Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2015; 21(10): 2949-2958
Published online Mar 14, 2015. doi: 10.3748/wjg.v21.i10.2949
Tumor suppressor role of miR-133a in gastric cancer by repressing IGF1R
Yu Gong, Jun Ren, Kun Liu, Li-Ming Tang
Yu Gong, Jun Ren, Kun Liu, Li-Ming Tang, Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People’s Hospital, Changzhou 213000, Jiangsu Province, China
Author contributions: Gong Y and Ren J performed the majority of the experiments and collected the clinical data; Liu K provided vital reagents and analytical tools and was also involved in revising the manuscript; Tang LM designed the study and wrote the paper.
Supported by Nanjing Medical University institutional grant, No. 11ZLKF06 (to SYC and LMT); and the Changzhou basic research program of science and technology, No. CJ20122014.
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: Li-Ming Tang, MD, PhD, Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People’s Hospital, No. 188 Gehu Road, Changzhou 213000, Jiangsu Province, China. drtanglm@njmu.edu.cn
Telephone: +86-519-81087722 Fax: +86-519-81087711
Received: July 17, 2014
Peer-review started: July 17, 2014
First decision: August 6, 2014
Revised: August 29, 2014
Accepted: October 21, 2014
Article in press: October 21, 2014
Published online: March 14, 2015
Processing time: 242 Days and 2.2 Hours
Abstract

AIM: To investigate the function and mechanism of miR-133a in gastric cancer (GC) and its relationship with clinicopathological characteristics of GC.

METHODS: A total of 105 GC patients who underwent surgical resection as primary treatment were selected for this study. Real-time quantitative reverse transcriptase polymerase chain (qRT-PCR) was used to examine the expression levels of miR-133a in human GC and adjacent non-tumor tissues, as well as in GC cell lines (SGC-7901, BGC-823, MGC-803, and AGS) and a human gastric mucosal epithelial cell line (GES-1). The biological role of miRNA (miR)-133a was assessed in the GC cell lines using MTT, apoptosis, migration and invasion, and colony formation assays, and xenograft tumorigenesis. qRT-PCR and western blot analyses were used to evaluate the potential target gene expression of miR-133a. Pearson’s correlation was calculated to evaluate the correlation between miR-133a and insulin-like growth factor 1 receptor (IGF1R) expression. The regulation of IGF1R by miR-133a was verified using the luciferase reporter assay.

RESULTS: In 80% of the 105 GC patients, the mean expression of miR-133a was significantly downregulated in tumor tissues compared with adjacent normal tissues (1.215 ± 0.1477 vs 3.093 ± 0.4104, P < 0.0001). Downregulation of miR-133a was significantly correlated with the degree of differentiation (P = 0.01), local invasion (P = 0.001) and TNM stage (P = 0.02) in GC patients. Compared with a control construct, forced expression of miR-133a in GC cell lines inhibited proliferation (0.4787 ± 0.0219 vs 0.7050 ± 0.0147, P = 0.0013 in SGC-7901 cells; and 0.5448 ± 0.0085 vs 0.7270 ± 0.0084, P = 0.001 in MGC-803 cells); migration (0.6333 ± 0.0233 vs 1.037 ± 0.0584, P = 0.003 in SGC-7901 cells; 0.6126 ± 0.0311 vs 1.024 ± 0.0456, P = 0.0017 in MGC-803 cells); and invasion (0.613 ± 0.0399 vs 1.033 ± 0.0278, P = 0.0013 in SGC-7901 cells; 0.7433 ± 0.0221 vs 1.017 ± 0.0311, P = 0.002 in MGC-803 cells). It also induced apoptosis (18.19% ± 0.2483% vs 5.887% ± 0.3837%, P < 0.0001 in SGC-7901 cells; 22.69% ± 0.7846% vs 9.347% ± 0.3012%, P < 0.0001 in MGC-803 cells). Furthermore, miR-133a inhibited tumor growth and xenograft tumorigenesis of SGC -7901 cells in vivo. In addition, we identified IGF1R as a regulatory target of miR-133a in GC.

CONCLUSION: This study suggests that miR-133a is downregulated in GC and functions as a tumor suppressor in vitro and in vivo partly by repressing IGF1R.

Keywords: Gastric cancer; miR-133a; Tumor suppressor; Insulin-like growth factor 1 receptor

Core tip: miRNA (miR)-133a is a tumor suppressor in several cancers. It was recently shown that miR-133a inhibits proliferation, migration and invasion in gastric cancer (GC) by targeting transcription factor Sp1. Here, we further investigated the biological role of miR-133a in apoptosis and xenograft tumorigenesis, and its relationship with clinicopathological parameters. miR-133a downregulation was associated with degree of differentiation, local invasion and TNM stage, whereas forced miR-133a expression inhibited cell proliferation, migration and invasion, and xenograft tumorigenesis, and induced apoptosis. Furthermore, insulin-like growth factor 1 receptor was found to be another target gene of miR-133a in GC.