Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2019; 25(10): 1224-1237
Published online Mar 14, 2019. doi: 10.3748/wjg.v25.i10.1224
MicroRNA-596 acts as a tumor suppressor in gastric cancer and is upregulated by promotor demethylation
Zhen Zhang, Dong-Qiu Dai
Zhen Zhang, Dong-Qiu Dai, Department of Gastroenterological Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
Author contributions: Dai DQ designed this study; Zhang Z performed the experiments and analyzed the data; Dai DQ and Zhang Z drafted the article, made critical revisions related to the intellectual content of the manuscript, and approved the final version of the article to be published.
Supported by National Natural Science Foundation of China, No. 30572162; and Natural Science Foundation of Liaoning Province, No. 201602817.
Institutional review board statement: All gastric cancer specimens from the patients were taken after informed consent and ethical permission were obtained for participation in the study.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
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/
Corresponding author: Dong-Qiu Dai, PhD, Chief Doctor, Professor, Surgical Oncologist, Department of Gastroenterological Surgery, the Fourth Affiliated Hospital of China Medical University, 4 Chongshan Road, Shenyang 110032, Liaoning Province, China. daidq63@163.com
Telephone: +86-24-62043110 Fax: +86-24-62043110
Received: December 11, 2018
Peer-review started: December 11, 2018
First decision: December 28, 2018
Revised: January 27, 2019
Accepted: January 28, 2019
Article in press: January 28, 2019
Published online: March 14, 2019
Processing time: 93 Days and 17.6 Hours
Abstract
BACKGROUND

In the present study, we investigated a suppressive role of microRNA-596 (miR-596) in gastric cancer (GC). Moreover, the downregulation of miR-596 in GC cell lines was associated with an increase of miR-596 promoter methylation. We also established that miR-596 controls the expression of peroxiredoxin 1 (PRDX1), which has never been reported before, suggesting that this interaction could play an important role in GC progression.

AIM

To study the potential role and possible regulatory mechanism of miR-596 in GC.

METHODS

The expression levels of miR-596 and PRDX1 in gastric cancer tissues and cell lines were detected by quantitative real-time PCR (qRT-PCR). Western blot and luciferase reporter assay were used to detect the effect of miR-596 on PRDX1 expression. Then, the proliferation, metastasis, and invasion of GC cell lines transfected with miR-596 mimics were analyzed, respectively, by Cell Counting Kit-8 proliferation assay, wound healing assay, and transwell invasion assay. Meanwhile, the methylation status of the promoter CpG islands of miR-596 in GC cell lines was detected by methylation-specific PCR (MSP).

RESULTS

Expression of miR-596 was decreased and PRDX1 was upregulated in GC tissues and cell lines. Overexpression of miR-596 decreased the expression of PRDX1 and luciferase reporter assays detected the direct binding of miR-596 to the 3'-untranslated region (UTR) of PRDX1 transcripts. Furthermore, we found that overexpression of miR-596 remarkably suppressed cell proliferation, migration, and invasion in GC cells. We further analyzed miR-596 promoter methylation by MSP and qRT-PCR, and found the downregulation of miR-596 was associated with promoter methylation status in GC cell lines. Moreover, DNA demethylation and reactivation of miR-596 after treatment with 5-Aza-2’-deoxycytidine inhibited the proliferative ability of GC cells.

CONCLUSION

MiR-596 has a tumor suppressive role in GC and is downregulated partly due to promoter hypermethylation. Furthermore, PRDX1 is one of the putative target genes of miR-596.

Keywords: Gastric cancer; MicroRNA-596; Methylation; Peroxiredoxin 1

Core tip: In the present study, we investigated a suppressive role of microRNA-596 (miR-596) in gastric cancer (GC). MiR-596 was downregulated in human specimens of GC and GC cell lines, and overexpression of miR-596 significantly reduced GC cell proliferation. Downregulation of miR-596 in GC cell lines was associated with an increase of miR-596 promoter methylation. We also established that miR-596 controls the expression of peroxiredoxin 1, which has never been reported before, suggesting that this interaction could play an important role in GC progression. Overall, this study has an impact in understanding the role of miRNAs in cancer progression.