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

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


To explore the biological role and underlying mechanisms of USP15 in GC progression.


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


USP15 was up-regulated 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, tumor-node-metastasis stage, perineural invasion, and vascular invasion), and was related to poor prognosis. USP15 knockdown significantly inhibited cell proliferation, invasion and epithelial-mesenchymal transition (EMT) of GC in vitro, while overexpression of USP15 promoted these processes. Knockdown of USP15 inhibited tumor growth in vivo. Mechanistically, RNA sequencing analysis showed that USP15 regulated the Wnt signaling pathway in GC. Western blotting confirmed that USP15 silencing led to significant down-regulation of β-catenin and Wnt/β-catenin downstream genes (c-myc and cyclin D1), while overexpression of USP15 yielded an opposite result and USP15 mutation had no change. Immunofluorescence indicated that USP15 promoted 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 effect of USP15 on gastric cancer progression was dependent on Wnt/β-catenin pathway.


USP15 promotes cell proliferation, invasion and EMT progression of GC via regulating the Wnt/β-catenin pathway, which suggests that USP15 is a novel potential therapeutic target for GC.

Keywords: Ubiquitin-specific protease 15, Gastric cancer, Wnt/β-catenin, Cell proliferation, Cell invasion, Epithelial-mesenchymal transition

Core Tip: Ubiquitin-specific protease 15 (USP15) was upregulated in gastric cancer (GC) cells and tissues, and was associated with a poor prognosis in patients with GC. USP15 promoted cell proliferation, invasion, and epithelial-mesenchymal transition of GC cells in vitro and tumor growth in vivo. Mechanistic studies showed that USP15 functioned as a tumor promoter in GC by regulating the Wnt/β-catenin signaling pathway. Thus, USP15 is expected to be a novel potential target for GC therapy.