Published online Jul 14, 2021. doi: 10.3748/wjg.v27.i26.4221
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 (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.
To explore the underlying mechanisms of GC development and discover biomarkers for the treatment of GC.
To investigate the role and potential mechanism of USP15 in GC.
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.
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.
USP15 promotes cell proliferation, invasion, and EMT progression of GC via regulating the Wnt/β-catenin pathway.
USP15 is expected to be a novel potential therapeutic target for GC.