Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2017; 23(10): 1816-1827
Published online Mar 14, 2017. doi: 10.3748/wjg.v23.i10.1816
miR-34a mediates oxaliplatin resistance of colorectal cancer cells by inhibiting macroautophagy via transforming growth factor-β/Smad4 pathway
Chen Sun, Fu-Jing Wang, Hao-Gang Zhang, Xun-Zheng Xu, Rui-Chun Jia, Lei Yao, Peng-Fei Qiao
Chen Sun, Fu-Jing Wang, Hao-Gang Zhang, Xun-Zheng Xu, Lei Yao, Peng-Fei Qiao, Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Rui-Chun Jia, Department of Blood Transfusion, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Author contributions: Jia RC, Yao L and Qiao PF should be considered co-corresponding authors; Qiao PF designed the research and analyzed the data; Jia RC and Yao L performed the research; Zhang HG and Xu XZ contributed new reagents or analytic tools; Wang FJ, Yao L and Qiao PF wrote the article.
Supported by Science Foundation of Education Department of Heilongjiang Province, China, No. 12541430.
Institutional review board statement: This study was approved by the Institutional Review Board of Harbin Medical University, and the protocols used in the study were approved by the Committee of Human Subjects Protection of the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this study.
Data sharing statement: Technical appendices, statistical codes and datasets are available from the corresponding author at lunwenqpf@126.com. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Peng-Fei Qiao, Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China. lunwenqpf@126.com
Telephone: +86-13895761713 Fax: +86-451-86297283
Received: September 29, 2016
Peer-review started: October 1, 2016
First decision: December 1, 2016
Revised: December 21, 2016
Accepted: February 7, 2017
Article in press: February 8, 2017
Published online: March 14, 2017
Processing time: 165 Days and 2.5 Hours
Abstract
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)-β/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-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.

CONCLUSION

miR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-β/Smad4 pathway.

Keywords: miR-34a; Oxaliplatin; Colorectal cancer; Macroautophagy; Transforming growth factor-β/Smad pathway

Core tip: This study demonstrated a significant association between microRNA (miR)-34a expression and the acquired chemoresistance to oxaliplatin (OXA) in colorectal cancer (CRC). miR-34a mediates OXA resistance through its inhibitory effects on macroautophagy by the transforming growth factor (TGF)-β/Smad4 pathway. Our findings suggest that miR-34a is a potential therapeutic target for improving the chemotherapeutic effect of OXA in CRC.