Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2021; 27(26): 4221-4235
Published online Jul 14, 2021. doi: 10.3748/wjg.v27.i26.4221
Ubiquitin-specific protease 15 contributes to gastric cancer progression by regulating the Wnt/β-catenin signaling pathway
Min Zhong, Ling Zhou, Zhi Fang, Yang-Yang Yao, Jian-Ping Zou, Jian-Ping Xiong, Xiao-Jun Xiang, Jun Deng
Min Zhong, Ling Zhou, Zhi Fang, Jian-Ping Zou, Jun Deng, Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Yang-Yang Yao, Jian-Ping Xiong, Xiao-Jun Xiang, Department of Cancer Center, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Author contributions: Zhong M, Zhou L, and Fang Z contributed equally to this work; Zhong M performed data acquisition and drafted the manuscript; Zhou L and Fang Z completed the statistical analyses; Yao YY and Zou JP were involved in critically revising the manuscript for important intellectual content; Deng J, Xiong JP, and Xiang XJ conceived and designed the study.
Supported by National Natural Science Foundation of China, No. 81760432; Science and Technology Department of Jiangxi Province, No. 20202BBGL73036; and Jiangxi Provincial Outstanding Young Talents Projects, No. 20204BCJ23016.
Institutional review board statement: The study was reviewed and approved by the Medical Research Ethics Committee of the First Affiliated Hospital of Nanchang University.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals [license No. SYXK (GAN) 2015-0001, Laboratory Animal Science Center of Nanchang University; protocol No. 2020-130, The Medical Research Ethics Committee of the First Affiliated Hospital of Nanchang University].
Conflict-of-interest statement: The authors declare that they have no conflict of interest
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: Jun Deng, PhD, Assistant Professor, Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, No. 17 Yongwai Street, Nanchang 330006, Jiangxi Province, China.
Received: March 8, 2021
Peer-review started: March 8, 2021
First decision: April 17, 2021
Revised: April 27, 2021
Accepted: June 16, 2021
Article in press: June 16, 2021
Published online: July 14, 2021
Research background

Ubiquitin-specific protease 15 (USP15) is an important member of the ubiquitin-specific protease (USP) family, whose expression is dysregulated in many types of cancer. However, the function role and the underlying mechanism of USP15 in gastric cancer (GC) progression have not yet been elucidated.

Research motivation

To explore the underlying mechanisms of GC development and discover biomarkers for the treatment of GC.

Research objectives

To investigate the role and potential mechanism of USP15 in GC.

Research methods

Bioinformatics databases and western blot analysis were utilized to determine the expression of USP15 in GC. Immunohistochemistry was performed to evaluate the correlation between expression of USP15 and clinicopathological characteristics of GC patients. A loss- and gain-of-function experiment was used to investigate the biological effects of USP15 on GC carcinogenesis. RNA sequencing analysis, immunofluorescence, and western blotting were performed to explore the potential mechanism by which USP15 exerted its oncogenic functions.

Research results

USP15 was upregulated in GC tissue and cell lines. The expression level of USP15 was positively correlated with clinical characteristics (tumor size, depth of invasion, lymph node involvement (LNI), tumor-node-metastasis (TNM) stage, perineural invasion, and vascular invasion), and was related to poor prognosis. USP15 knockdown significantly inhibited cell proliferation, invasion and epithelial-mesenchymal transition of GC in vitro, while overexpression of USP15 promoted these processes. Knockdown of USP15 inhibited tumor growth in vivo. Mechanistically, RNA-seq analysis showed that USP15 regulated the Wnt signaling pathway in GC. Western blotting confirmed that USP15 silencing led to significant downregulation of β-catenin and Wnt/β-catenin downstream genes (c-myc and cyclin D1), while overexpression of USP15 yielded the opposite results and USP15 mutation showed no change. Immunofluorescence indicated that USP15 promoted the nuclear translocation of β-catenin, suggesting activation of the Wnt/β-catenin signaling pathway, which may be the critical mechanism promoting GC progression. Finally, rescue experiments showed that the effects of USP15 on gastric cancer progression were dependent on the Wnt/β-catenin pathway.

Research conclusions

USP15 promotes cell proliferation, invasion, and EMT progression of GC via regulating the Wnt/β-catenin pathway.

Research perspectives

USP15 is expected to be a novel potential therapeutic target for GC.