研究UBE2C基因在轉移性前列腺癌中的促腫瘤機制及其作為治療標誌之潛力

陳彥臻¹、湯智昕²、黃一勝³、張安辰⁴

中國醫藥大學 醫學院 ¹轉譯醫學暨新藥開發研究所；²藥理學科

新光吳火獅紀念醫院 ³泌尿外科；⁴轉譯醫學中心

Study on the Pro-tumor Function of UBE2C Gene in Metastatic Prostate Cancer and Its Potential as a Therapeutic Marker

Yen-Chen Chen¹、 Chih-Hsin Tang²、Thomas I-Sheng Hwang³、An-Chen Chang⁴

¹Department of Institute of Translational Medicine and New Drug Development；²Department of Pharmacology, School of Medicine, China Medical University

³Department of Urology；⁴Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital

Purpose:

Prostate cancer (PCa), a malignant tumor of the urinary tract, is one of the most common cancers in men. PCa tends to metastasize to bones and lymph nodes, resulting in increased mortality. Therefore, understanding the detail mechanism(s) of how tumor progression is important. Ubiquitin-conjugating enzyme E2 C (UBE2C) is a member of the E2 family of ubiquitin-conjugating enzymes that are required for the destruction of mitotic cyclins and cell cycle progression. UBE2C has reported to be overexpressed in different human cancers, leading to chromosome missegregation, altering the cell cycle, and promoting cell proliferation. Here, we aim to study the regulatory mechanism of the UBE2C gene in PCa and observe the effect of inhibiting UBE2C on the treatment of PCa metastasis.

Materials and Methods:

TCGA-PRAD dataset and NCBI-GEO dataset were used to analyze clinical importance of UBE2C gene in human PCa. Human PCa cell lines C4-2, DU145, and PC-3 were obtained from the Bioresource Collection and Research Center. The shRNA vector system was used to knockdown UBE2C gene expression in PCa cells by using a  K4® Transfection Reagent. Cell survival was detected by Colony formation assay. Wound healing assay and Anoikis assay were performed to analyze cell aggressiveness mediated by UBE2C gene.

Results:

Firstly, among the thirty screened UBE2 family members associated with PCa, UBE2C was the most significantly overexpressed gene in human PCa tissues (N=499) compared to normal tissues (N=51) in the TCGA-PRAD dataset. Moreover, the expression of UBE2C gene in human PCa was significantly positively correlated with clinical stage, Gleason score and lymphatic metastasis. The GSEA analysis indicated a relation of UBE2C gene to cell cycle, DNA replication and DNA damage repair. Furthermore, UBE2C levels were positively correlated with common mutation genes in metastatic PCa, such as BRCA1, BRCA2, ATM, and CHEK2, indicating that the UBE2C gene functions as a driver gene controlling tumor progression. From our in vitro analysis, we were the first to verify that overexpresses of the UBE2C genepromotes PCa cells survival, mobility, invasiveness, and anoikis resistance, while UBE2C blockade inhibited this phenomenon.

Conclusion:

These results suggest that UBE2C gene could be a theranostic biomarker for patients diagnosed with metastatic PCa. Developing therapeutic approaches for anti-UBE2C may benefit clinical treatment in metastatic PCa.