Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2019; 25(38): 5814-5825
Published online Oct 14, 2019. doi: 10.3748/wjg.v25.i38.5814
Up-regulated Wnt1-inducible signaling pathway protein 1 correlates with poor prognosis and drug resistance by reducing DNA repair in gastric cancer
Li-Hua Zhang, Yan Wang, Qian-Qian Fan, Yan-Kui Liu, Long-Hai Li, Xiao-Wei Qi, Yong Mao, Dong Hua
Li-Hua Zhang, Qian-Qian Fan, Yong Mao, Dong Hua, Department of Oncology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214062, Jiangsu Province, China
Li-Hua Zhang, Dong Hua, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, Jiangsu Province, China
Li-Hua Zhang, Yan Wang, Long-Hai Li, Wuxi Medical College, Jiangnan University, Wuxi 214122, Jiangsu Province, China
Qian-Qian Fan, Department of Gynecology, Zaozhuang Maternal and Child Health Hospital, Zaozhuang 277100, Shandong Province, China
Yan-Kui Liu, Xiao-Wei Qi, Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China
Author contributions: Zhang LH, Wang Y, and Fan QQ contributed equally to this work; Hua D and Mao Y designed the research; Li LH, Liu YK, and Qi XW performed the research; Hua D and Mao Y contributed new reagents/analytic tools; Li LH, Zhang LH, and Wang Y analyzed the data; Zhang LH and Fan QQ wrote the paper. Mao Y was co-corresponding author.
Institutional review board statement: This study was reviewed and approved by Affiliated Hospital of Jiangnan University Institutional Review Board.
Conflict-of-interest statement: The authors report no conflicts of interest in this work.
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 Hua, MD, PhD, Chief Doctor, Professor, Department of Oncology, Affiliated Hospital of Jiangnan University, No. 200, Huihe Road, Wuxi 214062, Jiangsu Province, China.
Telephone: +86-510-88682109 Fax: +86-510-85808820
Received: June 1, 2019
Peer-review started: June 3, 2019
First decision: July 21, 2019
Revised: August 16, 2019
Accepted: September 13, 2019
Article in press: September 13, 2019
Published online: October 14, 2019
Processing time: 135 Days and 18 Hours
Research background

Gastric cancer (GC) is the most prevalent gastrointestinal tract malignancy. The prognosis of GC patients remains relatively poor. Through bioinformatics data mining and integrated analysis, we found that Wnt1-inducible signaling pathway protein 1 (WISP1) mRNA was upregulated in GC tissues relative to normal gastric tissues. However, it needs to be further verified clinically.

Research motivation

There are insufficient reports about the correlation between WISP1 and GC.

Research objectives

The aim of the present study was to explore the expression pattern and clinical significance of WISP1 in GC.

Research methods

Public data portals, including Oncomine, the TCGA database, COEXPEDIA, and Kaplan-Meier plotter were analyzed for the expression and clinical significance of WISP1 mRNA levels in GC. One hundred and fifty patients who underwent surgery for GC between February 2010 and October 2012 at the Affiliated Hospital of Jiangnan University were selected for validation study. WISP1 expression was measured at both the mRNA and protein levels by RT-qPCR, Western blot analysis, and immunohistochemistry (IHC). The correlation of WISP1 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses. WISP1 was knocked down by RNA interference. IC50 was detected by CTB assay.

Research results

WISP1 expression at both the mRNA and protein levels was remarkably upregulated in GC tissues compared to normal tissues. Moreover, IHC revealed that WISP1 expression was associated with T stage and chemotherapy outcome, but not with lymph node metastasis, distant metastasis, age, sex, histological grade, or histological type. GC patients with high WISP1 expression showed a poor overall survival. Multivariate survival analysis indicated that WISP1 was an important prognostic factor for GC patients. The IC50 of oxaliplatin in MKN45 and AGS cell lines were significantly reduced after WISP1 knock-down. In addition, WISP1 knock-down enhanced γH2AX expression and reduced XRCC1 expression.

Research conclusions

WISP1 is overexpressed in GC tissues and is associated with a poor prognosis, indicating its potential as a novel prognosis biomarker for GC. Mechanistically, knock-down of WISP1 expression enhances oxaliplatin sensitivity by reducing DNA repair and enhancing DNA damage. WISP1 may be a potential therapeutic target for GC treatment.

Research perspectives

The present study suggested that WISP1 is a novel prognostic biomarker for GC, and the significance of WISP1 as a promising therapeutic target for GC is highlighted.