Downregulation of ubiquitin-specific protease 2 possesses prognostic and diagnostic value and promotes the clear cell renal cell carcinoma progression

Xiangui Meng; Zhiyong Xiong; Wen Xiao; Changfei Yuan; Cheng Wang; Yu Huang; Junwei Tong; Jian Shi; Zhixian Chen; Chenchen Liu; Kairu Xie; Hailong Xiong; Ke Chen; Hongmei Yang; Xiaoping Zhang

doi:10.21037/atm.2020.02.141

Downregulation of ubiquitin-specific protease 2 possesses prognostic and diagnostic value and promotes the clear cell renal cell carcinoma progression

Ann Transl Med. 2020 Mar;8(6):319. doi: 10.21037/atm.2020.02.141.

Authors

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
² Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC), characterized by high mortality, invasion, metastasis, recurrence and drug resistance, is the most common malignant tumor of the urinary system. A clear understanding of the underlying molecular mechanisms and its role during tumorigenesis of RCC can contribute to development of prognostic and targeted therapies.

Methods: We analyzed datasets from the public database, TCGA, Oncomine, for differential expression of ubiquitin-specific protease 2 (USP2), and further investigated its relationship with the clinical stage, pathological grade and prognosis of renal cancer. We used real-time quantitative PCR and western blot analysis to validate USP2 expression in clinical samples and renal cancer cell lines. Finally, we used CCK-8 and transwell assays to determine its effects on biological functions in cells.

Results: We observed significantly lower levels of USP2 mRNA in renal cancer, relative to normal, tissues across the four datasets from the Oncomine database (P<0.001), 533 cases from TCGA database (P<0.0001) and 30 pairs of clinical samples (P<0.0001). Similarly, a decreased USP2 protein expression in ccRCC was detected following immunohistochemical (IHC) and western blot analyses. Furthermore, the aberrant expression of USP2 resulted in significant relationship with clinical stage, pathological grade and lower USP2 mRNA expression was interrelated to poor prognosis of renal cell carcinoma. USP2 acted as an independent factor for ccRCC diagnosis, with an AUC of 0.8888 (95% CI: 0.8529 to 0.9246; P<0.0001). Exogenous restoration of USP2 in ccRCC cells resulted in repression of cell proliferation, migration, and invasion.

Conclusions: Overall, these results show that USP2 acts as an anti-oncogene and an independent factor for ccRCC prognosis. Positive modulation of USP2 might lead to development of a novel strategy for ccRCC treatment.

Keywords: Ubiquitin-specific protease 2 (USP2); biomarker; clear cell renal cell carcinoma (ccRCC); deubiquitination; prognosis; targeted therapy.