Unlocking the Therapeutic Potential: Harnessing miR-125a-5p To Enhance Autophagy and Apoptosis in Pancreatic Cancer through Targeting STAT3.

Abstract

Objectives: miR-125a-5p's role in various cancers has been recognized, yet its specific function in pancreatic cancer (PCa) demands further exploration. This study aimed to reveal the potential function of miR-125a-5p in PCa. Methods: With publicly available databases, we explored the expression pattern and prognostic relevance of miR-125a-5p and STAT3 in PCa. We measured miR-125a-5p levels in PCa tissues, plasma and cell lines using RT-qPCR. To assess functional effects, PANC-1 cells were transfected with miR-125a-5p mimics and inhibitors, as well as siRNA-STAT3 and STAT3 vectors. Cell proliferation was estimated using Cell Counting Kit-8, while autophagy and apoptosis were examined by transmission electron microscopy and TUNEL assay, respectively. Western blot analysis was also performed to detect proteins associated with autophagy and apoptosis. The regulatory relationship of miR-125a-5p on STAT3 was verified using a dual luciferase reporter assay. The influence of miR-125a-5p on tumor development was evaluated in xenograft models. Results: Decreased expression of miR-125a-5p was found in PCa samples, and low expression of miR-125a-5p was associated with a poorer prognosis in PCa patients. Functional assays indicated miR-125a-5p suppressed cell growth while enhancing apoptosis and autophagy in PCa cells. STAT3 represents a specific target of miR-125a-5p, inhibiting STAT3 reversed the inhibitory effect of overexposed miR-125a-5p. Additionally, miR-125a-5p significantly restrained tumor development in mice. Conclusions: miR-125a-5p functions as a tumor suppressor in PCa by targeting STAT3, thereby inducing autophagy and apoptosis. Its regulatory role underscores its potential as a valuable biomarker for PCa diagnosis and therapy, warranting further clinical investigation.