miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy

Abstract

The chemoresistance of colon cancer cells limits the efficacy of chemotherapy. miR-409-3p has been shown to be downregulated in various types of cancer. In the present study, we examined the role of miR-409-3p in colon cancer as well as the effects of miR‑409-3p on the sensitivity of colon cancer cells to oxaliplatin. The expression of miR-409 was significantly downregulated in the human colon cancer cell lines compared with the normal colon epithelial cells. Importantly, the miR-409-3p expression levels were lower in human colon cancer patient samples than in normal colon tissues. Moreover, we observed a negative correlation between the miR‑409-3p levels and resistance to oxaliplatin: the oxaliplatin-resistant colon cancer cells exhibited significantly downregulated miR‑409-3p levels, but higher autophagic activity than the oxaliplatin-sensitive cells. Using bioinformatics analysis, we predicted that miR‑409-3p miRNA binds to the key autophagy gene encoding Beclin-1. Our findings indicated that the overexpression of miR‑409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR‑409-3p enhanced the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR‑409-3p. In a xenograft model using nude mice, we examined the effects of miR‑409-3p on tumor growth during chemotherapy. miR‑409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1. The findings of our study suggest that miR-409-3p is capable of enhancing the chemosensitivity of colon cancer cells by inhibiting Beclin-1-mediated autophagy.

The Network of Non-coding RNAs in Cancer Drug Resistance

“…Furthermore, miR-425-5p ihnibition reversed oxaliplatin resistance both in HTC116-resistant cells lines and xenograft models by modulating the expression of PDCD10 (364). Tan et al observed a negative correlation between miR-409-3p and resistance to Oxaliplatin in CRC resistant cells (365). Moreover, as a putative miRNAs modulator, also long intergenic noncoding RNA (LINC00152), can be involved in chemosensitivity of Oxaliplatin in CRC.…”

MicroRNAs as Regulators, Biomarkers and Therapeutic Targets in the Drug Resistance of Colorectal Cancer

“…Beclin-1, a key autophagy gene, was predicted as the target of miR-409-3p. Overexpression of miR-409-3p inhibited cell autophagic activity and enhanced the sensitivity to oxaliplatin, which were abrogated by restoration of beclin-1, suggesting that miR-409-3p sensitized CRC to oxaliplatin by inhibiting beclin-1-mediated autophagy [63].…”

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

“…Beclin‐1 is a unique autophagy‐related protein that drives autophagosome formation, the inhibition of which suppresses cell proliferation, but increases apoptosis in CRC cells . It has been shown that miR‐409‐3p sensitizes colon cancer cells to oxaliplatin by targeting beclin‐1 and inhibition of autophagy . Furthermore, transforming growth factor‐β (TGF‐β) signaling plays an important role in autophagy, the activation of which is mediated by the Smads.…”