Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2017; 23(33): 6100-6110
Published online Sep 7, 2017. doi: 10.3748/wjg.v23.i33.6100
HOX transcript antisense intergenic RNA represses E-cadherin expression by binding to EZH2 in gastric cancer
Wen-Ming Chen, Wei-Dong Chen, Xue-Mei Jiang, Xue-Feng Jia, Hong-Mei Wang, Qiu-Jie Zhang, Yong-Qian Shu, Hai-Bo Zhao
Wen-Ming Chen, Wei-Dong Chen, Xue-Feng Jia, Qiu-Jie Zhang, Hai-Bo Zhao, Department of Oncology, Jining NO.1 People’s Hospital, Jining 272011, Shandong Province, China
Xue-Mei Jiang, Traditional Chinese Medicine Hospital of Jining City, Jining 272011, Shandong Province, China
Hong-Mei Wang, The Special Hospital Serving the Municipal Officials of Jining City, Jining 272011, Shandong Province, China
Yong-Qian Shu, Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu Province, China
Author contributions: Chen WM and Chen WD contributed equally to this article; Shu YQ and Zhao HB conceived and designed the study; Chen WM, Chen WD, Zhao HB, Jiang XM and Wang HM performed the research; Zhang QJ and Jia XF analyzed and interpreted the data; Chen WM and Zhao HB drafted the manuscript.
Supported by the Shandong Provincial Natural Science Foundation of China, No. ZR2016HQ08; Shandong Province Medical Science and Technology Development Projects of China, No. 2016WS0151; and the Jining Municipal Project on Science and Technology Development of China, No. 2013jnwk58.
Institutional review board statement: This study was reviewed and approved by the Jining NO.1 People’s Hospital Institutional Review Board and Nanjing Medical University Institutional Review Board.
Conflict-of-interest statement: The authors declare that no conflict of interest exists in relation 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/
Correspondence to: Dr. Hai-Bo Zhao, Associate Chief Physician, Department of Oncology, Jining NO.1 People’s Hospital, NO.6, Jiankang Road, Jining 272011, Shandong Province, China. zhbys@sina.com
Telephone: +86-537-6051446 Fax: +86-537-2256374
Received: December 24, 2016
Peer-review started: December 29, 2016
First decision: March 18, 2017
Revised: April 13, 2017
Accepted: July 22, 2017
Article in press: July 24, 2017
Published online: September 7, 2017
Processing time: 256 Days and 20.3 Hours
Abstract
AIM

To clarify the mechanisms of HOX transcript antisense intergenic RNA (HOTAIR) in gastric cancer (GC) migration and invasion.

METHODS

Quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression level of HOTAIR in GC tissues. The correlation of its expression with clinicopathological features was analyzed. Area under receiver operating characteristic curve (AUCROC) was constructed to evaluate the diagnostic value of HOTAIR. Wound-healing assay and Transwell assay were performed to detect the biological effects of HOTAIR in GC cells. qPCR, western blot and immunohistochemistry were used to evaluate the mRNA and protein expression of E-cadherin. RNA-binding protein immunoprecipitation was used for the analysis of EZH2 interactions with HOTAIR. Chromatin immunoprecipitation assay was performed to investigate direct interactions between EZH2 and E-cadherin.

RESULTS

The expression of HOTAIR was up-regulated in GC tumorous tissues compared with the para-tumorous tissues (P < 0.001). Its over-expression was correlated with tumor-node-metastasis (TNM) stage (P = 0.024), tumor invasion (P = 0.018), lymph node metastasis (P = 0.023), and poor prognosis (P < 0.001). Multivariate Cox regression analysis confirmed expression of HOTAIR as an independent predictor of overall survival (P = 0.033), together with TNM stage (P = 0.002) and lymph node metastasis (P = 0.002). The AUCROC was up to 0.709 (95%CI: 0.623-0.785, P < 0.001). Knockdown of HOTAIR by siRNA in GC cells suppressed the migration and invasion of GC cells. Significantly negative correlation between HOTAIR and E-cadherin was found in GC tissues and cell lines, and HOTAIR contributed to the regulation of E-cadherin through binding to EZH2 with the E-cadherin promoter.

CONCLUSION

HOTAIR may play a pivotal role in tumor cell migration and invasion. It can be used as a potential diagnostic and prognostic biomarker for GC.

Keywords: Long noncoding RNA; HOX transcript antisense intergenic RNA; Gastric cancer; Migration and invasion; E-cadherin

Core tip: In this study, we found that HOX transcript antisense intergenic RNA (HOTAIR) expression was up-regulated in gastric cancer (GC) tissues. High expression of HOTAIR was associated with clinicopathological characteristics and poor prognosis in GC patients. Additional experiments revealed that HOTAIR knockdown significantly inhibited the invasion and migration of GC cells. We also tested whether HOTAIR recruited EZH2 to promote tumor cell migration and invasion by repressing E-cadherin in GC. The findings from our study will help clarify the role of HOTAIR in GC progression and its potential as a therapeutic target.