between the ncRNA expression profile and cancer risk in obese people, as reported by Yau and colleagues [ 206 ]. As expected, this is equally true also for sncRNAs (mainly miRs). A recent study compared the ncRNAs in obese people, colorectal cancer patients, and healthy controls, showing that there is a significant overlap in dysregulated ncRNAs in obese people and cancer patients [ 207 ]. Moreover, another group showed that dysregulated miRs (especially miR-31 and miR-215) are a hallmark of obesity, and that weight loss can change the expression profile of these patients, showing a highly dynamic response of miR expression related to weight [ 208 ]. Leptin is a hormone that is predominantly made by adipose cells and enterocytes in the small intestine; it helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes. It has recently been demonstrated that exposure to leptin downregulates the expression of miR-628 and increases cell proliferation and migration in prostate cancer cells [ 209 ]. Another group showed that platelets from patients with visceral obesity can strongly promote colon cancer growth, likely via the activation of miR-19a [ 210 ], while Su and collaborators recently demonstrated that miR-27a promotes obesity-associated hepatocellular carcinoma by mediating mitochondrial dysfunction [ 211 ]. Several other reports can be found in the literature, reaching similar results. However, it is important to emphasize here that the link between oncogenic miR expression and obesity is strong, and that weight-related miR patient profiling is advisable when planning a cancer therapy.

4.4. Physical Activity

The research findings from various epidemiological studies have pointed to the pivotal role played by physical exercise in reducing the risk of developing cancer. Physical training has in fact been investigated as a non-pharmaceutical strategy to counter breast cancer [ 212 , 213 ], thanks to a wide array of benefits arising from improvements in outcomes such as muscle hypertrophy and strength levels, cardiorespiratory health, and body mass composition, all of which have been linked to an improved quality of life and reduced mortality risk in cancer patients [ 213 , 214 , 215 ]. The World Health Organization itself has highlighted the importance of structured exercise for public health, so much so that inadequate levels of physical activity have been deemed to be a major risk factor in breast and colon cancers (21–25% of cases), diabetes (27% of cases), and ischemic heart disease (30% of cases) [ 216 , 217 ]. Several epidemiological studies have stressed the beneficial effects of regular and moderate structured exercise (i.e., forms of exercise in adherence to international guidelines such as those proposed by the American College of Sports and Medicine), particularly in terms of protection [ 218 , 219 ]. Such beneficial effects involve the prevention of cancer onset (i.e., primary prevention) and prevention of relapse (tertiary prevention), as well as a degree of effectiveness against chronic degenerative diseases [ 220 ]. The mounting scientific evidence points to exercise and its ability to directly affect cancer (particularly breast tumor) through alterations in exercise-induced c-miRNA dynamics, which play a key role in the molecular interactions between skeletal muscle and cancer cells [ 221 , 222 ]. A 2016 study, which relied on the inbred female BALB/c mice (6–8 weeks old) model of breast cancer, showed how a 5-week exercise training protocol along with neoadjuvant hormone therapy led to higher levels of miRNA-206 and let-7a expression (both of which are linked to tumor suppression) and lower expression of the oncomiR miR-21 in cancer tissue [ 223 ]. Lower ERα and HIF-1 mRNA levels, associated with tumor growth and angiogenesis [ 224 , 225 ], and lower Ki67 expression (a nuclear marker pointing to cell proliferation and linked to lower survival rates in women with breast cancer) were also observed. Such findings are indeed relevant, even though the role of c-miRNAs triggered by regular exercise in breast cancer patients is still inconclusive. Such dynamics may be explained in light of the fact that the expression modulation of a rather broad array of miRNAs such as miR-1, -21, -23a, -133a, -133b, -181a, -206, -378, and -486 takes place in skeletal muscle tissue [ 226 , 227 , 228 ] and in the bloodstream [ 229 , 230 ] after various exercise-based approaches. The expression of miR-133a has been found to be considerably lower in five cell lines of breast cancer (MCF-7, MDA-MB-231, BT-549, SK-BR-3, and T47D) as opposed to the normal line HBL-100, and in human breast cancer tissue versus adjacent non-cancerous breast tissue. Such findings seem to point to the possibility that miR-133a can act as a systemic factor downregulating tumor progression and following physical exercise, after migrating from the skeletal muscle to the bloodstream and ultimately to cancer cells [ 231 ]. It is worth pointing out that several such miRNAs can inhibit or slow down cancer development, metastasis, and progression. Studies have highlighted noteworthy variations in the c-miR-133a-3p in high responders relative to low ones following supervised sessions of resistance training in breast cancer [ 232 ]. Moreover, alterations in the expression of c-miRNAs, lower expression levels of c-oncomiRs, and a more considerable enhancement of tumor suppressor miRNAs in the control group undergoing hormonal therapy-exercise training (aerobic exercise-based training three times per week over a 12-week period, via a high-intensity interval training protocol) were reported in a recent study [ 233 ]. Exercise-based approaches have recently been shown to impact the rno-miRNA-regulated target cancer gene candidates ITPR3, SOCS6, ITGA6, and NKX2-1 as biomarkers for cancer prognosis in rheumatoid arthritis diagnoses in pristane-induced arthritis (PIA) rat models [ 234 ]. Overall, the research points to as many as 14 miRNAs involved in pathways relevant to cancer whose expression can be modulated by regular structured exercise, while the most noteworthy effects include the different expression levels of two miRNAs that affect breast cancer progression, in addition to the already mentioned upregulation of miR-206 and downregulation of anti-miR-30c. Such effects are indeed relevant in light of the fact that miR-206 transfection and anti-miR-30c silencing can inhibit cell growth and enhance MCF-7 cells apoptosis [ 235 , 236 , 237 ]. In addition, apoptosis and induced growth arrest in the G1/S phase of the cell cycle can be further driven by the combined use of these two miRNAs, which can be assessed and used as non-invasive biomarkers for breast cancer [ 220 , 238 ]. The regulation of the cellular immune system constitutes another noteworthy association between cancer and exercise, as cytotoxic immune cells have been observed to be mobilized to the circulation during exercise via blood-flow-induced shear stress and adrenergic signaling [ 239 ]. Studies on animal models observed how the tumors from running mice exhibited higher mRNA expression levels of receptor ligands capable of mobilizing NK cells (namely H60a, MULT1, Clr-b), in addition to IL-2, IL-15, and IFNγ cytokines and CCL3, CXCL10, CX3CL1, and chemerin chemokines, all associated with natural killer (NK) cell activation and chemotaxis. No changes in the expression of markers of angiogenesis (i.e., CD31 and VEGF-A) were observed [ 240 ]. The cytotoxic immune cells, thus, “scan” the system in order to recognize and eliminate altered cells. A noteworthy capability for the suppression of tumor growth mediated by exercise has been reported in animal-based studies, possibly linked to the epinephrine-dependent mobilization of NK cells, followed by higher levels of immune cell infiltration into cancerous tissues [ 241 ]. The adrenergic signaling was shown to be at the heart of the exercise-induced cancerous growth suppression. Immune cell stimulation and mobilization fostered by exercise were investigated in depth in a recent study involving cancer patients, which concluded that breast cancer survivors were capable of mobilizing NK cells to the circulation to the same extent as healthy controls of the same age [ 240 ].

5. Analyzing ceRNETs for Diagnosis and Targeting Them for Therapy: The State of the Art

The deregulation of several ncRNAs in most—if not all—cancers is a well-known and proven fact; for example, in the abovementioned case of endometrial cancer (EC), it has been reported that hundreds of ncRNAs are potentially deregulated [ 242 , 243 , 244 ], and this holds true for all tumors investigated so far. The levels of ncRNAs in cancer are dramatically altered by stress from the tumor microenvironment. The stress conditions include defined characteristics of cancer, such as hypoxia, chronic inflammation, and the deprivation of nutrients, including some that are essential in cancer metabolism, such as glucose or glutamine [ 4 ]. The microenvironment of the tumor presents significant differences compared to healthy tissues, including in terms of oxygenation and the metabolic status. Indeed, hypoxia is a hallmark characteristic of the tumor microenvironment and plays a crucial role in growth and metastasis. Upon hypoxia, hypoxia-inducible factors (HIFs) modulate many ncRNAs [ 245 , 246 ], including MALAT1 [ 247 ], the lncRNA HOTAIR in non-small cell lung cancer (NSCLC) [ 248 ], and the lncRNA H19 in glioblastoma [ 249 ]. An interesting aspect of this relationship between the tumor microenvironment and ncRNAs is that it is a reciprocal relationship. If on the one hand, as described, the tumor microenvironment modulates the expression of ncRNAs, it is also true that circulating ncRNAs have the ability to strongly modulate the behavior of cells populating the tumor microenvironment, thereby remodeling the metastatic niche and eventually favoring carcinogenesis [ 250 ]. Indeed, carcinogenesis appears as a multistage process to which both exogenous and endogenous factors contribute [ 251 , 252 ]. The lncRNAs, and particularly circRNAs, are found to act as ceRNAs that play critical roles in the development and progression of cancers. Abnormally expressed ncRNAs may have repercussions on many processes related to tumorigeneses, such as cell proliferation, metastasis formation, and drug resistance, by regulating different intracellular pathways. In several types of cancer, most lncRNAs are either up- or downregulated. These lncRNAs favor all stages of tumor development through the promotion of mRNA expression and constancy [ 253 ], by favoring mRNA stability [ 254 ], or by modulating miR [ 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 ]. The aberrant phenotype is the result of the modulation of typical pathways playing key roles in cell survival [ 255 , 259 , 263 , 265 , 283 ], apoptosis [ 256 , 258 , 272 , 276 , 286 , 289 , 297 ], or glucose metabolism [ 253 , 294 , 295 , 300 ]. For example, a recent study [ 255 ] demonstrated the molecular mechanisms of action of the lncRNA named MALAT1, which was found t be upregulated in osteosarcoma. This study showed that MALAT1, via the downregulation of miR-376a, accelerates osteosarcoma via the Wnt/β-catenin pathway [ 255 ], which is a conserved signaling axis participating in diverse physiological processes such as proliferation, differentiation, apoptosis, migration, and invasion [ 301 ]. The Wnt/β-catenin signaling pathways is also activated in colorectal cancer by the lncRNA NEAT1 (nuclear-enriched abundant transcript 1), which modulates the miR-34a/SIRT1 axis [ 281 ]. Another important pathway in cancer is the phosphoinositide 3-kinase-AKT-mammalian target of the rapamycin (PI3K-AKT-mTOR) pathway, which is frequently hyperactivated in cancer and is essential for tumor cell growth and survival [ 61 ]. Indeed, several lncRNAs such as HOTAIR, HOXD-AS1, LINC00511, H19, and LINC01554, by targeting specific miRs, increase the expression of AKT and mTOR, promoting aberrant phenotypes [ 262 , 264 , 271 , 274 , 278 , 287 , 296 ].

VEGF has been proposed to serve as a crucial gene promoting angiogenesis during tumor metastasis. The lncRNA NUTM2A-AS1 (an antisense transcript) positively regulates ROS production, and finally VEGF expression, favoring gastric cancer progression and drug resistance [ 269 ]. Additionally, LINC00173.v1 in NSCLC, by downregulating miR-511-5p [ 270 ], and NEAT1 in colorectal cancer, by downregulating miR-205-5p [ 282 ], increased VEGFA expression. Circular RNAs (circRNAs) are a novel class of endogenous covalently closed RNA molecules that function as microRNA sponges. Several circRNAs were upregulated in cancer-promoting proliferation, migration, and invasion [ 284 , 285 , 291 , 293 ]. The deregulation lncRNAs provides important advantages in cancer diagnosis. First, this is a way to understand the mechanism of the formation of a good fraction of neoplasms for which an evident mutation in the coding sequence of a tumor suppressor gene or oncogene cannot be found. Secondly, usually only a subset of these ncRNAs is deregulated in a given tumor, and this provides a way to identify not only different tumor subtypes, but even different cell populations inside the same lesion. Third, on the basis of the altered panel of ncRNAs, and knowing or guessing (through an in silico approach) the possible mRNA targets, it is possible to identify the molecular pathway(s) altered in the transformed cells, allowing one to foresee whether a tumor can be treated with a certain drug instead of another, or to evaluate the tumor resilience to radio- or chemotherapy or the ability of the tumor to escape apoptosis or the immune system. Fourth, the analysis of the altered target genes, coupled with other investigations such as cytology and histology, may allow the oncologist to evaluate the malignancy of the tumor, as well as its chance of relapsing. With a systematic approach involving molecular biology, biochemistry, high-throughput sequencing, and artificial-intelligence-assisted data analysis, and coupling these approaches with well-established diagnostic tools currently used in the everyday medicine, the road towards personalized medicine is at hand. The identification of ncRNAs as fundamental players in gene expression raises the possibility of using them as both diagnostic markers and possible therapeutic targets [ 302 , 303 , 304 , 305 , 306 ]. Indeed, numerous clinical trials of ncRNAs are ongoing [ 307 ]. When we consider ncRNA-based therapies, we should take into account two important aspects: (1) the RNA target and (2) the delivery methods of RNA therapeutics. Regarding the first aspect, among the ncRNAs, miRNAs are the most extensively investigated as therapeutic targets. The two major therapeutic forms used are miRNA mimics and inhibitors of miRNAs, known as anti-miRs/antagomiRs. The first group are used to mimic the function of endogenous tumor suppressor miRNAs, and the latter to deplete oncogenic miRNAs. Among the miRNA mimic therapeutics, we recall here MRX34, which is a synthetic double-stranded mimic of the miR-34a and was the first miRNA-based therapy to be introduced into the clinic. In 2020, the final phase 1 results for the pharmacodynamics and determination and evaluation of the recommended phase 2 dose (RP2D) of MRX34 were reported [ 308 ]. Patients with advanced solid tumors refractory to standard treatments were enrolled to receive MRX34, with oral dexamethasone premedication, intravenously daily for 5 days in 3-week cycles. MRX34 demonstrated a manageable toxicity profile; the pharmacodynamic results showed the delivery of miR-34a to tumors and the dose-dependent modulation of target gene expression in white blood cells. The trial was closed early due to serious immune-mediated adverse events [ 308 ], indicating that although very promising, the use of these molecules in cancer therapy is still an issue, and in many cases needs deeper analyses and testing. The miRNA inhibitors include several groups, such as (1) antisense oligonucleotides (ASOs), which are single-stranded RNAs with lengths ranging from 18 to 30 base pairs (bp). They function by modifying the expression of a target mRNA, by either altering the splicing or by recruiting RNase H, leading to target degradation [ 309 ]; (2) the CRISPR/Cas system, the use of which is an innovative strategy showing robustness, specificity, and stability in the modulation of miRNA expression [ 310 ]. CRISPR genome-editing technology has been successfully used to modulate the expression of miRNAs in several types of tumors [ 311 , 312 , 313 ]. For example, Zhou et al. [ 311 ], in a hepatocellular carcinoma (HCC) cell line, knocked out miR-3188, which is markedly overexpressed in HCC tissues. They demonstrated that the miR-3188 knockdown successfully decreased cell growth, invasion, and migration [ 311 ]. The CRISPR/Cas system was also widely used to modulate the expression of lncRNAs [ 300 , 314 , 315 , 316 ]. Ali et al. [ 314 ] performed the CRISPR/Cas9-mediated knockout of lncRNA-RP11-156p1.3 in an HCC cell line, resulting in decreases in the cell count and viability [ 314 ]. CRISPR/Cas9 gene editing was also used to knockout lncRNA XLOC_005950, which works as a molecular sponge of hsa-miR-542-2p in osteosarcoma [ 300 ]. The results showed that the lncRNA XLOC_005950 knockout, by decreasing the PFK muscle (PFKM) activity, reduced the intracellular glucose, lactic acid content, and cell proliferation in osteosarcoma cells [ 300 ]. Other significant approaches to target lncRNAs are double-stranded RNA-mediated interference (RNAi) approaches and ASOs. For example, the effect of the knockdown of MALAT1 using ASOs was observed in a mouse model of breast cancer, the MMTV-PyMT model (mouse mammary tumor virus–polyoma middle tumor antigen), which develops spontaneous mammary tumors that closely resemble the progression and morphology of human breast cancers [ 317 ]. The MALAT1 loss results in slower tumor growth by inducing alterations in the gene expression and changes in the splicing patterns of the genes involved in differentiation and protumorigenic signaling pathways [ 318 ]. The positive effects were confirmed later by Gong and colleagues, who constructed a MALAT1-specific ASO that reduced the MALAT1 expression levels, decreased the migration ability in lung cancer cells, and significantly reduced the metastatic tumor nodule formation in vivo [ 319 ]. MALAT1 was also the target in preclinical studies with short interfering RNAs (siRNAs) to overcome the anti-androgen enzalutamide (Enz) resistance (EnzR) in castration-resistant prostate cancer. The administration of the MALAT1 short interfering RNA (10 mg/kg) for 2 weeks in xenograft mice, injected with EnzR cells, significantly suppressed the EnzR tumors [ 320 ]. Even if these RNA-based therapeutic modalities have great potential to generate a new therapeutic approach in disease in general, and in cancer in particular, to reach their full potential they first need to overcome the lipid bilayer of the cell wall to deliver RNA into cells. Indeed, the delivery methods remain the major problem to solve for the widespread development of RNA therapeutics [ 321 ]. Besides the cellular barrier, specific pharmacological barriers should also be improved. Indeed, synthetic ncRNA mimics and inhibitors generally degrade rapidly in biological fluids, absorb poorly into the intracellular space, and often may fail to reach specific target locations [ 305 ]. The delivery of drugs with nanoparticles can overcome many of these limitations. Indeed, nanocarriers encapsulate drugs and control their pharmacokinetic properties by regulating the drug release and increasing the half-life. To date, the delivery approaches with nanoparticles include lipid-based nanoparticles (LNP), polymer-based nanoparticles (PNP), and lipid–polymer hybrids. LNP are vesicles with a diameter range of 10–500 nm composed of multiple lipid layers stabilized in aqueous media by a single layer of surfactants (phospholipids, poly(ethylene glycol)-based surfactants). LNPs represent a well-established delivery system for gene therapies and are approved by the FDA for liver siRNA delivery [ 322 ]. LNPs offer several advantages, including enhanced drug stability, reduced toxicity, and control of the release rate [ 323 , 324 ]. Despite these promising aspects, several drawbacks remain to be addressed. For example, small molecules are encapsulated with low efficiency; moreover, cytotoxicity and systemic toxicity problems remain to be solved [ 324 ]. The other RNA delivery systems include polymer-based nanoparticles. These are between 20 and 1500 nm in particle size and made up of natural or synthetic polymers [ 325 ]. Even if they present increased stability compared to LNPs and technical advantages due to several fabrication methods, the aspects related to their toxicity have not yet been fully clarified. Finally, lipid–polymer hybrids were synthesized by adding lipids to polymeric nanoparticles, improving their delivery [ 326 , 327 ]. Such hybrid systems rely on the specific characteristics of lipid-based and polymer-based nanoparticles but also overcome their limits, such as their structural disintegration, limited circulation time, and loss of content [ 328 ]. Structurally, they are composed of a polymer core encapsulating the drug, surrounded by a lipid monolayer and an outer lipid–PEG layer. This structure ensures many advantages, including enhanced stability and controlled drug delivery [ 328 , 329 ]; however, as the use of lipid–polymer hybrids represents an innovative method, the research remains open to verifying their applicability in clinical practice. Furthermore, it is also necessary to identify lipid–polymer hybrids with the highest quality for specific uses [ 329 ]. There are several major challenges that stand in the way of treating human conditions by ncRNAs, which explains why only a very limited number of molecules are available as therapeutic agents to date. First, the choice of the target molecule is fundamental; as already mentioned, a tumor is a disease that is heterogeneous not only in different patients, but also in its cell subpopulations. Targeting one mRNA may not be sufficient to obtain relevant results. Second, the administration route is challenging as well. In some cases the therapeutic may be administered locally and directly (for example, inside a bladder cavity), but in other cases it should reach its destination through indirect routes, such as the blood flow. Third, the choice of the vector responsible for delivering the therapeutic to its target cells is far from trivial. The ncRNA may be conjugated with other molecules such as antibodies, cell-penetrating peptides (or other polymers), or metal nanoparticles; alternatively, it can be embedded in lipid nanoparticles, exosomes, or viral or mini-bacterial vectors. Each possibility has pros and cons, and deciding which one is the better in a particular situation is very complex. Fourth, the escape of the vector from the host immune system, which may recognize both the vector and the therapeutic RNA as exogenous substances and promote their degradation before they reach their target organ, may impair the whole approach. Fifth, the specificity of the target is pivotal; the vector should discriminate between healthy and sick cells inside the same organ, and frequently the adhesion molecules used by the vector to recognize their target are shared between tumor and normal cells. In addition, off-target binding to different cell types, either inside or outside the target organ, must be avoided, further complicating this setup. Sixth, the efficiency of the penetration of the vector inside the cell, a problem closely related to the preceding point, might make the therapy inefficient. Seventh, the efficacy of the therapeutic once it is inside the target celli s important; in this case, several variables should be considered—its half-life before full and possibly constant expression; the specificity of the mRNA target (avoiding off-target binding to mRNAs not involved in the disease, which is especially true for miRs and siRNAs); the use of a suitable promoter to allow sustained expression over time; and its shape (circular vs. linear, which impacts on its stability and function). Table 1 summarizes ncRNAs in terms of their tumorigenesis and drug resistance, in addition to their regulation of different intracellular pathways. In several types of cancer, most lncRNAs are either up- or downregulated. Table 2 outlines the delivery approaches via nanoparticles, including lipid-based nanoparticles (LNP), polymer-based nanoparticles (PNP), and lipid–polymer hybrids.

6. Ethical, Legal, and Social Issues of Personalized Medicine

Despite the potential and benefits of personalized medicine in terms of providing therapeutic options better suited to each patient’s genetic profile, a set of standards is needed to ensure the protection and fair treatment of individuals [ 332 ]. The issues concerning personalized medicine range from individual privacy to the stratification and discrimination of sub-populations based on ethnicity, equality of access, and the fair allocation of resources [ 333 ]. As such practices become mainstream, such ethical challenges need to be dealt with in order to ensure that the opportunities and benefits provided by such new scientific avenues are ethically implemented [ 334 ]. The European Union has acknowledged the importance of personalized medicine by issuing two policy papers arguing in favor of a broader use of personalized medicine (focusing on cancer diagnostics or therapeutics in particular) [ 335 , 336 ], while remarking that such a goal may be hampered by the still high degree of uncertainty surrounding the outcomes [ 337 ]. The key factor that can enable and unleash the full potential of personalized medicine is, according to the analysis laid out in the EU papers, an effective synergy between health data and new technologies, which is necessary to pave the way for the beneficial development of personalized medicine [ 338 ]. We can rely on its unique potential to confront cancer by means of prevention and treatment strategies enabling patients to receive the therapies that can ultimately work best for them. Such dynamics may entail considerable benefits for healthcare spending as well, since less money would be wasted on trials and ineffective treatments. For 2022, the EU plans to take further steps to harness the potential of new developing technologies such as AI, big data, and genomics through a European Cancer Imaging Initiative aimed at fostering the application of new computer-aided tools in order to improve the field of personalized medicine and provide innovative solutions [ 339 , 340 ]. In addition, the new Partnership on Personalized Medicine is scheduled to be launched in 2023 through funding provided by Horizon Europe, the EU’s key funding programme for research and innovation, which can tap into a budget of €95.5 billion. The partnership will aim to define priorities for research and education in personalized medicine; support research projects on cancer prevention, diagnosis, and treatment; and outline a set of recommendations for the establishment of personalized medicine approaches in clinical practice and medical research. Those goals have also been pursued by the International Consortium for Personalized Medicine (ICPerMed), launched in November 2016 [ 341 , 342 ]. The ICPerMed has outlined a vision for what personalized medicine will come to represent: the ultimate expression of medical evolution in the era of biotechnology and big data. Such a change, however, does call for broad-ranging adjustments and growth in the fundamental ways in which healthcare is delivered, prioritizing training and new skills for healthcare professionals and innovative tools for large-scale implementation [ 343 ]. The ICPerMed vision has been shaped and endorsed by consulting European and international experts and specialists in key areas of research, who have provided feedback on the opportunities and challenges related to personalized medicine and highlighted specific concerns and possible solutions [ 344 ]. A road map to tailored preventive strategies and approaches will be laid out by the European Commission as a preliminary step towards launching the partnership [ 345 ]. The prospect that data will likely fundamentally change healthcare has been acknowledged by established European policies, both at the individual patient level and as it pertains to the healthcare system (noteworthy in that regard is the report from the European Alliance for Personalized Medicine, “Cooperating on Data: The Missing Element in Bringing Real Innovation to Europe’s Healthcare System” [ 346 ]). It is in fact worth bearing in mind that medical records, patient information, clinical studies, and diagnostic results are but some of the data sources available in healthcare. The digitization of patient records will be an important contributor to this evolution. Big data gathered and elaborated from electronic archives will also be needed, including data from digital applications, wearable devices, and social media, providing informations on environment- and lifestyle-related factors, socio-demographics, genomics, metabolomics, proteomics, radiomics, standardized electronic health records, or precision medicine platforms [ 347 ]. An ethically and legally tenable path towards the mainstream use of personalized medicine can only be achieved by prioritizing the management of biobanking and informed consent, confidentiality [ 348 ], access to treatment, clinical translation, and direct-to-consumer genetic testing, and by putting in place measures to prevent the stratification and genetic discrimination of sub-populations based on ethnicity [ 349 , 350 ]. An inadequate level of genetic literacy and an inadequate understanding of personal and familial implications of germline and somatic genomic testing among patients have been cited by specialists as sources of concern arising from personalized medicine use, particularly when seeking informed consent [ 351 ]. Inequalities in terms of access are also likely to arise according to the patient’s socioeconomic status, insurance provider (or level of coverage by the national healthcare system), and cancer care facilities [ 352 ]. Although patients living in countries with publicly funded universal healthcare are less likely to be affected by access inequalities, such systems often provide coverage for procedures and treatments whose efficacy has already been established [ 353 ]. For the clinical applications of personalized medicine to be validated in terms of their efficacy, they may require larger study samples vis-a-vis conventional treatments of already acknowledged clinical value. Hence, such applications may take longer to be recognized as evidence-based [ 354 ]. The fair and equitable distribution of healthcare resources can be negatively affected by such aspects. The already cited 2022 European Union Communication [ 335 ] mentions legal and ethical standards as some of the major barriers that need to be overcome if personalized medicine and the European Digital Strategy are to be harnessed to their full capacity. Litigation cases stemming from alleged negligence and malpractice allegations [ 355 ] are in fact likely to grow as a result of personalized medicine becoming more widespread [ 356 ]. As the degree of complexity of the medical interventions grows, so does the risk that an error may do damage to the patient, leading to liability and litigation [ 357 ]. The parties that could be held accountable include the manufacturers of genome sequencers and medical devices, laboratories, pharmaceutical companies, and healthcare facilities, but most of all the doctors responsible for diagnoses and therapeutic interventions. The notion of “genetic malpractice” has been defined as the failure on the part of doctors to recommend or properly interpret genetic testing, and such dynamics can be further compounded by the still unsolved disagreements within the medical community as to the scope and timing of the implementation of genetic testing in the clinical context, or even whether such testing ought to be performed at all [ 343 , 356 , 357 ]. It is quite hard at this stage to make predictions as to how the several novel liability risks (arising from personalized medicine based on clinical genomics), which have been already explored in scientific literature [ 355 , 356 ], will materialize in trial courts. The outcome of such lawsuits will likely rest on the specific circumstances and facts surrounding each case, as well as the approaches put in place by plaintiffs, attorneys, experts, and judges. It is, therefore, safe to assume that the early court rulings will substantially affect the future feasibility, attractiveness, and frequency of such litigation, as both medical and legal operators will look at those rulings for guidance. Nonetheless, the need for harmonized and broadly shared legislative, regulatory, and policy standards, i.e., up-to-date clinical guidelines specifying when and where genetic testing can be useful and where it is not (at least for now), is even more transparent, in order to help guide clinical judgment, provide a degree of objectivity for judicial rulings to look at, and to partially shield doctors from malpractice lawsuits.

7. Conclusions

Overall, ncRNAs provide a powerful weapon against human diseases, but we are still learning how to use them. The repertoire of ncRNAs is still growing, and the process of understanding their mechanisms of action is ongoing. However, the promise of finding cures for many diseases is in sight, and the advent of new computational tools coupled with advanced massive sequencing and innovative techniques such as CRISPR-Cas9 should speed up our race towards a healthier world. At the same time, it is of the utmost importance to prioritize ethically, legally, and socially sound approaches when undertaking such innovative pathways. Personalized medicine is information-intensive in nature. The predictive, diagnostic, and therapeutic capabilities of personalized medicine rely on high-dimensionality data created using genomics and other technologies. The legal and regulatory frameworks governing such dynamics need to be adequately updated and improved so as to meet the growing challenges and unique complexities arising from the future mainstream application of personalized medicine and the vast array of technologies on which it relies. A new ethical and legal set of standards aimed at avoiding inequalities in healthcare access and genetic discrimination (which personalized medicine, with its ability to draw ever-more subtle and precise distinctions among patients, could exacerbate) is all the more necessary.

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Author Contributions

Conceptualization: R.P. (Roberto Piergentili), C.N. and R.C.; methodology: R.P. (Roberto Piergentili), E.M., R.P. (Renato Patrone) and S.Z.; data curation for ncRNAs: R.P. (Roberto Piergentili), C.N. and R.C.; data curation for ethical, legal, and social issues: S.Z., G.B. and E.M.; original draft preparation: R.P. (Roberto Piergentili) and S.Z.; supervision: R.P. (Roberto Piergentili) and S.Z. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Beadle G.W. Tatum E.L. Genetic Control of Biochemical Reactions in Neurospora Proc. Natl. Acad. Sci. USA 1941 27 499 506 10.1073/pnas.27.11.499 16588492 PMC1078370

2. Ingram V.M.A. Specific chemical difference between the globins of normal human and sickle-cell anæmia hæmoglobin Nature 1956 178 792 794 10.1038/178792a0 13369537

3. Watson J.D. Crick F.H.C. Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid Nature 1953 171 737 738 10.1038/171737a0 13054692

4. Crick F.H.C. Barnett L. Brenner S. Watts-Tobin R.J. General nature of the genetic code for proteins Nature 1961 192 1227 1232 10.1038/1921227a0 13882203

5. Tamura K. The genetic code: Francis Crick’s legacy and beyond Life 2016 6 36 10.3390/life6030036 PMC5041012 27571106

6. Rattner J.B. Chapter 5 Centromeres and telomeres Princ. Med. Biol. 1995 2 93 120 10.1016/S1569-2582(06)80038-3

7. Achrem M. Szućko I. Kalinka A. The epigenetic regulation of centromeres and telomeres in plants and animals Comp. Cytogenet. 2020 14 265 311 10.3897/CompCytogen.v14i2.51895 32733650 PMC7360632

8. Hoagland M.B. Stephenson M.L. Scott J.F. Hecht L.I. Zamecnik P.C. A soluble ribonucleic acid intermediate in protein synthesis J. Biol. Chem. 1958 231 241 257 10.1016/S0021-9258(19)77302-5 13538965

9. Palade G.E. Microsomes and Ribonucleoprotein Particles Microsomal Particles and Protein Synthesis Pergamon Press New York, NY, USA 1958 36 61

10. Palazzo A.F. Lee E.S. Non-coding RNA: What is functional and what is junk? Front. Genet. 2015 5 10.3389/fgene.2015.00002 PMC4306305 25674102

11. Henderson A.S. Warburton D. Atwood K.C. Location of ribosomal DNA in the human chromosome complement Proc. Natl. Acad. Sci. USA 1972 69 3394 3398 10.1073/pnas.69.11.3394 4508329 PMC389778

12. Lander E.S. Linton L.M. Birren B. Nusbaum C. Zody M.C. Baldwin J. Devon K. Dewar K. Doyle M. Fitzhugh W. Initial sequencing and analysis of the human genome Nature 2001 409 860 921 10.1038/35057062 11237011

13. Brenner S. Jacob F. Meselson M. An unstable intermediate carrying information from genes to ribosomes for protein synthesis Nature 1961 190 576 581 10.1038/190576a0 20446365

14. Gros F. Hiatt H. Gilbert W. Kurland C.G. Risebrough R.W. Watson J.D. Unstable ribonucleic acid revealed by pulse labelling of Escherichia coli Nature 1961 190 581 585 10.1038/190581a0 13708983

15. Jacob F. Monod J. Genetic regulatory mechanisms in the synthesis of proteins J. Mol. Biol. 1961 3 318 356 10.1016/S0022-2836(61)80072-7 13718526

16. Willingham A.T. Gingeras T.R. TUF Love for “Junk” DNA Cell 2006 125 1215 1220 10.1016/j.cell.2006.06.009 16814704

17. Bhatti G.K. Khullar N. Sidhu I.S. Navik U.S. Reddy A.P. Reddy P.H. Bhatti J.S. Emerging role of non-coding RNA in health and disease Metab. Brain Dis. 2021 36 1119 1134 10.1007/s11011-021-00739-y 33881724 PMC8058498

18. Dou S. Wang Y. Lu J. Metazoan tsRNAs: Biogenesis, evolution and regulatory functions Non-Coding RNA 2019 5 18 10.3390/ncrna5010018 PMC6468576 30781726

19. Ye R. Cao C. Xue Y. Enhancer RNA: Biogenesis, function, and regulation Essays Biochem. 2020 64 883 894 33034351 10.1042/EBC20200014

20. Kim H.K. Yeom J.H. Kay M.A. Transfer RNA-Derived Small RNAs: Another Layer of Gene Regulation and Novel Targets for Disease Therapeutics Mol. Ther. 2020 28 2340 2357 10.1016/j.ymthe.2020.09.013 32956625 PMC7647673

21. Gulìa C. Signore F. Gaffi M. Gigli S. Votino R. Nucciotti R. Bertacca L. Zaami S. Baffa A. Santini E. Y RNA: An overview of their role as potential biomarkers and molecular targets in human cancers Cancers 2020 12 1238 10.3390/cancers12051238 PMC7281143 32423154

22. Wang Y. Sušac L. Feigon J. Structural biology of telomerase Cold Spring Harb. Perspect. Biol. 2019 11 a032383 10.1101/cshperspect.a032383 31451513 PMC6886448

23. Romito A. Rougeulle C. Origin and evolution of the long non-coding genes in the X-inactivation center Biochimie 2011 93 1935 1942 10.1016/j.biochi.2011.07.009 21820484

24. Djebali S. Davis C.A. Merkel A. Dobin A. Lassmann T. Mortazavi A. Tanzer A. Lagarde J. Lin W. Schlesinger F. Landscape of transcription in human cells Nature 2012 489 101 108 10.1038/nature11233 22955620 PMC3684276

25. Hubé F. Francastel C. Coding and Non-coding RNAs, the Frontier Has Never Been So Blurred Front. Genet. 2018 9 140 10.3389/fgene.2018.00140 29720998 PMC5915474

26. Rao M. Long Non Coding RNA Biology Rao M.R.S. Advances in Experimental Medicine and Biology Springer Singapore 2017 Volume 1008 978-981-10-5202-6

27. Craig Venter J. Adams M.D. Myers E.W. Li P.W. Mural R.J. Sutton G.G. Smith H.O. Yandell M. Evans C.A. Holt R.A. The sequence of the human genome Science 2001 291 1304 1351 10.1126/science.1058040 11181995

28. Cipriano A. Ballarino M. The ever-evolving concept of the gene: The use of RNA/Protein experimental techniques to understand genome functions Front. Mol. Biosci. 2018 5 20 10.3389/fmolb.2018.00020 29560353 PMC5845540

29. Arun G. Aggarwal D. Spector D.L. MALAT1 Long Non-Coding RNA: Functional Implications Non-Coding RNA 2020 3 22 10.3390/ncrna6020022 PMC7344863 32503170

30. Signorini L. Dolci M. Favi E. Colico C. Ferraresso M. Ticozzi R. Basile G. Ferrante P. Delbue S. Viral Genomic Characterization and Replication Pattern of Human Polyomaviruses in Kidney Transplant Recipients Viruses 2020 12 1280 10.3390/v12111280 PMC7696855 33182443

31. Zhang Z. Zhang J. Diao L. Han L. Small non-coding RNAs in human cancer: Function, clinical utility, and characterization Oncogene 2021 40 1570 1577 10.1038/s41388-020-01630-3 33452456

32. Zhang X.Z. Liu H. Chen S.R. Mechanisms of long non-coding RNAs in cancers and their dynamic regulations Cancers 2020 12 1245 10.3390/cancers12051245 PMC7281179 32429086

33. Busch A. Eken S.M. Maegdefessel L. Prospective and therapeutic screening value of non-coding rna as biomarkers in cardiovascular disease Ann. Transl. Med. 2016 4 1 12 10.21037/atm.2016.06.06 27429962 PMC4930509

34. D’Anca M. Buccellato F.R. Fenoglio C. Galimberti D. Circular RNAs: Emblematic Players of Neurogenesis and Neurodegeneration Int. J. Mol. Sci. 2022 23 4134 10.3390/ijms23084134 35456950 PMC9032451

35. Liu S. Fan M. Zheng Q. Hao S. Yang L. Xia Q. Qi C. Ge J. MicroRNAs in Alzheimer’s disease: Potential diagnostic markers and therapeutic targets Biomed. Pharmacother. 2022 148 12681 10.1016/j.biopha.2022.112681 35177290

36. Ala U. Competing Endogenous RNAs, Non-Coding RNAs and Diseases: An Intertwined Story Cells 2020 9 1574 10.3390/cells9071574 PMC7407898 32605220

37. Lou W. Ding B. Fu P. Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer Front. Cell Dev. Biol. 2020 8 85 10.3389/fcell.2020.00085 32185172 PMC7058547

38. Slack F.J. Chinnaiyan A.M. The Role of Non-coding RNAs in Oncology Cell 2019 179 1033 1055 10.1016/j.cell.2019.10.017 31730848 PMC7347159

39. Cavaliere A.F. Perelli F. Zaami S. Piergentili R. Mattei A. Vizzielli G. Scambia G. Straface G. Restaino S. Signore F. Towards personalized medicine: Non-coding rnas and endometrial cancer Healthcare 2021 9 965 10.3390/healthcare9080965 34442102 PMC8393611

40. Kumar S. Gonzalez E.A. Rameshwar P. Etchegaray J.-P. Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies Cancers 2020 12 3657 10.3390/cancers12123657 PMC7762117 33291485

41. Piergentili R. Zaami S. Cavaliere A.F. Signore F. Scambia G. Mattei A. Marinelli E. Gulia C. Perelli F. Non-coding rnas as prognostic markers for endometrial cancer Int. J. Mol. Sci. 2021 22 3151 10.3390/ijms22063151 33808791 PMC8003471

42. Gulìa C. Baldassarra S. Signore F. Rigon G. Pizzuti V. Gaffi M. Briganti V. Porrello A. Piergentili R. Role of non-coding RNAs in the etiology of bladder cancer Genes 2017 8 339 10.3390/genes8110339 PMC5704252 29165379

43. Abdollahzadeh R. Daraei A. Mansoori Y. Sepahvand M. Amoli M.M. Tavakkoly-Bazzaz J. Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer J. Cell. Physiol. 2019 234 10080 10100 10.1002/jcp.27941 30537129

44. Moreno-García L. López-Royo T. Calvo A.C. Toivonen J.M. de la Torre M. Moreno-Martínez L. Molina N. Aparicio P. Zaragoza P. Manzano R. Competing endogenous rna networks as biomarkers in neurodegenerative diseases Int. J. Mol. Sci. 2020 21 9582 10.3390/ijms21249582 33339180 PMC7765627

45. Cen L. Liu R. Liu W. Li Q. Cui H. Competing Endogenous RNA Networks in Glioma Front. Genet. 2021 12 10.3389/fgene.2021.675498 33995499 PMC8117106

46. Salmena L. Poliseno L. Tay Y. Kats L. Pandolfi P.P. A ceRNA hypothesis: The rosetta stone of a hidden RNA language? Cell 2011 146 353 358 10.1016/j.cell.2011.07.014 21802130 PMC3235919

47. Karreth F.A. Pandolfi P.P. CeRNA cross-talk in cancer: When ce-bling rivalries go awry Cancer Discov. 2013 3 1113 1121 10.1158/2159-8290.CD-13-0202 24072616 PMC3801300

48. Chan J.J. Tay Y. Noncoding RNA: RNA regulatory networks in cancer Int. J. Mol. Sci. 2018 19 1310 10.3390/ijms19051310 PMC5983611 29702599

49. Anand P. Kunnumakkara A.B. Sundaram C. Harikumar K.B. Tharakan S.T. Lai O.S. Sung B. Aggarwal B.B. Cancer is a preventable disease that requires major lifestyle changes Pharm. Res. 2008 25 2097 2116 Erratum in Pharm. Res. 2008 , 25 , 2200 10.1007/s11095-008-9661-9 18626751 PMC2515569

50. Stepanov I. Carcinogens and Toxicants in Combusted Tobacco Products and Related Cancer Risks Tobacco and Cancer, the Science and the Story Hecht S.S. Hatsukami D.K. World Scientific Publishing Co Pte Ltd. Singapore 2022 101 127 10.1142/9789811239533_0004

51. Hecht S.S. Hatsukami D.K. Smokeless tobacco and cigarette smoking, chemical mechanisms and cancer prevention Nat. Rev. Cancer 2022 22 143 155 10.1038/s41568-021-00423-4 34980891 PMC9308447

52. Yan R. Chen X.L. Xu Y.M. Lau A.T.Y. Epimutational effects of electronic cigarettes Environ. Sci. Pollut. Res. Int. 2021 28 17044 17067 10.1007/s11356-021-12985-9 33655478

53. Solleti S.K. Bhattacharya S. Ahmad A. Wang Q. Mereness J. Rangasamy T. Mariani T.J. MicroRNA expression profiling defines the impact of electronic cigarettes on human airway epithelial cells Sci. Rep. 2017 7 1081 10.1038/s41598-017-01167-8 28439113 PMC5430826

54. Rager J.E. Smeester L. Jaspers I. Sexton K.G. Fry R.C. Epigenetic changes induced by air toxics, formaldehyde exposure alters miRNA expression profiles in human lung cells Environ. Health Perspect. 2011 119 494 500 10.1289/ehp.1002614 21147603 PMC3080931

55. Zhao Y. Liu H. Li Y. Wu J. Greenlee A.R. Yang C. Jiang Y. The role of miR-506 in transformed 16HBE cells induced by anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide Toxicol. Lett. 2011 205 320 326 10.1016/j.toxlet.2011.06.022 21726609

56. Yu M.A. Kiang A. Wang-Rodriguez J. Rahimy E. Haas M. Yu V. Ellies L.G. Chen J. Fan J.B. Brumund K.T. Nicotine promotes acquisition of stem cell and epithelial-to-mesenchymal properties in head and neck squamous cell carcinoma PLoS ONE 2012 7 e51967 10.1371/journal.pone.0051967 23300583 PMC3530520

57. Han Z. Yang Q. Liu B. Wu J. Li Y. Yang C. Jiang Y. MicroRNA-622 functions as a tumor suppressor by targeting K-Ras and enhancing the anticarcinogenic effect of resveratrol Carcinogenesis 2012 33 131 139 10.1093/carcin/bgr226 22016468

58. Wu J. Yang T. Li X. Yang Q. Liu R. Huang J. Li Y. Yang C. Jiang Y. Alteration of serum miR-206 and miR-133b is associated with lung carcinogenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Toxicol. Appl. Pharmacol. 2013 267 238 246 10.1016/j.taap.2013.01.002 23337359

59. Zhang Y. Pan T. Zhong X. Cheng C. Nicotine upregulates microRNA-21 and promotes TGF-β-dependent epithelial-mesenchymal transition of esophageal cancer cells Tumour Biol. 2014 35 7063 7072 10.1007/s13277-014-1968-z 24756761

60. Lei Z. Xiaomin Y. He H. Jian C. Xiaowu X. Nicotine downregulates microRNA-200c to promote metastasis and the epithelial-mesenchymal transition in human colorectal cancer cells J. Cell. Physiol. 2019 234 1369 1379 10.1002/jcp.26933 30076725

61. Shiah S.G. Hsiao J.R. Chang H.J. Hsu Y.M. Wu G.H. Peng H.Y. Chou S.T. Kuo C.C. Chang J.Y. MiR-30a and miR-379 modulate retinoic acid pathway by targeting DNA methyltransferase 3B in oral cancer J. Biomed. Sci. 2020 27 46 10.1186/s12929-020-00644-z 32238162 PMC7114797

62. Lu L. Xu H. Luo F. Liu X. Lu X. Yang Q. Xue J. Chen C. Shi L. Liu Q. Epigenetic silencing of miR-218 by the lncRNA CCAT1; acting via BMI1; promotes an altered cell cycle transition in the malignant transformation of HBE cells induced by cigarette smoke extract Toxicol. Appl. Pharmacol. 2016 304 30 41 10.1016/j.taap.2016.05.012 27212446

63. Arunkumar G. Deva Magendhra Rao A.K. Manikandan M. Arun K. Vinothkumar V. Revathidevi S. Rajkumar K.S. Rajaraman R. Munirajan A.K. Expression profiling of long non-coding RNA identifies linc-RoR as a prognostic biomarker in oral cancer Tumour Biol. 2017 39 1010428317698366 10.1177/1010428317698366 28443494

64. Liu Z. Liu A. Nan A. Cheng Y. Yang T. Dai X. Chen L. Li X. Jia Y. Zhang N. The linc00152 Controls Cell Cycle Progression by Regulating CCND1 in 16HBE Cells Malignantly Transformed by Cigarette Smoke Extract Toxicol. Sci. 2019 167 496 508 10.1093/toxsci/kfy254 30289508

65. Zhao H. Wang Y. Ren X. Nicotine promotes the development of non-small cell lung cancer through activating LINC00460 and PI3K/Akt signaling Biosci. Rep. 2019 39 BSR20182443 10.1042/BSR20182443 31123168 PMC6554215

66. Gao S. Lin H. Yu W. Zhang F. Wang R. Yu H. Qian B. LncRNA LCPAT1 is involved in DNA damage induced by CSE Biochem. Biophys. Res Commun. 2019 508 512 515 10.1016/j.bbrc.2018.11.171 30509493

67. Wu Y. Niu Y. Leng J. Xu J. Chen H. Li H. Wang L. Hu J. Xia D. Wu Y. Benzo(a)pyrene regulated A549 cell migration; invasion and epithelial-mesenchymal transition by up-regulating long non-coding RNA linc00673 Toxicol. Lett. 2020 320 37 45 10.1016/j.toxlet.2019.11.024 31778776

68. Wang G. Ye M. Zheng S. Wu K. Geng H. Liu C. Cigarette Smoke Extract induces H19 in Esophageal Squamous Cell Carcinoma in Smoking Patients, Based on A Chronic Exposed Cell Model Toxicol. Lett. 2020 333 62 70 10.1016/j.toxlet.2020.07.030 32739445

69. Chen E. Zhou J. Xu E. Zhang C. Liu J. Zhou J. Li M. Wu J. Yang Q. A genome-wide screen for differentially methylated long noncoding RNAs identified that lncAC007255.8 is regulated by promoter DNA methylation in Beas-2B cells malignantly transformed by NNK Toxicol. Lett. 2021 346 34 46 10.1016/j.toxlet.2021.04.013 33872747

70. Verplaetse T.L. McKee S.A. An overview of alcohol and tobacco/nicotine interactions in the human laboratory Am. J. Drug Alcohol Abuse 2017 43 186 196 10.1080/00952990.2016.1189927 27439453 PMC5588903

71. Soares do Amaral N. Cruz E. Melo N. de Melo Maia B. Malagoli Rocha R. Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases Genes 2016 8 6 10.3390/genes8010006 PMC5295001 28025544

72. Luo Y. Ye J. Wei J. Zhang J. Li Y. Long non-coding RNA-based risk scoring system predicts prognosis of alcohol-related hepatocellular carcinoma Mol. Med. Rep. 2020 22 997 1007 10.3892/mmr.2020.11179 32468063 PMC7339747

73. Yu V. Singh P. Rahimy E. Zheng H. Kuo S.Z. Kim E. Wang-Rodriguez J. Ongkeko W.M. RNA-seq analysis identifies key long non-coding RNAs connected to the pathogenesis of alcohol-associated head and neck squamous cell carcinoma Oncol. Lett. 2016 12 2846 2853 10.3892/ol.2016.4972 27698869 PMC5038566

74. Yang X.Z. He Q.J. Cheng T.T. Chi J. Lei Z.Y. Tang Z. Liao Q.X. Zhang H. Zeng L.S. Cui S.Z. Predictive Value of LINC01133 for Unfavorable Prognosis was Impacted by Alcohol in Esophageal Squamous Cell Carcinoma Cell Physiol. Biochem. 2018 48 251 262 10.1159/000491724 30007982

75. Hu X. Qiu Z. Zeng J. Xiao T. Ke Z. Lyu H. A novel long non-coding RNA, AC012456.4, as a valuable and independent prognostic biomarker of survival in oral squamous cell carcinoma PeerJ 2018 6 e5307 10.7717/peerj.5307 30128179 PMC6095106

76. Du Q. Xiao R.D. Luo R.G. Xie J.B. Su Z.D. Wang Y. Construction of long non-coding RNA- and microRNA-mediated competing endogenous RNA networks in alcohol-related esophageal cancer PLoS ONE 2022 17 e0269742 10.1371/journal.pone.0269742 35704638 PMC9200351

77. Doll R. Peto R. The causes of cancer, quantitative estimates of avoidable risks of cancer in the United States today J. Natl. Cancer Inst. 1981 66 1191 1308 10.1093/jnci/66.6.1192 7017215

78. Willett W.C. Diet and cancer Oncologist 2000 5 393 404 10.1634/theoncologist.5-5-393 11040276

79. Disner G.R. Lopes-Ferreira M. Lima C. Where the Aryl Hydrocarbon Receptor Meets the microRNAs, Literature Review of the Last 10 Years Front. Mol. Biosci. 2021 8 725044 10.3389/fmolb.2021.725044 34746229 PMC8566438

80. Li M. Huo X. Davuljigari C.B. Dai Q. Xu X. MicroRNAs and their role in environmental chemical carcinogenesis Environ. Geochem. Health 2019 41 225 247 10.1007/s10653-018-0179-8 30171477

81. Miguel V. Cui J.Y. Daimiel L. Espinosa-Díez C. Fernández-Hernando C. Kavanagh T.J. Lamas S. The Role of MicroRNAs in Environmental Risk Factors, Noise-Induced Hearing Loss, and Mental Stress Antioxid. Redox Signal. 2018 28 773 796 10.1089/ars.2017.7175 28562070 PMC5911706

82. Béliveau R. Gingras D. Role of nutrition in preventing cancer Can. Fam. Physician 2007 53 1905 1911 18000267 PMC2231485

83. Giordano A. Tommonaro G. Curcumin and Cancer Nutrients 2019 11 2376 10.3390/nu11102376 PMC6835707 31590362

84. Gallardo M. Kemmerling U. Aguayo F. Bleak T.C. Muñoz J.P. Calaf G.M. Curcumin rescues breast cells from epithelial-mesenchymal transition and invasion induced by anti-miR-34a Int. J. Oncol. 2020 56 480 493 10.3892/ijo.2019.4939 31894298 PMC6959390

85. Javan N. Khadem Ansari M.H. Dadashpour M. Khojastehfard M. Bastami M. Rahmati-Yamchi M. Zarghami N. Synergistic Antiproliferative Effects of Co-nanoencapsulated Curcumin and Chrysin on MDA-MB-231 Breast Cancer Cells Through Upregulating miR-132 and miR-502c Nutr. Cancer 2019 71 1201 1213 10.1080/01635581.2019.1599968 30955355

86. Norouzi S. Majeed M. Pirro M. Generali D. Sahebkar A. Curcumin as an Adjunct Therapy and microRNA Modulator in Breast Cancer Curr. Pharm. Des. 2018 24 171 177 10.2174/1381612824666171129203506 29189128

87. Yeap S.K. Mohd Ali N. Akhtar M.N. Razak N.A. Chong Z.X. Ho W.Y. Boo L. Zareen S. Kurniawan T.A. Avtar R. Induction of Apoptosis and Regulation of MicroRNA Expression by (2E;6E)-2;6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) Treatment on MCF-7 Breast Cancer Cells Molecules 2021 26 1277 10.3390/molecules26051277 33652854 PMC7956517

88. Nirgude S. Desai S. Choudhary B. Curcumin alters distinct molecular pathways in breast cancer subtypes revealed by integrated miRNA/mRNA expression analysis Cancer Rep. 2022 e1596 10.1002/cnr2.1596 34981672 PMC9575497

89. Duan Y. Chen H.L. Ling M. Zhang S. Ma F.X. Zhang H.C. Lv X.A. The Curcumin Analog EF24 Inhibits Proliferation and Invasion of Triple-Negative Breast Cancer Cells by Targeting the Long Noncoding RNA HCG11/Sp1 Axis Mol. Cell Biol. 2022 42 e0016321 10.1128/MCB.00163-21 34780286 PMC8773073

90. Sun C. Zhang S. Liu C. Liu X. Curcumin Promoted miR-34a Expression and Suppressed Proliferation of Gastric Cancer Cells Cancer Biother. Radiopharm. 2019 34 634 641 10.1089/cbr.2019.2874 31539270

91. Qiang Z. Meng L. Yi C. Yu L. Chen W. Sha W. Curcumin regulates the miR-21/PTEN/Akt pathway and acts in synergy with PD98059 to induce apoptosis of human gastric cancer MGC-803 cells J. Int. Med. Res. 2019 47 1288 1297 10.1177/0300060518822213 30727807 PMC6421392

92. Zhang J. Zhang T. Ti X. Shi J. Wu C. Ren X. Yin H. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway Biochem. Biophys. Res. Commun. 2010 399 1 6 10.1016/j.bbrc.2010.07.013 20627087

93. Xu X. Zhang X. Zhang Y. Wang Z. Curcumin suppresses the malignancy of non-small cell lung cancer by modulating the circ-PRKCA/miR-384/ITGB1 pathway Biomed. Pharmacother. 2021 138 111439 10.1016/j.biopha.2021.111439 33684690

94. He Y.Z. Yu S.L. Li X.N. Bai X.H. Li H.T. Liu Y.C. Lv B.L. Zhao X.M. Wei D. Zhang H.L. Curcumin increases crizotinib sensitivity through the inactivation of autophagy via epigenetic modulation of the miR-142-5p/Ulk1 axis in non-small cell lung cancer Cancer Biomark. 2022 34 297 307 10.3233/CBM-210282 34957997 PMC12364285

95. Wang N. Feng T. Liu X. Liu Q. Curcumin inhibits migration and invasion of non-small cell lung cancer cells through up-regulation of miR-206 and suppression of PI3K/AKT/mTOR signaling pathway Acta Pharm. 2020 70 399 409 10.2478/acph-2020-0029 32074070

96. Pan Y. Sun Y. Liu Z. Zhang C. miR-192-5p upregulation mediates the suppression of curcumin in human NSCLC cell proliferation; migration and invasion by targeting c-Myc and inactivating the Wnt/β-catenin signaling pathway Mol. Med. Rep. 2020 22 1594 1604 10.3892/mmr.2020.11213 32626956

97. Taverna S. Giallombardo M. Pucci M. Flugy A. Manno M. Raccosta S. Rolfo C. De Leo G. Alessandro R. Curcumin inhibits in vitro and in vivo chronic myelogenous leukemia cells growth, a possible role for exosomal disposal of miR-21 Oncotarget 2015 6 21918 21933 10.18632/oncotarget.4204 26116834 PMC4673136

98. Liu J.M. Li M. Luo W. Sun H.B. Curcumin attenuates Adriamycin-resistance of acute myeloid leukemia by inhibiting the lncRNA HOTAIR/miR-20a-5p/WT1 axis Lab. Investig. 2021 101 1308 1317 10.1038/s41374-021-00640-3 34282279

99. Dou H. Shen R. Tao J. Huang L. Shi H. Chen H. Wang Y. Wang T. Curcumin Suppresses the Colon Cancer Proliferation by Inhibiting Wnt/β-Catenin Pathways via miR-130a Front. Pharmacol. 2017 8 877 10.3389/fphar.2017.00877 29225578 PMC5705620

100. Li B. Shi C. Li B. Zhao J.M. Wang L. The effects of Curcumin on HCT-116 cells proliferation and apoptosis via the miR-491/PEG10 pathway J. Cell Biochem. 2018 119 3091 3098 10.1002/jcb.26449 29058812

101. Fan W.H. Wang F.C. Jin Z. Zhu L. Zhang J.X. Curcumin Synergizes with Cisplatin to Inhibit Colon Cancer through Targeting the MicroRNA-137-Glutaminase Axis Curr. Med. Sci. 2022 42 108 117 10.1007/s11596-021-2469-0 34958454

102. Wang H. Cai X. Ma L. Curcumin Modifies Epithelial-Mesenchymal Transition in Colorectal Cancer Through Regulation of miR-200c/EPM5 Cancer Manag. Res. 2020 12 9405 9415 10.2147/CMAR.S260129 33061628 PMC7534868

103. Han W. Yin H. Ma H. Wang Y. Kong D. Fan Z. Curcumin Regulates ERCC1 Expression and Enhances Oxaliplatin Sensitivity in Resistant Colorectal Cancer Cells through Its Effects on miR-409-3p Evid.-Based Complement. Alternat. Med. 2020 2020 8394574 10.1155/2020/8394574 33014113 PMC7519441

104. Tang Y. Cao Y. Curcumin Inhibits the Growth and Metastasis of Melanoma via miR-222-3p/SOX10/Notch Axis Dis. Markers 2022 2022 3129781 10.1155/2022/3129781 35585935 PMC9110126

105. Bimonte S. Barbieri A. Leongito M. Piccirillo M. Giudice A. Pivonello C. de Angelis C. Granata V. Palaia R. Izzo F. Curcumin AntiCancer Studies in Pancreatic Cancer Nutrients 2016 8 433 10.3390/nu8070433 27438851 PMC4963909

106. Liu T. Chi H. Chen J. Chen C. Huang Y. Xi H. Xue J. Si Y. Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR Genes 2017 631 29 38 10.1016/j.gene.2017.08.008 28843521

107. Liu J. Li M. Wang Y. Luo J. Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition J. Drug Target. 2017 25 645 652 10.1080/1061186X.2017.1315686 28391715

108. Zhu M. Zheng Z. Huang J. Ma X. Huang C. Wu R. Li X. Liang Z. Deng F. Wu J. Modulation of miR-34a in curcumin-induced antiproliferation of prostate cancer cells J. Cell. Biochem. 2019 120 15616 15624 10.1002/jcb.28828 31042325

109. Ravindran F. Koroth J. Manjunath M. Narayan S. Choudhary B. Curcumin derivative ST09 modulates the miR-199a-5p/DDR1 axis and regulates proliferation and migration in ovarian cancer cells Sci. Rep. 2021 11 23025 10.1038/s41598-021-02454-1 34837026 PMC8626492

110. Sun S. Fang H. Curcumin inhibits ovarian cancer progression by regulating circ-PLEKHM3/miR-320a/SMG1 axis J. Ovarian Res. 2021 14 158 10.1186/s13048-021-00916-8 34784955 PMC8594156

111. Chen Q. Guo H. Zong Y. Zhao X. Curcumin restrains hepatocellular carcinoma progression depending on the regulation of the circ_0078710/miR-378b/PRIM2 axis J. Recept. Signal. Transduct. Res. 2022 42 313 324 10.1080/10799893.2021.1936554 34139933

112. Zhou C. Hu C. Wang B. Fan S. Jin W. Curcumin Suppresses Cell Proliferation; Migration; and Invasion Through Modulating miR-21-5p/SOX6 Axis in Hepatocellular Carcinoma Cancer Biother. Radiopharm. 2020 10.1089/cbr.2020.3734 32757994

113. Hatab H.M. Abdel Hamid F.F. Soliman A.F. Al-Shafie T.A. Ismail Y.M. El-Houseini M.E. A combined treatment of curcumin; piperine; and taurine alters the circulating levels of IL-10 and miR-21 in hepatocellular carcinoma patients, a pilot study J. Gastrointest. Oncol. 2019 10 766 776 10.21037/jgo.2019.03.07 31392057 PMC6657326

114. Xue L. Tao Y. Yuan Y. Qu W. Wang W. Curcumin suppresses renal carcinoma tumorigenesis by regulating circ-FNDC3B/miR-138-5p/IGF2 axis Anticancer Drugs 2021 32 734 744 10.1097/CAD.0000000000001063 34001703

115. Kang T. Sun W.L. Lu X.F. Wang X.L. Jiang L. MiR-28-5p mediates the anti-proliferative and pro-apoptotic effects of curcumin on human diffuse large B-cell lymphoma cells J. Int. Med. Res. 2020 48 300060520943792 10.1177/0300060520943792 32721183 PMC7388109

116. Chen L. Zhan C.Z. Wang T. You H. Yao R. Curcumin Inhibits the Proliferation; Migration; Invasion; and Apoptosis of Diffuse Large B-Cell Lymphoma Cell Line by Regulating MiR-21/VHL Axis Yonsei Med. J. 2020 61 20 29 10.3349/ymj.2020.61.1.20 31887796 PMC6938780

117. Zhu D. Shao M. Yang J. Fang M. Liu S. Lou D. Gao R. Liu Y. Li A. Lv Y. Curcumin Enhances Radiosensitization of Nasopharyngeal Carcinoma via Mediating Regulation of Tumor Stem-like Cells by a CircRNA Network J. Cancer 2020 11 2360 2370 10.7150/jca.39511 32127962 PMC7052922

118. Yang J. Zhu D. Liu S. Shao M. Liu Y. Li A. Lv Y. Huang M. Lou D. Fan Q. Curcumin enhances radiosensitization of nasopharyngeal carcinoma by regulating circRNA network Mol. Carcinog. 2020 59 202 214 10.1002/mc.23143 31793078

119. Zhou L. Lu Y. Liu J.S. Long S.Z. Liu H.L. Zhang J. Zhang T. The role of miR-21/RECK in the inhibition of osteosarcoma by curcumin Mol. Cell Probes 2020 51 101534 10.1016/j.mcp.2020.101534 32081769

120. Pan J.X. Chen T.N. Ma K. Wang S. Yang C.Y. Cui G.Y. A negative feedback loop of H19/miR-675/VDR mediates therapeutic effect of cucurmin in the treatment of glioma J. Cell. Physiol. 2020 235 2171 2182 10.1002/jcp.29127 31468534

121. Xu R. Li H. Wu S. Qu J. Yuan H. Zhou Y. Lu Q. MicroRNA-1246 regulates the radio-sensitizing effect of curcumin in bladder cancer cells via activating P53 Int. Urol. Nephrol. 2019 51 1771 1779 10.1007/s11255-019-02210-5 31236854

122. Ahmad A. Sarkar S.H. Bitar B. Ali S. Aboukameel A. Sethi S. Li Y. Bao B. Kong D. Banerjee S. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo; leading to anticancer activity against breast cancer cells Mol. Cancer Ther. 2012 11 2193 2201 10.1158/1535-7163.MCT-12-0232-T 22821148 PMC3836047

123. Parasramka M.A. Ali S. Banerjee S. Deryavoush T. Sarkar F.H. Gupta S. Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures Mol. Nutr. Food Res. 2013 57 235 248 10.1002/mnfr.201200297 23293055

124. Huang C.C. Lin C.M. Huang Y.J. Wei L. Ting L.L. Kuo C.C. Hsu C. Chiou J.F. Wu A.T.H. Lee W.H. Garcinol downregulates Notch1 signaling via modulating miR-200c and suppresses oncogenic properties of PANC-1 cancer stem-like cells Biotechnol. Appl. Biochem. 2017 64 165 173 10.1002/bab.1446 26400206

125. Farhan M. Malik A. Ullah M.F. Afaq S. Faisal M. Farooqi A.A. Biersack B. Schobert R. Ahmad A. Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs Int. J. Mol. Sci. 2019 20 800 10.3390/ijms20040800 30781783 PMC6413107

126. Liu H.W. Lee P.M. Bamodu O.A. Su Y.K. Fong I.H. Yeh C.T. Chien M.H. Kan I.H. Lin C.M. Enhanced Hsa-miR-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A Ratios Mediate the Anticancer Effect of Garcinol in STAT3/5A-Addicted Glioblastoma Cancers 2019 11 1888 10.3390/cancers11121888 PMC6966688 31783691

127. Zaman M.S. Shahryari V. Deng G. Thamminana S. Saini S. Majid S. Chang I. Hirata H. Ueno K. Yamamura S. Up-regulation of microRNA-21 correlates with lower kidney cancer survival PLoS ONE 2012 7 e31060 10.1371/annotation/6662579f-3a41-4bce-9298-9d15f6582ef5 22347428 PMC3275568

128. Zaman M.S. Thamminana S. Shahryari V. Chiyomaru T. Deng G. Saini S. Majid S. Fukuhara S. Chang I. Arora S. Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer PLoS ONE 2012 7 e50203 10.1371/journal.pone.0050203 23189187 PMC3506541

129. Hirata H. Ueno K. Nakajima K. Tabatabai Z.L. Hinoda Y. Ishii N. Dahiya R. Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells Br. J. Cancer 2013 108 2070 2078 10.1038/bjc.2013.173 23591200 PMC3670482

130. Hirata H. Hinoda Y. Shahryari V. Deng G. Tanaka Y. Tabatabai Z.L. Dahiya R. Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells Br. J. Cancer 2014 110 1645 1654 10.1038/bjc.2014.48 24504368 PMC3960620

131. Chiyomaru T. Yamamura S. Zaman M.S. Majid S. Deng G. Shahryari V. Saini S. Hirata H. Ueno K. Chang I. Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151 PLoS ONE 2012 7 e43812 10.1371/journal.pone.0043812 22928040 PMC3426544

132. Chen Y. Zaman M.S. Deng G. Majid S. Saini S. Liu J. Tanaka Y. Dahiya R. MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer Cancer Prev. Res. 2011 4 76 86 10.1158/1940-6207.CAPR-10-0167 PMC3894108 21071579

133. Ma J. Cheng L. Liu H. Zhang J. Shi Y. Zeng F. Miele L. Sarkar F.H. Xia J. Wang Z. Genistein down-regulates miR-223 expression in pancreatic cancer cells Curr. Drug Targets 2013 14 1150 1156 10.2174/13894501113149990187 23834147

134. Majid S. Dar A.A. Saini S. Chen Y. Shahryari V. Liu J. Zaman M.S. Hirata H. Yamamura S. Ueno K. Regulation of minichromosome maintenance gene family by microRNA-1296 and genistein in prostate cancer Cancer Res. 2010 70 2809 2818 10.1158/0008-5472.CAN-09-4176 20332239

135. Chiyomaru T. Yamamura S. Fukuhara S. Yoshino H. Kinoshita T. Majid S. Saini S. Chang I. Tanaka Y. Enokida H. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR PLoS ONE 2013 8 e70372 10.1371/journal.pone.0070372 23936419 PMC3731248

136. Chiyomaru T. Yamamura S. Fukuhara S. Hidaka H. Majid S. Saini S. Arora S. Deng G. Shahryari V. Chang I. Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer PLoS ONE 2013 8 e58929 10.1371/journal.pone.0058929 23554959 PMC3595226

137. Lynch S.M. O’Neill K.M. McKenna M.M. Walsh C.P. McKenna D.J. Regulation of miR-200c and miR-141 by Methylation in Prostate Cancer Prostate 2016 76 1146 1159 10.1002/pros.23201 27198154 PMC5082568

138. Sun Q. Cong R. Yan H. Gu H. Zeng Y. Liu N. Chen J. Wang B. Genistein inhibits growth of human uveal melanoma cells and affects microRNA-27a and target gene expression Oncol. Rep. 2009 22 563 567 10.3892/or_00000472 19639204

139. Xia J. Cheng L. Mei C. Ma J. Shi Y. Zeng F. Wang Z. Wang Z. Genistein inhibits cell growth and invasion through regulation of miR-27a in pancreatic cancer cells Curr. Pharm. Des. 2014 20 5348 5353 10.2174/1381612820666140128215756 24479798

140. Yang Y. Zang A. Jia Y. Shang Y. Zhang Z. Ge K. Zhang J. Fan W. Wang B. Genistein inhibits A549 human lung cancer cell proliferation via miR-27a and MET signaling Oncol. Lett. 2016 12 2189 2193 10.3892/ol.2016.4817 27602162 PMC4998592

141. Xu L. Xiang J. Shen J. Zou X. Zhai S. Yin Y. Li P. Wang X. Sun Q. Oncogenic MicroRNA-27a is a target for genistein in ovarian cancer cells Anticancer Agents Med. Chem. 2013 13 1126 1132 10.2174/18715206113139990006 23438830

142. De la Parra C. Castillo-Pichardo L. Cruz-Collazo A. Cubano L. Redis R. Calin G.A. Dharmawardhane S. Soy Isoflavone Genistein-Mediated Downregulation of miR-155 Contributes to the Anticancer Effects of Genistein Nutr. Cancer 2016 68 154 164 10.1080/01635581.2016.1115104 26771440 PMC4936403

143. Avci C.B. Susluer S.Y. Caglar H.O. Balci T. Aygunes D. Dodurga Y. Gunduz C. Genistein-induced mir-23b expression inhibits the growth of breast cancer cells Contemp. Oncol. 2015 19 32 35 10.5114/wo.2014.44121 PMC4507883 26199568

144. Yu Y. Xing Y. Zhang Q. Zhang Q. Huang S. Li X. Gao C. Soy isoflavone genistein inhibits hsa_circ_0031250/miR-873-5p/FOXM1 axis to suppress non-small-cell lung cancer progression IUBMB Life 2021 73 92 107 10.1002/iub.2404 33159503

145. Hsieh P.L. Liao Y.W. Hsieh C.W. Chen P.N. Yu C.C. Soy Isoflavone Genistein Impedes Cancer Stemness and Mesenchymal Transition in Head and Neck Cancer through Activating miR-34a/RTCB Axis Nutrients 2020 12 1924 10.3390/nu12071924 32610494 PMC7400540

146. Wei D. Yang L. Lv B. Chen L. Genistein suppresses retinoblastoma cell viability and growth and induces apoptosis by upregulating miR-145 and inhibiting its target ABCE1 Mol. Vis. 2017 23 385 394 28706438 PMC5501691

147. Xie J. Wang J. Zhu B. Genistein inhibits the proliferation of human multiple myeloma cells through suppression of nuclear factor-κB and upregulation of microRNA-29b Mol. Med. Rep. 2016 13 1627 1632 10.3892/mmr.2015.4740 26718793

148. Xia J. Duan Q. Ahmad A. Bao B. Banerjee S. Shi Y. Ma J. Geng J. Chen Z. Rahman K.M. Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells Curr. Drug Targets 2012 13 1750 1756 10.2174/138945012804545597 23140286

149. Li Y. Vandenboom T.G. 2nd Kong D. Wang Z. Ali S. Philip P.A. Sarkar F.H. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells Cancer Res. 2009 69 6704 6712 10.1158/0008-5472.CAN-09-1298 19654291 PMC2727571

150. Li Y. Vandenboom T.G. 2nd Wang Z. Kong D. Ali S. Philip P.A. Sarkar F.H. miR-146a suppresses invasion of pancreatic cancer cells Cancer Res. 2010 70 1486 1495 10.1158/0008-5472.CAN-09-2792 20124483 PMC2978025

151. Sarkar S. Dubaybo H. Ali S. Goncalves P. Kollepara S.L. Sethi S. Philip P.A. Li Y. Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA Am. J. Cancer Res. 2013 3 465 477 24224124 PMC3816966

152. Kang Q. Zhang X. Cao N. Chen C. Yi J. Hao L. Ji Y. Liu X. Lu J. EGCG enhances cancer cells sensitivity under 60Coγ radiation based on miR-34a/Sirt1/p53 Food Chem. Toxicol. 2019 133 110807 10.1016/j.fct.2019.110807 31494133

153. Mostafa S.M. Gamal-Eldeen A.M. Maksoud N.A.E. Fahmi A.A. Epigallocatechin gallate-capped gold nanoparticles enhanced the tumor suppressors let-7a and miR-34a in hepatocellular carcinoma cells An. Acad. Bras. Cienc. 2020 92 e20200574 10.1590/0001-3765202020200574 33206791

154. Gordon M.W. Yan F. Zhong X. Mazumder P.B. Xu-Monette Z.Y. Zou D. Young K.H. Ramos K.S. Li Y. Regulation of p53-targeting microRNAs by polycyclic aromatic hydrocarbons, Implications in the etiology of multiple myeloma Mol. Carcinog. 2015 54 1060 1069 10.1002/mc.22175 24798859 PMC4223015

155. Khan M.I. Rath S. Adhami V.M. Mukhtar H. Targeting epigenome with dietary nutrients in cancer: Current advances and future challenges Pharmacol. Res. 2018 129 375 387 10.1016/j.phrs.2017.12.008 29233676

156. Li B.B. Huang G.L. Li H.H. Kong X. He Z.W. Epigallocatechin-3-gallate Modulates MicroRNA Expression Profiles in Human Nasopharyngeal Carcinoma CNE2 Cells Chin. Med. J. 2017 130 93 99 10.4103/0366-6999.196586 28051030 PMC5221119

157. Yu C.C. Chen P.N. Peng C.Y. Yu C.H. Chou M.Y. Suppression of miR-204 enables oral squamous cell carcinomas to promote cancer stemness, EMT traits, and lymph node metastasis Oncotarget 2016 7 20180 20192 10.18632/oncotarget.7745 26933999 PMC4991446

158. Zhou D.H. Wang X. Feng Q. EGCG enhances the efficacy of cisplatin by downregulating hsa-miR-98-5p in NSCLC A549 cells Nutr. Cancer 2014 66 636 644 10.1080/01635581.2014.894101 24712372

159. Siddiqui I.A. Asim M. Hafeez B.B. Adhami V.M. Tarapore R.S. Mukhtar H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer FASEB J. 2011 25 1198 1207 10.1096/fj.10-167924 21177307 PMC3058706

160. Zhao Y. Chen X. Jiang J. Wan X. Wang Y. Xu P. Epigallocatechin gallate reverses gastric cancer by regulating the long noncoding RNA LINC00511/miR-29b/KDM2A axis Biochim. Biophys. Acta Mol. Basis Dis. 2020 1866 165856 10.1016/j.bbadis.2020.165856 32512188

161. Zan L. Chen Q. Zhang L. Li X. Epigallocatechin gallate (EGCG) suppresses growth and tumorigenicity in breast cancer cells by downregulation of miR-25 Bioengineered 2019 10 374 382 10.1080/21655979.2019.1657327 31431131 PMC6738446

162. La X. Zhang L. Li Z. Li H. Yang Y. (-)-Epigallocatechin Gallate (EGCG) Enhances the Sensitivity of Colorectal Cancer Cells to 5-FU by Inhibiting GRP78/NF-κB/miR-155-5p/MDR1 Pathway J. Agric. Food Chem. 2019 67 2510 2518 10.1021/acs.jafc.8b06665 30741544

163. Jiang P. Xu C. Chen L. Chen A. Wu X. Zhou M. Haq I.U. Mariyam Z. Feng Q. Epigallocatechin-3-gallate inhibited cancer stem cell-like properties by targeting hsa-mir-485-5p/RXRα in lung cancer J. Cell Biochem. 2018 119 8623 8635 10.1002/jcb.27117 30058740

164. Bae S. Lee E.M. Cha H.J. Kim K. Yoon Y. Lee H. Kim J. Kim Y.J. Lee H.G. Jeung H.K. Resveratrol alters microRNA expression profiles in A549 human non-small cell lung cancer cells Mol. Cells 2011 32 243 249 10.1007/s10059-011-1037-z 21887509 PMC3887628

165. Kumar A. Rimando A.M. Levenson A.S. Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer Ann. N. Y. Acad. Sci. 2017 1403 15 26 10.1111/nyas.13372 28662290

166. Venkatadri R. Muni T. Iyer A.K. Yakisich J.S. Azad N. Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death Cell Death Dis. 2016 7 e2104 10.1038/cddis.2016.6 26890143 PMC5399194

167. Liu P. Liang H. Xia Q. Li P. Kong H. Lei P. Wang S. Tu Z. Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression Clin. Transl. Oncol. 2013 15 741 746 10.1007/s12094-012-0999-4 23359184

168. Su N. Li L. Zhou E. Li H. Wu S. Cao Z. Resveratrol Downregulates miR-155-5p to Block the Malignant Behavior of Gastric Cancer Cells Biomed. Res. Int. 2022 2022 6968641 10.1155/2022/6968641 35789645 PMC9250436

169. Li T. Zhang X. Cheng L. Li C. Wu Z. Luo Y. Zhou K. Li Y. Zhao Q. Huang Y. Modulation of lncRNA H19 enhances resveratrol-inhibited cancer cell proliferation and migration by regulating endoplasmic reticulum stress J. Cell Mol. Med. 2022 26 2205 2217 10.1111/jcmm.17242 35166018 PMC8995452

170. Cesmeli S. Goker Bagca B. Caglar H.O. Ozates N.P. Gunduz C. Biray Avci C. Combination of resveratrol and BIBR1532 inhibits proliferation of colon cancer cells by repressing expression of LncRNAs Med. Oncol. 2021 39 12 10.1007/s12032-021-01611-w 34779924

171. Lin T.A. Lin W.S. Chou Y.C. Nagabhushanam K. Ho C.T. Pan M.H. Oxyresveratrol inhibits human colon cancer cell migration through regulating epithelial-mesenchymal transition and microRNA Food Funct. 2021 12 9658 9668 10.1039/D1FO01920A 34664597

172. Song F. Zhang Y. Pan Z. Zhang Q. Lu X. Huang P. Resveratrol inhibits the migration, invasion and epithelial-mesenchymal transition in liver cancer cells through up- miR-186-5p expression Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 50 582 590 10.3724/zdxbyxb-2021-0197 34986537 PMC8732253

173. Yao S. Gao M. Wang Z. Wang W. Zhan L. Wei B. Upregulation of MicroRNA-34a Sensitizes Ovarian Cancer Cells to Resveratrol by Targeting Bcl-2 Yonsei Med. J. 2021 62 691 701 10.3349/ymj.2021.62.8.691 34296546 PMC8298871

174. Zhang B. Lari Najafi M. Resveratrol inhibits skin squamous cell carcinoma proliferation; migration and invasion through up-regulating miR-126 Cell Mol. Biol. 2020 66 142 147 10.14715/cmb/2020.66.5.25 33040828

175. Zhao S. Tang L. Chen W. Su J. Li F. Chen X. Wu L. Resveratrol-induced apoptosis is associated with regulating the miR-492/CD147 pathway in malignant melanoma cells Naunyn Schmiedebergs Arch. Pharmacol. 2021 394 797 807 10.1007/s00210-020-01981-4 33009925

176. Xiao X. Zhang Y. Pan W. Chen F. miR-139-mediated NOTCH1 regulation is crucial for the inhibition of osteosarcoma progression caused by resveratrol Life Sci. 2020 242 117215 10.1016/j.lfs.2019.117215 31881225

177. Nwaeburu C.C. Bauer N. Zhao Z. Abukiwan A. Gladkich J. Benner A. Herr I. Up-regulation of microRNA let-7c by quercetin inhibits pancreatic cancer progression by activation of Numbl Oncotarget 2016 7 58367 58380 10.18632/oncotarget.11122 27521217 PMC5295436

178. Du F. Feng Y. Fang J. Yang M. MicroRNA-143 enhances chemosensitivity of Quercetin through autophagy inhibition via target GABARAPL1 in gastric cancer cells Biomed. Pharmacother. 2015 74 169 177 10.1016/j.biopha.2015.08.005 26349981

179. Sonoki H. Sato T. Endo S. Matsunaga T. Yamaguchi M. Yamazaki Y. Sugatani J. Ikari A. Quercetin Decreases Claudin-2 Expression Mediated by Up-Regulation of microRNA miR-16 in Lung Adenocarcinoma A549 Cells Nutrients 2015 7 4578 4592 10.3390/nu7064578 26061016 PMC4488803

180. Wang Q. Chen Y. Lu H. Wang H. Feng H. Xu J. Zhang B. Quercetin radiosensitizes non-small cell lung cancer cells through the regulation of miR-16-5p/WEE1 axis IUBMB Life 2020 72 1012 1022 10.1002/iub.2242 32027086

181. Zhou J. Gong J. Ding C. Chen G. Quercetin Induces the Apoptosis of Human Ovarian Carcinoma Cells by Upregulating the Expression of MicroRNA-145 Mol. Med. Rep. 2015 12 3127 3131 10.3892/mmr.2015.3679 25937243

182. Tao S.F. He H.F. Chen Q. Quercetin inhibits proliferation and invasion acts by up-regulating miR-146a in human breast cancer cells Mol. Cell Biochem. 2015 402 93 100 10.1007/s11010-014-2317-7 25596948

183. Lou G. Liu Y. Wu S. Xue J. Yang F. Fu H. Zheng M. Chen Z. The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis Cell Physiol. Biochem. 2015 35 2192 2202 10.1159/000374024 25896587

184. Mohammadi E. Alemi F. Maleki M. Malakoti F. Farsad-Akhtar N. Yousefi B. Quercetin and Methotrexate in Combination have Anticancer Activity in Osteosarcoma Cells and Repress Oncogenic MicroRNA-223 Drug Res. 2022 72 226 233 10.1055/a-1709-0658 35385884

185. Abdel-Latif M. Riad A. Soliman R.A. Elkhouly A.M. Nafae H. Gad M.Z. Motaal A.A. Youness R.A. MALAT-1/p53/miR-155/miR-146a ceRNA circuit tuned by methoxylated quercitin glycoside alters immunogenic and oncogenic profiles of breast cancer Mol. Cell Biochem. 2022 477 1281 1293 10.1007/s11010-022-04378-4 35129780

186. Ahmed Youness R. Amr Assal R. Mohamed Ezzat S. Zakaria Gad M. Abdel Motaal A. A methoxylated quercetin glycoside harnesses HCC tumor progression in a TP53/miR-15/miR-16 dependent manner Nat. Prod. Res. 2020 34 1475 1480 10.1080/14786419.2018.1509326 30526087

187. Wang Y. Chen X. Li J. Xia C. Quercetin Antagonizes Esophagus Cancer by Modulating miR-1-3p/TAGLN2 Pathway-Dependent Growth and Metastasis Nutr. Cancer 2022 74 1872 1881 10.1080/01635581.2021.1972125 34498538

188. Chai R. Xu C. Lu L. Liu X. Ma Z. Quercetin inhibits proliferation of and induces apoptosis in non-small-cell lung carcinoma via the lncRNA SNHG7/miR-34a-5p pathway Immunopharmacol. Immunotoxicol. 2021 43 693 703 10.1080/08923973.2021.1966032 34448661

189. Chen L. Xia J.S. Wu J.H. Chen Y.G. Qiu C.J. Quercetin suppresses cell survival and invasion in oral squamous cell carcinoma via the miR-1254/CD36 cascade in vitro Hum. Exp. Toxicol. 2021 40 1413 1421 10.1177/0960327121991912 33686878

190. Hu S.A. Cheng J. Zhao W.H. Zhao H.Y. Quercetin induces apoptosis in meningioma cells through the miR-197/IGFBP5 cascade Environ. Toxicol. Pharmacol. 2020 80 103439 10.1016/j.etap.2020.103439 32585423

191. Krakowsky R.H. Tollefsbol T.O. Impact of Nutrition on Non-Coding RNA Epigenetics in Breast and Gynecological Cancer Front. Nutr. 2015 2 16 10.3389/fnut.2015.00016 26075205 PMC4445322

192. Biersack B. Current state of phenolic and terpenoidal dietary factors and natural products as non-coding RNA/microRNA modulators for improved cancer therapy and prevention Noncoding RNA Res. 2016 1 12 34 10.1016/j.ncrna.2016.07.001 30159408 PMC6096431

193. Ahmed F. Ijaz B. Ahmad Z. Farooq N. Sarwar M.B. Husnain T. Modification of miRNA Expression through plant extracts and compounds against breast cancer, Mechanism and translational significance Phytomedicine 2020 68 153168 10.1016/j.phymed.2020.153168 31982837

194. Tyagi G. Kapoor N. Chandra G. Gambhir L. Cure lies in nature, medicinal plants and endophytic fungi in curbing cancer 3 Biotech 2021 11 263 10.1007/s13205-021-02803-x 33996375 PMC8116431

195. Irshad R. Husain M. Natural products in the reprogramming of cancer epigenetics Toxicol. Appl. Pharmacol. 2021 417 115467 10.1016/j.taap.2021.115467 33631231

196. Romero-Corral A. Somers V.K. Sierra-Johnson J. Thomas R.J. Collazo-Clavell M.L. Korinek J. Allison T.G. Batsis J.A. Sert-Kuniyoshi F.H. Lopez-Jimenez F. Accuracy of body mass index in diagnosing obesity in the adult general population Int. J. Obes. 2008 32 959 966 10.1038/ijo.2008.11 18283284 PMC2877506

197. Mayoral L.P. Andrade G.M. Mayoral E.P. Huerta T.H. Canseco S.P. Rodal Canales F.J. Cabrera-Fuentes H.A. Cruz M.M. Pérez Santiago A.D. Alpuche J.J. Obesity subtypes, related biomarkers & heterogeneity Indian J. Med. Res. 2020 151 11 21 10.4103/ijmr.IJMR_1768_17 32134010 PMC7055173

198. Shukla A. Kumar K. Singh A. Association between obesity and selected morbidities, a study of BRICS countries PLoS ONE 2014 9 e94433 10.1371/journal.pone.0094433 24718033 PMC3981786

199. Kolb R. Sutterwala F.S. Zhang W. Obesity and cancer, inflammation bridges the two Curr. Opin. Pharmacol. 2016 29 77 89 10.1016/j.coph.2016.07.005 27429211 PMC4992602

200. Avgerinos K.I. Spyrou N. Mantzoros C.S. Dalamaga M. Obesity and cancer risk, Emerging biological mechanisms and perspectives Metabolism 2019 92 121 135 10.1016/j.metabol.2018.11.001 30445141

201. Vucenik I. Stains J.P. Obesity and cancer risk: Evidence, mechanisms, and recommendations Ann. N. Y. Acad. Sci. 2012 1271 37 43 10.1111/j.1749-6632.2012.06750.x 23050962 PMC3476838

202. Sun L. Goff L.A. Trapnell C. Alexander R. Lo K.A. Hacisuleyman E. Sauvageau M. Tazon-Vega B. Kelley D.R. Hendrickson D.G. Long noncoding RNAs regulate adipogenesis Proc. Natl. Acad. Sci. USA 2013 110 3387 3392 10.1073/pnas.1222643110 23401553 PMC3587215

203. Cheng Y. Gao W.W. Tang H.M. Deng J.J. Wong C.M. Chan C.P. Jin D.Y. β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H Sci. Rep. 2016 6 23938 10.1038/srep23938 27029215 PMC4814919

204. Yang L. Li P. Yang W. Ruan X. Kiesewetter K. Zhu J. Cao H. Integrative Transcriptome Analyses of Metabolic Responses in Mice Define Pivotal LncRNA Metabolic Regulators Cell Metab. 2016 24 627 639 10.1016/j.cmet.2016.08.019 27667668 PMC5181118

205. Sun J. Ruan Y. Wang M. Chen R. Yu N. Sun L. Liu T. Chen H. Differentially expressed circulating LncRNAs and mRNA identified by microarray analysis in obese patients Sci. Rep. 2016 6 35421 10.1038/srep35421 27767123 PMC5073332

206. Yau M.Y. Xu L. Huang C.L. Wong C.M. Long Non-Coding RNAs in Obesity-Induced Cancer Non-Coding RNA 2018 4 19 10.3390/ncrna4030019 PMC6162378 30154386

207. Tait S. Baldassarre A. Masotti A. Calura E. Martini P. Varì R. Scazzocchio B. Gessani S. Del Cornò M. Integrated Transcriptome Analysis of Human Visceral Adipocytes Unravels Dysregulated microRNA-Long Non-coding RNA-mRNA Networks in Obesity and Colorectal Cancer Front. Oncol. 2020 10 1089 10.3389/fonc.2020.01089 32714872 PMC7351520

208. Breininger S.P. Sabater L. Malcomson F.C. Afshar S. Mann J. Mathers J.C. Obesity and Roux-en-Y gastric bypass drive changes in miR-31 and miR-215 expression in the human rectal mucosa Int. J. Obes. 2022 46 333 341 10.1038/s41366-021-01005-y PMC8794786 34716428

209. Colon L.R. Chijioke J. Niture S. Afzal Z. Qi Q. Srivastava A. Ramalinga M. Kedir H. Cagle P. Arthur E. Abstract 5822: Leptin Modulated MicroRNA-628-5p Targets Jagged1 and Inhibits Prostate Cancer Hallmarks Cancer Res. 2022 82 5822 10.1158/1538-7445.AM2022-5822 PMC9203512 35710817

210. Cariello M. Piccinin E. Pasculli E. Arconzo M. Zerlotin R. D’Amore S. Mastropasqua F. Peres C. Graziano G. Villani G. Platelets from patients with visceral obesity promote colon cancer growth Commun. Biol. 2022 5 553 10.1038/s42003-022-03486-7 35672444 PMC9174292

211. Su Q. Xu Z.X. Xiong M.L. Li H.Y. Xu M.Y. Luo S.Z. The oncogenic miR-27a/BTG2 axis promotes obesity-associated hepatocellular carcinoma by mediating mitochondrial dysfunction Neoplasma 2022 69 820 831 10.4149/neo_2022_211227N1837 35532294

212. Patel A.V. Friedenreich C.M. Moore S.C. Hayes S.C. Silver J.K. Campbell K.L. Winters-Stone K. Gerber L.H. George S.M. Fulton J.E. American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control Med. Sci. Sports Exerc. 2019 51 2391 2402 10.1249/MSS.0000000000002117 31626056 PMC6814265

213. Campbell K.L. Winters-Stone K.M. Wiskemann J. May A.M. Schwartz A.L. Courneya K.S. Zucker D.S. Matthews C.E. Ligibel J.A. Gerber L.H. Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable Med. Sci. Sports Exerc. 2019 51 2375 2390 10.1249/MSS.0000000000002116 31626055 PMC8576825

214. Hojman P. Gehl J. Christensen J.F. Pedersen B.K. Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment Cell Metab. 2018 27 10 21 10.1016/j.cmet.2017.09.015 29056514

215. De Paulo T.R.S. Winters-Stone K.M. Viezel J. Rossi F.E. Aro B.L. Trindade A.C.A.C. Codogno J.S. Freitas Junior I.F. Comparing Exercise Responses to Aerobic plus Resistance Training between Postmenopausal Breast Cancer Survivors Undergoing Aromatase Inhibitor Therapy and Healthy Women Disabil. Rehabil. 2019 41 2175 2182 10.1080/09638288.2018.1460877 29644889

216. World Health Organization Global Recommendation on Structured Exercise for Health Available online: https://www.who.int/publications/i/item/9789241599979 (accessed on 7 August 2022)

217. Sanchis-Gomar F. Lucia A. Yvert T. Ruiz-Casado A. Pareja-Galeano H. Santos-Lozano A. Fiuza-Luces C. Garatachea N. Lippi G. Bouchard C. Physical Inactivity and Low Fitness Deserve More Attention to Alter Cancer Risk and Prognosis Cancer Prev. Res. 2015 8 105 110 10.1158/1940-6207.CAPR-14-0320 PMC4315717 25416409

218. Kashyap D. Pal D. Sharma R. Garg V.K. Goel N. Koundal D. Zaguia A. Koundal S. Belay A. Global Increase in Breast Cancer Incidence: Risk Factors and Preventive Measures BioMed Res. Int. 2022 2022 9605439 10.1155/2022/9605439 35480139 PMC9038417

219. Smith-Turchyn J. McCowan M.E. O’Loughlin E. Fong A.J. McDonough M.H. Santa Mina D. Arbour-Nicitopoulos K.P. Trinh L. Jones J.M. Bender J.L. Connecting Breast Cancer Survivors for Exercise: Protocol for a Two-Arm Randomized Controlled Trial BMC Sports Sci. Med. Rehabil. 2021 13 128 10.1186/s13102-021-00341-w 34649590 PMC8515152

220. Pulliero A. You M. Chaluvally-Raghavan P. Marengo B. Domenicotti C. Banelli B. Degan P. Molfetta L. Gianiorio F. Izzotti A. Anticancer Effect of Physical Activity Is Mediated by Modulation of Extracellular MicroRNA in Blood Oncotarget 2020 11 2106 2119 10.18632/oncotarget.27609 32547708 PMC7275780

221. Dufresne S. Rébillard A. Muti P. Friedenreich C.M. Brenner D.R. A Review of Physical Activity and Circulating MiRNA Expression: Implications in Cancer Risk and Progression Cancer Epidemiol. Biomark. Prev. 2018 27 11 24 10.1158/1055-9965.EPI-16-0969 29141851

222. Figueira A. Cortinhas A. Soares J. Leitão J. Ferreira R. Duarte J. Efficacy of Exercise on Breast Cancer Outcomes: A Systematic Review and Meta-Analysis of Preclinical Data Int. J. Sports Med. 2018 39 327 342 10.1055/s-0044-101149 29564842

223. Isanejad A. Alizadeh A.M. Amani Shalamzari S. Khodayari H. Khodayari S. Khori V. Khojastehnjad N. MicroRNA-206, Let-7a and MicroRNA-21 Pathways Involved in the Anti-Angiogenesis Effects of the Interval Exercise Training and Hormone Therapy in Breast Cancer Life Sci. 2016 151 30 40 10.1016/j.lfs.2016.02.090 26924493

224. Akao Y. Nakagawa Y. Naoe T. Let-7 MicroRNA Functions as a Potential Growth Suppressor in Human Colon Cancer Cells Biol. Pharm. Bull. 2006 29 903 906 10.1248/bpb.29.903 16651716

225. Liu L.-Z. Li C. Chen Q. Jing Y. Carpenter R. Jiang Y. Kung H.-F. Lai L. Jiang B.-H. MiR-21 Induced Angiogenesis through AKT and ERK Activation and HIF-1α Expression PLoS ONE 2011 6 e19139 10.1371/journal.pone.0019139 21544242 PMC3081346

226. Telles G.D. Libardi C.A. Conceição M.S. Vechin F.C. Lixandrão M.E. De Andrade A.L.L. Guedes D.N. Ugrinowitsch C. Camera D.M. Time Course of Skeletal Muscle MiRNA Expression after Resistance, High-Intensity Interval, and Concurrent Exercise Med. Sci. Sports Exerc. 2021 53 1708 1718 10.1249/MSS.0000000000002632 33731656

227. Ogasawara R. Akimoto T. Umeno T. Sawada S. Hamaoka T. Fujita S. MicroRNA Expression Profiling in Skeletal Muscle Reveals Different Regulatory Patterns in High and Low Responders to Resistance Training Physiol. Genom. 2016 48 320 324 10.1152/physiolgenomics.00124.2015 26850043

228. D’Souza R.F. Markworth J.F. Aasen K.M.M. Zeng N. Cameron-Smith D. Mitchell C.J. Acute Resistance Exercise Modulates MicroRNA Expression Profiles: Combined Tissue and Circulatory Targeted Analyses PLoS ONE 2017 12 e0181594 10.1371/journal.pone.0181594 28750051 PMC5531502

229. Nielsen S. Åkerström T. Rinnov A. Yfanti C. Scheele C. Pedersen B.K. Laye M.J. The MiRNA Plasma Signature in Response to Acute Aerobic Exercise and Endurance Training PLoS ONE 2014 9 e87308 10.1371/journal.pone.0087308 24586268 PMC3929352

230. Baggish A.L. Park J. Min P.-K. Isaacs S. Parker B.A. Thompson P.D. Troyanos C. D’Hemecourt P. Dyer S. Thiel M. Rapid Upregulation and Clearance of Distinct Circulating MicroRNAs after Prolonged Aerobic Exercise J. Appl. Physiol. 2014 116 522 531 10.1152/japplphysiol.01141.2013 24436293 PMC3949215

231. Cui W. Zhang S. Shan C. Zhou L. Zhou Z. MicroRNA-133a Regulates the Cell Cycle and Proliferation of Breast Cancer Cells by Targeting Epidermal Growth Factor Receptor through the EGFR/Akt Signaling Pathway FEBS J. 2013 280 3962 3974 10.1111/febs.12398 23786162

232. Hagstrom A. Denham J. MicroRNAs in High and Low Responders to Resistance Training in Breast Cancer Survivors Int. J. Sports Med. 2018 39 482 489 10.1055/a-0592-7691 29698983

233. Alizadeh S. Isanejad A. Sadighi S. Khalighfard S. Alizadeh A.M. Effect of a High-Intensity Interval Training on Serum MicroRNA Levels in Women with Breast Cancer Undergoing Hormone Therapy. A Single-Blind Randomized Trial Ann. Phys. Rehabil. Med. 2019 62 329 335 10.1016/j.rehab.2019.07.001 31400480

234. Tansathitaya V. Sarasin W. Phakham T. Sawaswong V. Chanchaem P. Payungporn S. Regulation of Mi-RNAs Target Cancer Genes Between Exercise and Non-Exercise in Rat Rheumatoid Arthritis Induction: Pilot Study Epigenet. Insights 2022 15 25168657221110484 10.1177/25168657221110485 PMC9253985 35800470

235. Yan B. Zhao L. Guo J. Zhao J. MiR-206 Regulates the Growth of the Teleost Tilapia (Oreochromis Niloticus) through the Modulation of IGF-1 Gene Expression J. Exp. Biol. 2012 216 1265 1269 10.1242/jeb.079590 23197102

236. Joyce D.P. Kerin M.J. Dwyer R.M. Exosome-Encapsulated MicroRNAs as Circulating Biomarkers for Breast Cancer: Exosomal MicroRNAs as Circulating Biomarkers for Breast Cancer Int. J. Cancer 2016 139 1443 1448 10.1002/ijc.30179 27170104

237. Min W. Wang B. Li J. Han J. Zhao Y. Su W. Dai Z. Wang X. Ma Q. The Expression and Significance of Five Types of MiRNAs in Breast Cancer Med. Sci. Monit. Basic Res. 2014 20 97 104 10.12659/MSMBR.891246 25047098 PMC4117676

238. Georgantas R.W. Streicher K. Luo X. Greenlees L. Zhu W. Liu Z. Brohawn P. Morehouse C. Higgs B.W. Richman L. MicroRNA-206 Induces G1 Arrest in Melanoma by Inhibition of CDK4 and Cyclin D Pigment. Cell Melanoma Res. 2014 27 275 286 10.1111/pcmr.12200 24289491

239. Idorn M. Hojman P. Exercise-Dependent Regulation of NK Cells in Cancer Protection Trends Mol. Med. 2016 22 565 577 10.1016/j.molmed.2016.05.007 27262760

240. Evans E.S. Hackney A.C. McMurray R.G. Randell S.H. Muss H.B. Deal A.M. Battaglini C.L. Impact of Acute Intermittent Exercise on Natural Killer Cells in Breast Cancer Survivors Integr. Cancer Ther. 2015 14 436 445 10.1177/1534735415580681 25873292

241. Pedersen L. Idorn M. Olofsson G.H. Lauenborg B. Nookaew I. Hansen R.H. Johannesen H.H. Becker J.C. Pedersen K.S. Dethlefsen C. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution Cell Metab. 2016 23 554 562 10.1016/j.cmet.2016.01.011 26895752

242. Dong P. Xiong Y. Yue J. Xu D. Ihira K. Konno Y. Kobayashi N. Todo Y. Watari H. Long Noncoding RNA NEAT1 Drives Aggressive Endometrial Cancer Progression via MiR-361-Regulated Networks Involving STAT3 and Tumor Microenvironment-Related Genes J. Exp. Clin. Cancer Res. 2019 38 295 10.1186/s13046-019-1306-9 31287002 PMC6615218

243. Huo X.-L. Wang S.-F. Yang Q. Yu X.-L. Gu T. Hua H.-X. Yang M. Bai L.-L. Zhang X.-L. Diagnostic and Prognostic Value of Genomic Instability-Derived Long Non-Coding RNA Signature of Endometrial Cancer Taiwan J. Obs. Gynecol. 2022 61 96 101 10.1016/j.tjog.2021.11.018 35181055

244. Shetty A. Venkatesh T. Kabbekodu S.P. Tsutsumi R. Suresh P.S. LncRNA-MiRNA-MRNA Regulatory Axes in Endometrial Cancer: A Comprehensive Overview Arch. Gynecol. Obstet. 2022 10.1007/s00404-022-06423-5 35182183

245. Lv Y. Lv Y. Wang Z. Yuan K. Zeng Y. Noncoding RNAs as sensors of tumor microenvironmental stress J. Exp. Clin. Cancer Res. 2022 1 20 10.1186/s13046-022-02433-y 35842651 PMC9288030

246. Peng X. Gao H. Xu R. Wang H. Mei J. Liu C. The interplay between HIF-1α and noncoding RNAs in cancer J. Exp. Clin. Cancer Res. 2020 39 1 19 10.1186/s13046-020-1535-y 32122375 PMC7053112

247. Sallé-Lefort S. Miard S. Nolin M.A. Boivin L. Paré M.È. Debigaré R. Picard F. Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1α axis Int. J. Oncol. 2016 49 1731 1736 10.3892/ijo.2016.3630 27499160

248. Zhou C. Ye L. Jiang C. Bai J. Chi Y. Zhang H. Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1α activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer Tumor Biol. 2015 36 9179 9188 10.1007/s13277-015-3453-8 26088446

249. Wu W. Hu Q. Nie E. Yu T. Wu Y. Zhi T. Jiang K. Shen F. Wang Y. Zhang J. Hypoxia induces H19 expression through direct and indirect Hif-1α activity, promoting oncogenic effects in glioblastoma Sci. Rep. 2017 7 45029 10.1038/srep45029 28327666 PMC5361208

250. Di Agostino S. Vahabi M. Turco C. Fontemaggi G. Secreted Non-Coding RNAs: Functional Impact on the Tumor Microenvironment and Clinical Relevance in Triple-Negative Breast Cancer Non-Coding RNA 2022 8 5 10.3390/ncrna8010005 35076579 PMC8788502

251. Baba A.I. Catoi C. Comparative Oncology. Chapter 2: Carcinogenesis The Publishing House of the Romanian Academy Bucharest, Romania 2007 Available online: https://www.ncbi.nlm.nih.gov/books/NBK9552/ (accessed on 1 August 2022) 20806453

252. Dolci M. Favero C. Toumi W. Favi E. Tarantini L. Signorini L. Basile G. Bollati V. D’Alessandro S. Bagnoli P. Human Endogenous Retroviruses Long Terminal Repeat Methylation, Transcription, and Protein Expression in Human Colon Cancer Front. Oncol. 2020 10 2145 10.3389/fonc.2020.569015 PMC7653092 33194657

253. Sun X. Li Q. Yang L. Sevoflurane Inhibits lncRNA HOTAIR-Modulated Stability of HK2 mRNA in a m6A-Dependent Manner to Dampen Aerobic Glycolysis and Proliferation in Lung Cancer BioMed Res. Int. 2022 2022 4668774 10.1155/2022/4668774 35845960 PMC9279057

254. Zhang P. Liu X. Pan G. Xu J. Shen B. Ding X. Lv W. LINC00518 Promotes Cell Malignant Behaviors via Influencing EIF4A3-Mediated mRNA Stability of MITF in Melanoma BioMed Res. Int. 2022 2022 3546795 10.1155/2022/3546795 35813236 PMC9262545

255. Xie W. Chang W. Wang X. Liu F. Wang X. Yuan D. Zhang Y. Allicin Inhibits Osteosarcoma Growth by Promoting Oxidative Stress and Autophagy via the Inactivation of the lncRNA MALAT1-miR-376a-Wnt/β-Catenin Signaling Pathway Oxid. Med. Cell. Longev. 2022 2022 4857814 10.1155/2022/4857814 35783190 PMC9249524

256. Wang X. Yu H. Yu Z. Wang D. Exosomal lncRNA HEIH promotes cisplatin resistance in tongue squamous cell carcinoma via targeting miR-3619-5p/HDGF axis Acta Histochem. 2020 122 151647 10.1016/j.acthis.2020.151647 33130420

257. Wan T. Wang H. Gou M. Si H. Wang Z. Yan H. Liu T. Chen S. Fan R. Qian N. LncRNA HEIH promotes cell proliferation, migration and invasion in cholangiocarcinoma by modulating miR-98-5p/HECTD4. Biomed Biomed. Pharmacother. 2020 125 109916 10.1016/j.biopha.2020.109916 32062383

258. Cui C. Zhai D. Cai L. Duan Q. Xie L. Yu J. Long noncoding rna heih promotes colorectal cancer tumorigenesis via counteracting mir-939-mediated transcriptional repression of Bcl-Xl Cancer Res. Treat. 2018 50 992 1008 10.4143/crt.2017.226 29081216 PMC6056985

259. Chen L. Niu W. Zhu D. Shao W. Qian Y. Long noncoding RNA HOXD-AS1 promotes the progression of pancreatic cancer through miR-664b-3p/PLAC8 axis Pathol. Res. Pract. 2022 232 153836 10.1016/j.prp.2022.153836 35279480

260. Jiang Y. Zhao H. Chen Y. Li K. Li T. Chen J. Zhang B. Guo C. Qing L. Shen J. Exosomal long noncoding RNA HOXD-AS1 promotes prostate cancer metastasis via miR-361-5p/FOXM1 axis Cell Death Dis. 2022 12 1129 10.1038/s41419-021-04421-0 PMC8643358 34864822

261. Chen S. Li K. HOXD-AS1 facilitates cell migration and invasion as an oncogenic lncRNA by competitively binding to miR-877-3p and upregulating FGF2 in human cervical cancer BMC Cancer 2020 20 924 10.1186/s12885-020-07441-9 32977766 PMC7519495

262. Dong S. Wang R. Wang H. Ding Q. Zhou X. Wang J. Zhang K. Long Y. Lu S. Hong T. HOXD-AS1 promotes the epithelial to mesenchymal transition of ovarian cancer cells by regulating miR-186-5p and PIK3R3 J. Exp. Clin. Cancer Res. 2019 38 110 10.1186/s13046-019-1103-5 30823895 PMC6397490

263. Long J. Pi X. LncRNA-MEG3 suppresses the proliferation and invasion of melanoma by regulating CYLD expression mediated by sponging miR-499-5p BioMed Res. Int. 2018 2018 2086564 10.1155/2018/2086564 29808164 PMC5902079

264. Wang Z. Yang B. Zhang J. Chu X. Long Noncoding RNA LINC01554 Inhibits the Progression of NSCLC Progression by Functioning as a ceRNA for miR-1267 and Regulating ING3/Akt/mTOR Pathway BioMed Res. Int. 2022 2022 7162623 10.1155/2022/7162623 35845928 PMC9286878

265. Liang Y. Wang H. Song R. Yin X. lncRNA FOXD2-AS1 Promotes the Retinoblastoma Cell Viability and Migration by Sponging miR-31 BioMed Res. Int. 2022 2022 1 11 10.1155/2022/7723425 PMC9246629 35782084

266. Tie W. Ge F. MALAT1 Inhibits Proliferation of HPV16-Positive Cervical Cancer by Sponging miR-485-5p to Promote Expression of MAT2A DNA Cell Biol. 2021 40 1407 1417 10.1089/dna.2020.6205 34610246

267. Zhao T. Zhang J. Ye C. Tian L. Li Y. LncRNA FOXD2-AS1 promotes hemangioma progression through the miR-324-3p/PDRG1 pathway Cancer Cell Int. 2020 20 1 8 10.1186/s12935-020-01277-w 32489325 PMC7247140

268. Liu X. Fu Q. Li S. Liang N. Li F. Li C. Sui C. Dionigi G. Sun H. LncRNA FOXD2-AS1 functions as a competing endogenous RNA to regulate TERT expression by sponging miR-7-5p in thyroid cancer Front. Endocrinol. 2019 10 207 10.3389/fendo.2019.00207 31024447 PMC6463795

269. Ying H. Jin Y. Guo Y. Li Q. Ruan M. Zhu W. Yang C. Li Q. Zheng L. Long non-coding RNA NUT family member 2A-antisense RNA 1 sponges microRNA-613 to increase the resistance of gastric cancer cells to matrine through regulating oxidative stress and vascular endothelial growth factor A Aging 2022 14 5153 5162 10.18632/aging.204135 35771149 PMC9271296

270. Chen J. Liu A. Wang Z. Wang B. Chai X. Lu W. Cao T. Li R. Wu M. Lu Z. LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression Mol. Cancer 2020 19 1 19 10.1186/s12943-020-01217-2 32473645 PMC7260858

271. Wang Y. Mei X. Song W. Wang C. Qiu X. LncRNA LINC00511 promotes COL1A1—Mediated proliferation and metastasis by sponging miR-126-5p/miR-218-5p in lung adenocarcinoma BMC Pulm. Med. 2022 22 272 10.1186/s12890-022-02070-3 35842617 PMC9287882

272. Liu B. Zhou F. Liu H. Wang Y. Wang J. Ren F. Xu S. Knockdown of LINC00511 decreased cisplatin resistance in non-small cell lung cancer by elevating miR-625 level to suppress the expression of leucine rich repeat containing eight volume-regulated anion channel subunit E Hum. Exp. Toxicol. 2022 41 09603271221089000 10.1177/09603271221089000 35363093

273. Hu Y. Zhang Y. Ding M. Xu R. Lncrna linc00511 acts as an oncogene in colorectal cancer via sponging mir-29c-3p to upregulate nfia OncoTargets Ther. 2020 13 13413 13424 10.2147/OTT.S250377 PMC7847767 33536761

274. Zhong M.E. Chen Y. Zhang G. Xu L. Ge W. Wu B. LncRNA H19 regulates PI3K-Akt signal pathway by functioning as a ceRNA and predicts poor prognosis in colorectal cancer: Integrative analysis of dysregulated ncRNA-associated ceRNA network Cancer Cell Int. 2019 19 1 13 10.1186/s12935-019-0866-2 31164794 PMC6543669

275. Azizidoost S. Ghaedrahmati F. Anbiyaee O. Ahmad Ali R. Cheraghzadeh M. Farzaneh M. Emerging roles for lncRNA-NEAT1 in colorectal cancer Cancer Cell Int. 2022 22 1 10 10.1186/s12935-022-02627-6 35676702 PMC9178824

276. Mofidi M. Rahgozar S. Pouyanrad S. Increased level of long non coding RNA H19 is correlated with the downregulation of miR-326 and BCL-2 genes in pediatric acute lymphoblastic leukemia, a possible hallmark for leukemogenesis Mol. Biol. Rep. 2021 48 1531 1538 10.1007/s11033-021-06161-y 33580459

277. Zhang D. Fang C. Li H. Lu C. Huang J. Pan J. Yang Z. Liang E. Liu Z. Zhou X. Long ncRNA MALAT1 promotes cell proliferation, migration, and invasion in prostate cancer via sponging miR-145 Transl. Androl. Urol. 2021 10 2307 2319 10.21037/tau-20-1526 34295718 PMC8261405

278. Gong Z. Zhang Y. Jiang Y. Chen P. Ji J. LncRNA NEAT1 Targets miR-342-3p/CUL4B to Inhibit the Proliferation of Cutaneous Squamous Cell Carcinoma Cells J. Oncol. 2022 2022 1 8 10.1155/2022/8145129 35909905 PMC9337941

279. Liu R.J. Xu Z.P. Li S.Y. Yu J.J. Feng N.H. Xu B. Chen M. BAP1-Related ceRNA (NEAT1/miR-10a-5p/SERPINE1) Promotes Proliferation and Migration of Kidney Cancer Cells Front. Oncol. 2022 12 1 8 10.3389/fonc.2022.852515 PMC9004599 35425712

280. Ge J. Wang B. Zhao S. Xu J. Inhibition of lncRNA NEAT1 sensitizes medulloblastoma cells to cisplatin through modulating the miR-23a-3p-glutaminase (GLS) axis Bioengineered 2022 13 7670 7682 10.1080/21655979.2021.2008695 35313796 PMC9208477

281. Luo Y. Chen J.J. Lv Q. Qin J. Huang Y.Z. Yu M.H. Zhong M. Long non-coding RNA NEAT1 promotes colorectal cancer progression by competitively binding miR-34a with SIRT1 and enhancing the Wnt/β-catenin signaling pathway Cancer Lett. 2019 440–441 11 22 10.1016/j.canlet.2018.10.002 30312725

282. Liu H. Li A. Sun Z. Zhang J. Xu H. Long non-coding RNA NEAT1 promotes colorectal cancer progression by regulating miR-205-5p/VEGFA axis. Hum Cell 2020 33 386 396 10.1007/s13577-019-00301-0 32065361

283. Lu Y. Guo G. Hong R. Chen X. Sun Y. Liu F. Zhang Z. Jin X. Dong J. Yu K. LncRNA HAS2-AS1 Promotes Glioblastoma Proliferation by Sponging miR-137 Front. Oncol. 2021 11 1 10 10.3389/fonc.2021.634893 PMC8173206 34094916

284. Xu Y. Qian C. Liu C. Fu Y. Zhu K. Niu Z. Liu J. Investigation of the Mechanism of hsa_circ_000 1429 Adsorbed miR-205 to Regulate KDM4A and Promote Breast Cancer Metastasis Contrast Media Mol. Imaging 2022 2022 1 9 10.1155/2022/4657952 PMC9239777 35833065

285. Huang J. Zhou H. Diao Y. Yang Z. Hsa_circ_0000285 knockdown inhibits the progression of hepatocellular carcinoma by sponging miR-582-3p to regulate CCNB2 expression Hum. Exp. Toxicol. 2022 41 1 13 10.1177/09603271221115400 35839486

286. Wang X. Tan M. Huang H. Zou Y. Wang M. Hsa_circ_0000285 contributes to gastric cancer progression by upregulating FN1 through the inhibition of miR-1278 J. Clin. Lab. Anal. 2022 36 e24475 10.1002/jcla.24475 35535385 PMC9169205

287. Zhang B. Li Q. Song Z. Ren L. Gu Y. Feng C. Wang J. Liu T. Hsa_circ_0000285 facilitates thyroid cancer progression by regulating miR-127-5p/CDH2 J. Clin. Lab. Anal. 2022 36 e24421 10.1002/jcla.24421 35447001 PMC9279989

288. He W. Li D. Zhang X. LncRNA HOTAIR promotes the proliferation and invasion/metastasis of breast cancer cells by targeting the miR-130a-3p/Suv39H1 axis Biochem. Biophys. Rep. 2022 30 101279 10.1016/j.bbrep.2022.101279 35619625 PMC9126846

289. Zhang W. Zhang S. Downregulation of circrna_0000285 suppresses cervical cancer development by regulating mir197-3p–ELK1 axis Cancer Manag. Res. 2020 12 8663 8674 10.2147/CMAR.S253174 32982457 PMC7509321

290. Deng T. Liu Y. Yang Y. Yuan L. Liu F. Wang X. Zhang Q. Xie M. Regulation of microRNA miR-197-3p/CDC28 protein kinase regulatory subunit 1B (CKS1B) axis by Circular RNA hsa_circ_0000285 promotes glioma progression Bioengineered 2022 13 4757 4772 10.1080/21655979.2022.2031673 35174774 PMC8974215

291. Xu P. Wang L. Liu Q. Gao P. Hu F. Xie X. Jiang L. Bi R. Ding F. The abnormal expression of circ-ARAP2 promotes ESCC progression through regulating miR-761/FOXM1 axis-mediated stemness and the endothelial-mesenchymal transition J. Transl. Med. 2022 20 1 13 10.1186/s12967-022-03507-3 35842667 PMC9287963

292. Wang H. Feng L. Cheng D. Zheng Y. Xie Y. Fu B. Circular RNA MAT2B promotes migration, invasion and epithelial-mesenchymal transition of non-small cell lung cancer cells by sponging miR-431 Cell Cycle 2021 20 1617 1627 10.1080/15384101.2021.1956106 34288814 PMC8409757

293. Zhao J.P. Chen L.L. Circular RNA MAT2B Induces Colorectal Cancer Proliferation via Sponging miR-610, Resulting in an Increased E2F1 Expression Cancer Manag. Res. 2020 12 7107 7116 10.2147/CMAR.S251180 32848465 PMC7429114

294. Liu J. Liu H. Zeng Q. Xu P. Liu M. Yang N. Circular RNA circ-MAT2B facilitates glycolysis and growth of gastric cancer through regulating the miR-515-5p/HIF-1α axis Cancer Cell Int. 2020 20 1 12 10.1186/s12935-020-01256-1 32467667 PMC7231419

295. Li Q. Pan X. Zhu D. Deng Z. Jiang R. Wang X. Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma through the miR-338-3p/PKM2 Axis under Hypoxic Stress Hepatology 2019 70 1298 1316 10.1002/hep.30671 31004447

296. Fu K. Zhang K. Zhang X. LncRNA HOTAIR facilitates proliferation and represses apoptosis of retinoblastoma cells through the miR-20b-5p/RRM2/PI3K/AKT axis Orphanet J. Rare Dis. 2022 17 1 15 10.1186/s13023-022-02206-y 35248107 PMC8898492

297. Zhang J. Li N. Fu J. Zhou W. Long noncoding RNA HOTAIR promotes medulloblastoma growth, migration and invasion by sponging miR-1/miR-206 and targeting YY1 Biomed. Pharmacother. 2020 124 109887 10.1016/j.biopha.2020.109887 31986414

298. Wang W. Wu D. He X. Hu X. Hu C. Shen Z. Lin J. Pan Z. He Z. Lin H. CCL18-induced HOTAIR upregulation promotes malignant progression in esophageal squamous cell carcinoma through the miR-130a-5p-ZEB1 axis Cancer Lett. 2019 460 18 28 10.1016/j.canlet.2019.06.009 31207321

299. Shen R. Cai X. Shen D. Zhang R. Zhang W. Zhang Y. Li Y. Wang A. Zeng Y. Zhu J. An Long noncoding RNA LINC00518 contributes to proliferation and metastasis in lung adenocarcinoma via the miR-335-3p/CTHRC1 Axis Cell Death Discov. 2022 8 1 12 10.1038/s41420-022-00905-w 35246517 PMC8897435

300. Jia Z. Wang Y. Sun X. Zhao X. Zhang Y. Xu S. Wang Y. Li Y. Effect of lncRNA XLOC_005950 knockout by CRISPR/Cas9 gene editing on energy metabolism and proliferation in osteosarcoma MG63 cells mediated by hsa-miR-542-3p Oncol. Lett. 2021 22 1 12 10.3892/ol.2021.12930 34386091 PMC8298990

301. Zhang Y. Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer J. Hematol. Oncol. 2020 13 1 16 10.1186/s13045-020-00990-3 33276800 PMC7716495

302. Khan K.H. Yap T.A. Yan L. Cunningham D. Targeting the PI3K-AKT-mTOR singnaling network in cancer Chin. J. Cancer 2013 32 253 265 10.5732/cjc.013.10057 23642907 PMC3845556

303. Bolha L. Ravnik-Glavač M. Glavač D. Long Noncoding RNAs as Biomarkers in Cancer Dis. Markers 2017 2017 7243968 10.1155/2017/7243968 28634418 PMC5467329

304. Grillone K. Riillo C. Riillo C. Scionti F. Rocca R. Rocca R. Tradigo G. Guzzi P.H. Alcaro S. Alcaro S. Non-coding RNAs in cancer: Platforms and strategies for investigating the genomic “dark matter” J. Exp. Clin. Cancer Res. 2020 39 1 19 10.1186/s13046-020-01622-x 32563270 PMC7305591

305. Toden S. Zumwalt T.J. Goel A. Non-coding RNAs and potential therapeutic targeting in cancer Biochim. Biophys. Acta (BBA)—Rev. Cancer 2021 1875 188491 10.1016/j.bbcan.2020.188491 PMC7856203 33316377

306. Winkle M. El-Daly S.M. Fabbri M. Calin G.A. Noncoding RNA therapeutics—Challenges and potential solutions Nat. Rev. Drug Discov. 2021 20 629 651 10.1038/s41573-021-00219-z 34145432 PMC8212082

307. Wang W.T. Han C. Sun Y.M. Chen T.Q. Chen Y.Q. Noncoding RNAs in cancer therapy resistance and targeted drug development J. Hematol. Oncol. 2019 12 1 15 10.1186/s13045-019-0748-z 31174564 PMC6556047

308. Hong D.S. Kang Y.K. Borad M. Sachdev J. Ejadi S. Lim H.Y. Brenner A.J. Park K. Lee J.L. Kim T.Y. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours Br. J. Cancer 2020 122 1630 1637 10.1038/s41416-020-0802-1 32238921 PMC7251107

309. Scoles D.R. Minikel E.V. Pulst S.M. Antisense oligonucleotides: A primer. Neurol Genetics 2019 5 e323 10.1212/NXG.0000000000000323 PMC6501637 31119194

310. Chang H. Yi B. Ma R. Zhang X. Zhao H. Xi Y. CRISPR/cas9, a novel genomic tool to knock down microRNA in vitro and in vivo Sci. Rep. 2016 6 1 12 10.1038/srep22312 26924382 PMC4770416

311. Zhou S.J. Deng Y.L. Liang H.F. Jaoude J.C. Liu F.Y. Hepatitis B virus X protein promotes CREB-mediated activation of miR-3188 and notch signaling in hepatocellular carcinoma Cell Death Differ. 2017 24 1577 1587 10.1038/cdd.2017.87 28574502 PMC5563993

312. Hannafon B.N. Cai A. Calloway C.L. Xu Y.F. Zhang R. Fung K.M. Ding W.Q. MiR-23b and miR-27b are oncogenic microRNAs in breast cancer: Evidence from a CRISPR/Cas9 deletion study BMC Cancer 2019 19 642 10.1186/s12885-019-5839-2 31253120 PMC6599331

313. Nieland L. van Solinge T.S. Cheah P.S. Morsett L.M. El Khoury J. Rissman J.I. Kleinstiver B.P. Broekman M.L.D. Breakefield X.O. Abels E.R. CRISPR-Cas knockout of miR21 reduces glioma growth Mol. Ther. Oncolytics 2022 25 121 136 10.1016/j.omto.2022.04.001 35572197 PMC9052041

314. Ali H.S. Boshra M.S. El Meteini M.S. Shafei A.E.S. Matboli M. lncRNA- RP11-156p1.3, novel diagnostic and therapeutic targeting via CRISPR/Cas9 editing in hepatocellular carcinoma Genomics 2020 112 3306 3314 10.1016/j.ygeno.2020.06.020 32544548

315. Haghighi N. Doosti A. Kiani J. Evaluation of CRISPR/Cas9 System Effects on Knocking Out NEAT1 Gene in AGS Gastric Cancer Cell Line with Therapeutic Perspective J. Gastrointest. Cancer 2021 1 9 10.1007/s12029-021-00669-z 34357544

316. Zhen S. Hua L. Liu Y.H. Sun X.M. Jiang M.M. Chen W. Zhao L. Li X. Inhibition of long non-coding RNA UCA1 by CRISPR/Cas9 attenuated malignant phenotypes of bladder cancer Oncotarget 2017 8 9634 9646 10.18632/oncotarget.14176 28038452 PMC5354759

317. Christenson J.L. Butterfield K.T. Spoelstra N.S. Norris J.D. Josan J.S. Pollock J.A. McDonnell D.P. Katzenellenbogen B.S. Katzenellenbogen J.A. Richer J.K. MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression Horm. Cancer 2017 8 69 77 10.1007/s12672-017-0285-6 28194662 PMC5407486

318. Arun G. Diermeier S. Akerman M. Chang K.C. Wilkinson J.E. Hearn S. Kim Y. MacLeod A.R. Krainer A.R. Norton L. Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss Genes Dev. 2016 30 34 51 10.1101/gad.270959.115 26701265 PMC4701977

319. Gong N. Teng X. Li J. Liang X.J. Antisense Oligonucleotide-Conjugated Nanostructure-Targeting lncRNA MALAT1 Inhibits Cancer Metastasis ACS Appl. Mater. Interfaces 2019 11 37 42 10.1021/acsami.8b18288 30548064

320. Wang R. Sun Y. Li L. Niu Y. Lin W. Lin C. Antonarakis E.S. Luo J. Yeh S. Chang C. Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9 ® to Suppress Enzalutamide-resistant Prostate Cancer Progression Eur. Urol. 2017 72 835 844 10.1016/j.eururo.2017.04.005 28528814 PMC5802348

321. Dowdy S.F. Overcoming cellular barriers for RNA therapeutics Nat. Biotechnol. 2017 35 222 229 10.1038/nbt.3802 28244992

322. Adams D. Gonzalez-Duarte A. O’Riordan W.D. Yang C.-C. Ueda M. Kristen A.V. Tournev I. Schmidt H.H. Coelho T. Berk J.L. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis N. Engl. J. Med. 2018 379 11 21 10.1056/NEJMoa1716153 29972753

323. García-Pinel B. Porras-Alcalá C. Ortega-Rodríguez A. Sarabia F. Prados J. Melguizo C. López-Romero J.M. Lipid-based nanoparticles: Application and recent advances in cancer treatment Nanomaterials 2019 9 638 10.3390/nano9040638 PMC6523119 31010180

324. Zhang C. Ma Y. Zhang J. Kuo J.C.T. Zhang Z. Xie H. Zhu J. Liu T. Modification of Lipid-Based Nanoparticles: An Efficient Delivery System for Nucleic Acid-Based Immunotherapy Molecules 2022 27 1943 10.3390/molecules27061943 35335310 PMC8949521

325. Gagliardi A. Giuliano E. Venkateswararao E. Fresta M. Bulotta S. Awasthi V. Cosco D. Biodegradable Polymeric Nanoparticles for Drug Delivery to Solid Tumors Front. Pharmacol. 2021 12 17 10.3389/fphar.2021.601626 PMC7887387 33613290

326. Paunovska K. Loughrey D. Dahlman J.E. Drug delivery systems for RNA therapeutics Nat. Rev. Genet. 2022 23 265 280 10.1038/s41576-021-00439-4 34983972 PMC8724758

327. Kaczmarek J.C. Patel A.K. Kauffman K.J. Fenton O.S. Webber M.J. Heartlein M.W. DeRosa F. Anderson D.G. Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs Angew. Chem. Int. Ed. 2016 55 13808 13812 10.1002/anie.201608450 27690187 PMC5279893

328. Mukherjee A. Waters A.K. Kalyan P. Achrol A.S. Kesari S. Yenugonda V.M. Lipid-polymer hybrid nanoparticles as a nextgeneration drug delivery platform: State of the art, emerging technologies, and perspectives Int. J. Nanomed. 2019 14 1937 1952 10.2147/IJN.S198353 30936695 PMC6430183

329. Sivadasan D. Sultan M.H. Madkhali O. Almoshari Y. Thangavel N. Polymeric lipid hybrid nanoparticles (Plns) as emerging drug delivery platform—A comprehensive review of their properties, preparation methods, and therapeutic applications Pharmaceutics 2021 13 1921 10.3390/pharmaceutics13081291 34452251 PMC8399620

330. Liang H. Peng J. LncRNA HOTAIR promotes proliferation, invasion and migration in NSCLC cells via the CCL22 signaling pathway PLoS ONE 2022 17 e0263997 10.1371/journal.pone.0263997 35176085 PMC8853541

331. Wang G. Lin X. Han H. Zhang H. Li X. Feng M. Jiang C. lncRNA H19 promotes glioblastoma multiforme development by activating autophagy by sponging miR-491-5p Bioengineered 2022 13 11440 11455 10.1080/21655979.2022.2065947 35506168 PMC9275997

332. Salari P. Larijani B. Ethical Issues Surrounding Personalized Medicine: A Literature Review Acta Med. Iran. 2017 55 209 217 28282721

333. Fiore R.N. Goodman K.W. Precision Medicine Ethics: Selected Issues and Developments in next-Generation Sequencing, Clinical Oncology, and Ethics Curr. Opin. Oncol. 2016 28 83 87 10.1097/CCO.0000000000000247 26569425

334. Joly Y. Saulnier K.M. Osien G. Knoppers B.M. The ethical framing of personalized medicine Curr. Opin. Allergy Clin. Immunol. 2014 14 404 408 10.1097/ACI.0000000000000091 25054830

335. European Commission Europe’s Beating Cancer Plan Communication from the Commission to the European Parliament and the Council. Issued in February 2022 Available online: https://health.ec.europa.eu/system/files/2022-02/eu_cancer-plan_en_0.pdf (accessed on 20 July 2022)

336. European Commission Directorate General for Research and Innovation. Conquering Cancer: Mission Possible Publications Office Luxembourg 2020 Available online: https://op.europa.eu/en/publication-detail/-/publication/b389aad3-fd56-11ea-b44f-01aa75ed71a1/https://op.europa.eu/en/publication-detail/-/publication/b389aad3-fd56-11ea-b44f-01aa75ed71a1 (accessed on 20 July 2022)

337. Hickman J.A. Tannock I.F. Meheus L. Hutchinson L. The European Union and personalised cancer medicine Eur. J. Cancer 2021 150 95 98 10.1016/j.ejca.2021.03.013 33892410

338. Morgan A.A. Crawford D.C. Denny J.C. Mooney S.D. Aronow B.J. Brenner S.E. Precision medicine: Data and discovery for improved health and therapy Pac. Symp. Biocomput. 2017 22 348 355 10.1142/9789813207813_0033 27896988 PMC6192531

339. Morsella A. Cadeddu C. Castagna C. Hoxhaj I. Sassano M. Wang C.M. Wang L. Klessova S. de Belvis A.G. Boccia S. “Integrating China in the International Consortium for Personalized Medicine”: The Coordination and Support Action to Foster Collaboration in Personalized Medicine Development between Europe and China Public Health Genom. 2021 24 310 314 10.1159/000516264 34392247

340. McGowan M.L. Settersten R.A. Juengst E.T. Fishman J.R. Integrating genomics into clinical oncology: Ethical and social challenges from proponents of personalized medicine Urol. Oncol. Semin. Orig. Investig. 2014 32 187 192 10.1016/j.urolonc.2013.10.009 24445286 PMC3900115

341. Venne J. Busshoff U. Poschadel S. Menschel R. Evangelatos N. Vysyaraju K. Brand A. International Consortium for Personalized Medicine: An International Survey about the Future of Personalized Medicine Per. Med. 2020 17 89 100 10.2217/pme-2019-0093 32154758

342. Brothers K.B. Rothstein M.A. Ethical, legal and social implications of incorporating personalized medicine into healthcare Per. Med. 2015 12 43 51 10.2217/pme.14.65 25601880 PMC4296905

343. Vicente A.M. Ballensiefen W. Jönsson J.-I. How Personalised Medicine Will Transform Healthcare by 2030: The ICPerMed Vision J. Transl. Med. 2020 18 180 10.1186/s12967-020-02316-w 32345312 PMC7189458

344. Cesuroglu T. Syurina E. Feron F. Krumeich A. Other Side of the Coin for Personalised Medicine and Healthcare: Content Analysis of “personalised” Practices in the Literature BMJ Open 2016 6 e010243 10.1136/bmjopen-2015-010243 PMC4947721 27412099

345. Nimmesgern E. Norstedt I. Draghia-Akli R. Enabling Personalized Medicine in Europe by the European Commission’s Funding Activities Per. Med. 2017 14 355 365 10.2217/pme-2017-0003 29749834

346. Horgan D. Bernini C. Thomas P.P.M. Morre S.A. Cooperating on Data: The Missing Element in Bringing Real Innovation to Europe’s Healthcare Systems Public Health Genom. 2019 22 77 101 10.1159/000503296 PMC6943808 31634895

347. He K.Y. Ge D. He M.M. Big Data Analytics for Genomic Medicine Int. J. Mol. Sci. 2017 18 412 10.3390/ijms18020412 PMC5343946 28212287

348. Wagner J.K. Mozersky J.T. Pyeritz R.E. “Use It or Lose It” as an Alternative Approach to Protect Genetic Privacy in Personalized Medicine Urol. Oncol. 2014 32 198 201 10.1016/j.urolonc.2013.09.016 24445287 PMC3970576

349. Hong H. Zhang W. Shen J. Su Z. Ning B. Han T. Perkins R. Shi L. Tong W. Critical Role of Bioinformatics in Translating Huge Amounts of Next-Generation Sequencing Data into Personalized Medicine Sci. China Life Sci. 2013 56 110 118 10.1007/s11427-013-4439-7 23393026

350. Borry P. Bentzen H.B. Budin-Ljøsne I. Cornel M.C. Howard H.C. Feeney O. Jackson L. Mascalzoni D. Mendes Á. Peterlin B. The Challenges of the Expanded Availability of Genomic Information: An Agenda-Setting Paper J. Community Genet. 2018 9 103 116 10.1007/s12687-017-0331-7 28952070 PMC5849701

351. Clarke A.J. Managing the Ethical Challenges of Next-Generation Sequencing in Genomic Medicine Br. Med. Bull 2014 111 17 30 10.1093/bmb/ldu017 25122627

352. Shabaruddin F.H. Fleeman N.D. Payne K. Economic Evaluations of Personalized Medicine: Existing Challenges and Current Developments Pharmgenom. Pers. Med. 2015 8 115 126 10.2147/PGPM.S35063 26309416 PMC4538689

353. Gavan S.P. Thompson A.J. Payne K. The Economic Case for Precision Medicine Expert Rev. Precis. Med. Drug Dev. 2018 3 1 9 10.1080/23808993.2018.1421858 29682615 PMC5890303

354. Callier S.L. Abudu R. Mehlman M.J. Singer M.E. Neuhauser D. Caga-Anan C. Wiesner G.L. Ethical, Legal, and Social Implications of Personalized Genomic Medicine Research: Current Literature and Suggestions for the Future Bioethics 2016 30 698 705 10.1111/bioe.12285 27767224

355. Marchant G.E. Lindor R.A. Personalized medicine and genetic malpractice Genet. Med. 2013 15 921 922 10.1038/gim.2013.142 24071800 PMC4120832

356. Marchant G. Barnes M. Evans J.P. LeRoy B. Wolf S.M. LawSeq Liability Task Force from Genetics to Genomics: Facing the Liability Implications in Clinical Care J. Law Med. Ethics 2020 48 11 43 10.1177/1073110520916994 PMC7433684 32342786

357. Ledford H. US Personalized-Medicine Industry Takes Hit from Supreme Court Nature 2016 536 382 10.1038/nature.2016.20436 27558042