A disulfidptosis-related lncRNA prognostic model identifies MALINC1 as a regulator of platinum drug sensitivity in colon adenocarcinoma.

BACKGROUND

Triggering tumor cell death still serves as the core and ultimate goal to restrict tumors including colorectal cancer, a highly lethal malignant alimentary canal tumor. Disulfidptosis, a newly defined form of programmed cell death, offers a new potential possibility for anti-tumor purposes. Studies have shown that long non-coding RNAs (lncRNAs) are involved in the regulation of tumor disulfidptosis, however, their role in colorectal cancer is yet poorly defined. In this study, we aim to explore the relationship between lncRNAs and disulfidptosis in colorectal cancer.

METHODS

We used RNA sequencing data of patients with colon adenocarcinoma (COAD) from The Cancer Genome Atlas (TCGA) to screen disulfidptosis-related lncRNAs via correlation analysis. Univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression algorithm were performed to identify key disulfidptosis-related lncRNAs and develop prognostic model. After each sample was labelled with risk score, Kaplan-Meier (KM) and receiver operating characteristic (ROC) curve analyses were conducted in both high risk-score and low risk-score groups. Additionally, quantitative polymerase chain reaction (qPCR) was used to assess expression pattern of key disulfidptosis-related lncRNAs in colon cancer cell lines. Cell Counting Kit-8 (CCK-8) assay, cell colony formation assay, cell counting assay were employed to investigate the roles of MALINC1 in colon cancer growth. Deeply, free thiol and glutathione (GSH) content assay and the protein level of disulfidptosis key player SLC7A11 were further implemented to study the relationship between MALINC1 and disulfidptosis. Furthermore, the effect of MALINC1 on the sensitivity of COAD cell lines to platinum-based drugs by CCK-8 assay, cell colony formation assay and cell counting assay.

RESULTS

We identified six key disulfidptosis-related lncRNAs, AL354993.2, AP003555.1, MALINC1, AC013652.1, AC074212.1 and AC007128.1. The prognostic model we developed successfully predict survival of patients with COAD. One of the six key disulfidptosis-related lncRNAs, MALINC1, is highly expressed in COAD cell lines HCT8 and SW480. Knockdown of MALINC1 markedly suppressed cell proliferation, reduced intracellular free sulfhydryl groups and GSH, and upregulated SLC7A11. Moreover, MALINC1 knockdown enhanced the sensitivity of these cells to platinum-based drugs.

CONCLUSIONS

These findings suggest that a prognostic model based on six key disulfidptosis-related lncRNAs holds potential for predicting outcomes in patients with COAD, and that targeting MALINC1 may offer new insights into colorectal cancer chemotherapy.