Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies due to its aggressive progression and poor prognosis. Chemotherapy with gemcitabine is a standard treatment, yet the development of resistance severely limits gemcitabine effectiveness. Understanding the molecular mechanisms underlying this resistance is thus crucial for improving therapeutic outcomes. This study investigated the roles of microRNA-125b (miR-125b) in PDAC, focusing on its influence on cell proliferation and gemcitabine resistance. METHODS: We employed quantitative real-time polymerase chain reaction (qRT-PCR) to measure miR-125b levels in PDAC tissues and cell lines, and utilized cell proliferation assays, apoptosis assays, and luciferase reporter assays to elucidate miR-125b's functions and targets. Finally, the in vitro findings were validated by in vivo experiments using xenograft models in nude mice. RESULTS: MiR-125b was found to be significantly overexpressed in PDAC tissues and cell lines. Overexpression of miR-125b promoted cell proliferation by enhancing cell cycle progression and reducing apoptosis in response to gemcitabine and nutrient starvation. Luciferase reporter assays identified Bcl-2 homologous antagonist/killer 1 (BAK1), a pro-apoptotic protein, as a direct target of miR-125b. Downregulation of BAK1 by miR-125b was associated with decreased apoptosis and increased resistance to gemcitabine, whereas miR-125b silencing elicited opposite effects. In vivo, subcutaneous tumors derived from miR-125b-overexpressing cells were larger in size and more resistant to gemcitabine. CONCLUSIONS: In summary, our study indicated that miR-125b contributes to PDAC progression and gemcitabine resistance by downregulating BAK1. Targeting miR-125b might represent a promising therapeutic approach to overcome gemcitabine resistance in PDAC.