Journal
WORLD JOURNAL OF GASTROENTEROLOGY
Volume 23, Issue 10, Pages 1816-1827Publisher
BAISHIDENG PUBLISHING GROUP INC
DOI: 10.3748/wjg.v23.i10.1816
Keywords
miR-34a; Oxaliplatin; Colorectal cancer; Macroautophagy; Transforming growth factor-alpha/Smad pathway
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Funding
- Science Foundation of Education Department of Heilongjiang Province, China [12541430]
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AIM To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-alpha/Smad4 pathway. METHODS miR-34a 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-34a 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-34a was significantly reduced while expression of TGF-beta and Smad4 was increased in CRC patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-beta 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-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-alpha/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells. CONCLUSION miR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-alpha/Smad4 pathway.
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