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:
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.
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
Research background

Gastric cancer (GC) is one of the most common digestive malignancies and remains the second most common cause of cancer-related mortality worldwide. Currently, most patients are diagnosed at an advanced stage, leading to a low cure rate and a low 5-year survival rate. Therefore, it is necessary to further study the molecular mechanism of GC and identify more effective biomarkers for the diagnosis and treatment of GC.

Research motivation

Accumulating studies have indicated that microRNAs (miRNAs) have been associated with almost all known physiological and pathological processes, including cancer. In addition, it is suggested in recent studies that epigenetic modification, especially DNA methylation, is one of many mechanisms of miRNA suppression in human cancer. A greater understanding of these factors will play an important role in early diagnosis and treatment of GC and improvement of prognosis.

Research objectives

To study the potential role and possible regulatory mechanism of microRNA-596 (miR-596) in GC, and whether other targets of miR-596 exist in GC.

Research methods

In the present study, the levels of miR-596 expression in 55 pairs of GC and normal control tissues and cell lines were initially assessed using quantitative real-time (qRT-PCR). We further examined the relationship between miR-596 expression and clinicopathological factors in 55 GC tissues by Pearson's χ2 test. In addition, peroxiredoxin 1 (PRDX1) expression was analyzed in 55 paired GC and control tissues and cell lines by 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 cells transfected with miR-596 mimics were analyzed, respectively, by Cell Counting Kit-8 proliferation assay, wound healing assay, and transwell invasion assay. The methylation status of the promoter CpG islands of miR-596 in GC cell lines was detected by methylation-specific PCR. Meanwhile, we treated GC cells with the demethylating agent 5-Aza-2’-deoxycytidine (5-Aza-dC) to confirm whether miR-596 expression could be restarted. Finally, in order to evaluate whether 5-Aza-dC treatment affects GC cell growth, we analyzed the proliferation of GC cells treated with 5-Aza-dC.

Research results

Our current study demonstrated that the expression of miR-596 was downregulated in GC cells and GC tissues. The in vitro data further suggested that miR-596 expression was able to inhibit GC cell growth, migration, and invasion. Furthermore, miR-596 expression was regulated by epigenetic mechanisms. Moreover, we identified that PRDX1 is one of the putative target genes of miR-596.

Research conclusions

In the present study, we have investigated a suppressive role of microRNA-596 in GC. We reported that miR-596 was downregulated in human specimens of GC and GC cell lines, and that overexpression of miR-596 significantly reduced GC cell proliferation. 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 PRDX1, which has never been reported before, suggesting that this interaction could play an important role in GC progression.

Research perspectives

Our results further emphasize that miR-596 functions as a crucial tumor suppressor that is regulated by epigenetic mechanisms in GC and may offer a promising novel therapeutic approach for GC. Nonetheless, more studies are required to determine the precise mechanism of miR-596 in the progression of GC.