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: http://creativecommons.org/licenses/by-nc/4.0/
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. wx89211@163.com
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
Abstract
BACKGROUND

Wnt1-inducible signaling pathway protein 1 (WISP1) is upregulated in several types of human cancer, and has been implicated in cancer progression. However, its clinical implications in gastric cancer (GC) remain unclear.

AIM

To explore the expression pattern and clinical significance of WISP1 in GC.

METHODS

Public data portals, including Oncomine, The Cancer Genome Atlas 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 levels were measured at both the mRNA and protein levels by RT-qPCR, Western blot analysis, and immunohistochemistry (IHC). In addition, the in situ expression of WISP1 in the GC tissues was determined by IHC, and the patients were accordingly classified into high- and low-expression groups. 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. The 50% inhibitory concentration of oxaliplatin was detected by CellTiter-Blue assay.

RESULTS

WISP1 levels at both the mRNA and protein levels were 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, age, gender, 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. Mechanistically, knock-down of WISP1 expression enhanced sensitivity to oxaliplatin by reducing DNA repair and enhancing DNA damage.

CONCLUSION

Significantly upregulated WISP1 expression is associated with cancer progression, chemotherapy outcome, and prognosis in 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 or a potential biomarker for diagnosis and prognosis.

Keywords: Wnt1-inducible signaling pathway protein 1; Biomarker; Bioinformatics analysis; Chemotherapy outcome; Gastric cancer

Core tip: The present study for the first time revealed that significantly upregulated Wnt1-inducible signaling pathway protein 1 (WISP1) expression was associated with advanced cancer, drug resistance, and poor prognosis in gastric cancer (GC). WISP1 enhanced oxaliplatin resistance by reducing cell cytotoxicity through enhancing DNA repair. Overall, the findings of the present study suggest that WISP1 is a novel prognostic biomarker for GC and highlight the significance of WISP1 as a promising therapeutic target for GC.