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Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy

  • Authors:
    • Qiang Fu
    • Jing Cheng
    • Jindai Zhang
    • Yonglei Zhang
    • Xiaobing Chen
    • Jianguo Xie
    • Suxia Luo

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  • Published online on: October 21, 2016     https://doi.org/10.3892/or.2016.5195
  • Pages: 3682-3690
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Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Deregulation of microRNAs (miRNAs) has been reported to participate in CRC progression. In the present study, we observed downregulation of miR-218 and upregulation of YEATS domain containing 4 (YEATS4) in CRC tissues and in multidrug-resistant HCT-116/L-OHP cells compared with these levels in normal tissues and parental HCT-116 cells, respectively. The results indicated that miR-218 overexpression significantly decreased the IC50 value of oxaliplatin (L-OHP) in the HCT-116/L-OHP cells, and suppression of miR-218 significantly enhanced the IC50 of L-OHP in the HCT-116 cells. Flow cytometric analysis showed that miR-218 overexpression alone promoted cell apoptosis in the HCT-116/L-OHP cells, which was further enhanced in response to L-OHP, and miR-218 inhibition decreased cell apoptosis in the HCT-116 cells following treatment with L-OHP. Western blot analysis indicated that, compared with the small increase observed in HCT-116 cells, the relative LC3 II level in HCT-116/L-OHP cells after lysosome inhibition via chloroquine (CQ) was markedly upregulated following L-OHP treatment, suggesting induction of autophagy. Exposure of HCT-116/L-OHP cells to L-OHP after control mimic transfection increased autophagic flux, as reflected by increased LC3 II levels, while miR-218 overexpression partly reversed L-OHP-mediated LC3 II accumulation. Additionally, both miR-218 overexpression and CQ treatment promoted L-OHP-induced HCT-116/L-OHP cell apoptosis. Molecularly, our results confirmed that miR-218 directly targets the YEATS4 gene and inhibits YEATS4 expression. Furthermore, YEATS4 overexpression without the 3'-untranslated region (3'-UTR) restored miR-218-inhibited YEATS4 and LC3 II expression, and abolished miR-218-stimulated cell viability loss and cell apoptosis increase in response to L-OHP. In conclusion, miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression.
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December-2016
Volume 36 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Fu Q, Cheng J, Zhang J, Zhang Y, Chen X, Xie J and Luo S: Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy. Oncol Rep 36: 3682-3690, 2016
APA
Fu, Q., Cheng, J., Zhang, J., Zhang, Y., Chen, X., Xie, J., & Luo, S. (2016). Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy. Oncology Reports, 36, 3682-3690. https://doi.org/10.3892/or.2016.5195
MLA
Fu, Q., Cheng, J., Zhang, J., Zhang, Y., Chen, X., Xie, J., Luo, S."Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy". Oncology Reports 36.6 (2016): 3682-3690.
Chicago
Fu, Q., Cheng, J., Zhang, J., Zhang, Y., Chen, X., Xie, J., Luo, S."Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy". Oncology Reports 36, no. 6 (2016): 3682-3690. https://doi.org/10.3892/or.2016.5195