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

Abstract

AIMTo investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway.METHODSmiR-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.RESULTSExpression of miR-34a 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 miR-34a 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-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells.CONCLUSIONmiR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.

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“…Drug-specific mechanisms clustered into pathways, some of which were previously described. For example, TGFB1-dependent activation of the SMAD regulatory complex has been associated with oxaliplatin resistance (Mao et al, 2017;Sun et al, 2017) and hedgehog signaling has been linked to irinotecan resistance (Meng et al, 2015;Tripathi et al, 2014). Biosynthesis of heme and several phospholipid molecules were pathways uniquely associated with resistance to our nucleoside analogs.…”

Current and New Predictors for Treatment Response in Metastatic Colorectal Cancer. The Role of Circulating miRNAs as Biomarkers

“…Previous studies showed that miR-34a was down-regulated in multiple malignant tumors, CRC included. Sun et al [67] investigated the role of miR-34a in resistance to L-OHP chemotherapy on CRC cells. Thirty CRC patients that underwent potentially curative surgery and were treated with L-OHP based adjuvant chemotherapy were included in the study.…”

MicroRNAs as potential therapeutic targets to predict responses to oxaliplatin in colorectal cancer: From basic evidence to therapeutic implication

“…Furthermore, transforming growth factor‐β (TGF‐β) signaling plays an important role in autophagy, the activation of which is mediated by the Smads. MiR‐34a sensitizes CRC cells to oxaliplatin via targeting the Smad4/TGF‐β pathway . MiR‐218 also sensitizes CRC cells to oxaliplatin.…”

“…MiR-34a sensitizes CRC cells to oxaliplatin via targeting the Smad4/TGF-β pathway. 38 MiR-218 also sensitizes CRC cells to oxaliplatin. It inhibits cytoprotective autophagy by targeting the YEATS domain containing 4 (YEATS4)-mediated oncogenic pathways.…”