Hongyang Xie,Junyu Chen,Changyan Ma,Jingjing Zhao,Manhua Cui
Dysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR-3, Caov-3, TOV-112D, A2780, and SK-OV-3 cells. Furthermore, in vitro functional assays of A2780 and TOV-112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial–mesenchymal transition by inducing the nuclear transport of β-catenin, which was accompanied by enhanced N-cadherin but decreased E-cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43-silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that β-catenin is a key protein in the UBP43-mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of β-catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta-catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the β-catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.
Gastric cancer (GC) is the 5th most common cancer over the world. Ubiquitin protease 43 (UBP43) is a multifunctional protein with deubiquitinase activities. Abnormal expression of UBP43 has been reported in numerous types of malignancies. Bioinformatic analysis was performed to identify the differentially expressed genes (Fold change ≥2 or ≤ −2 and p < 0.01) in GC from the datasets downloaded from Gene Expression Omnibus and Gene Expression Profiling Interactive Analysis databases, which showed that UBP43 and stress-inducible phosphoprotein 1 (STIP1) were up-regulated in both datasets. Online databases displayed the binding of UBP43 to STIP1 and the positive correlation between the two proteins. This study aims to explore: the role of UBP43 in cell proliferation and apoptosis in GC; the relationship between UBP43 and STIP1; and whether UBP43 exerts its function via STIP1 in GC. Knockdown/overexpression stable GC cell lines were generated by transducing lentivirus carrying coding sequence/short hairpin RNA of UBP43 and puromycin selection. GC patients with higher expressions of UBP43 had poor prognosis. Loss-/gain-of-function experiments revealed that pro-proliferative and anti-apoptotic abilities of UBP43 in GC cells and xenografts. UBP43 could interact with STIP1, inhibit its ubiquitination, and promote its protein stability, thereby enhancing STIP1 expression. Moreover, STIP1 knockdown reversed the pro-proliferative ability of UBP43 in GC cells. Our study uncovers that the pro-proliferative role of UBP43 in GC development is STIP1-dependent and indicates that UBP43 may act as a potent therapeutic target in GC treatment.
危险品化学品经营许可证（带存储）