Fibromodulin positively regulated by Androgen Receptor, promotes prostate cancer progression via the PI3K/AKT signaling pathway and epithelial-medenchymal transition.

BACKGROUND

The progression of prostate cancer is predominantly driven by androgen receptor (AR) signaling; however, its downstream effector molecules are not fully characterized. Fibromodulin (FMOD), a proteoglycan with established roles in other cancers, has recently been implicated in prostate cancer; however, the precise molecular mechanisms underlying its regulation and oncogenic function remain elusive. Here, we sought to elucidate the functional role of FMOD and its regulation by the AR and the subsequent activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling axis.

METHODS

FMOD expression levels across multiple prostate cancer cell lines were quantified by qRT-PCR and Western blot analysis. To investigate its function, transient knockdown using small interfering RNA (siRNA) was Performed in LNCaP and 22Rv1 cells, while lentiviral-mediated overexpression of FMOD was established in LNCap cells, to assess cellular proliferation, migration, invasion, and cell cycle distribution in vitro. For in vivo studies, a stable FMOD-knockdown model was established using lentiviral-mediated shRNA to evaluate tumor growth in xenograft mice. Putative upstream transcription factors were predicted using the JASPAR database and validated through AR knockdown experiments. Downstream signaling pathways, specifically PI3K/AKT and epithelial-mesenchymal transition (EMT), were analyzed via Western blot.

RESULTS

FMOD was highly expressed in LNCaP and 22Rv1 cells. FMOD knockdown markedly suppressed cell proliferation, induced cell cycle arrest, and inhibited migration and invasion by reversing the EMT process. In vivo experiments confirmed that FMOD depletion significantly retarded tumor growth. Mechanistically, we identified FMOD as a transcriptional target positively regulated by AR. Furthermore, FMOD facilitated cancer progression by activating the PI3K/AKT signaling pathway.

CONCLUSION

Our findings delineate a critical AR-FMOD-PI3K/AKT signaling axis in prostate cancer progression. FMOD serves as a key downstream effector of AR and may represent a promising therapeutic target for clinical intervention.