1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
3. Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.
4. Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
*These authors contributed equally to this work.
Background: Dysregulated microRNA (miRNA) expression in cancer can act as a key factor that modifies biological processes, including chemoresistance. Our study aimed to identify the miRNAs associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC) and to explore the potential mechanisms.
Methods: The miRNA microarray was used to identify miRNAs associated with GEM resistance. Quantitative real-time PCR was used to examine miR-146a-5p expression in paired PDAC and adjacent normal tissues. Bioinformatics analysis, luciferase reporter assays, and chromatin immunoprecipitation assays were used to confirm tumor necrosis factor receptor-associated factor 6 (TRAF6) as a direct target of miR-146a-5p and to explore the potential transcription factor binding and regulation by miR-146a-5p. In vitro and in vivo experiments were performed to investigate the mechanisms.
Results: MiR-146a-5p expression was significantly decreased in PDAC tissues compared with adjacent normal tissues, and miR-146a-5p expression correlated with prognosis in PDAC patients. Functional studies indicated that miR-146a-5p suppressed PDAC cell proliferation and sensitized PDAC cells to GEM chemotherapy by targeting the 3'-untranslated region (3′-UTR) of TRAF6. MiR-146a-5p was also observed to downregulate the TRAF6/NF-κB p65/P-gp axis, which regulates PDAC cell growth and chemoresistance.
Conclusions: Taken together, the results indicate that the miR-146a-5p/TRAF6/NF-κB p65 axis drives pancreatic chemoresistance by regulating P-gp, suggesting that miR-146a-5p may be utilized as a new therapeutic target and prognostic marker in PDAC patients.
Keywords: microRNA, pancreatic cancer, chemoresistance, prognosis