miR-34a mediates oxaliplatin resistance of colorectal cancer cells by inhibiting macroautophagy via transforming growth factor-β/Smad4 pathway

AIM To investigate whether micro RNA(mi R)-34 a mediates oxaliplatin(OXA) resistance of colorectal cancer(CRC) cells by inhibiting macroautophagy via the transforming growth factor(TGF)-β/Smad4 pathway.METHODS miR-34 a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34 a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting.RESULTS Expression of miR-34 a was significantly reduced while expression of TGF-β and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased mi R-34 a levels and increased TGF-β and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34 a in CRC patients had a significant inverse correlation and overexpressing mi R-34 a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34 a and increased drug resistance by activating macroautophagy in CRC cells.CONCLUSION miR-34 a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.