Tumor Suppressor Role and Clinical Implication of the Fifth Ewing Variant (FEV) Gene, an ETS Family Gene, in Prostate Cancer

Abstract

Background: Our previous study identified a 32-gene risk index model as a robust prognostic tool for disease recurrence of prostate cancer (PCa) after surgery. Among the 32 genes, the Fifth Ewing Variant (FEV) Gene was one of the top downregulated genes in the relapsed PCa. However, very little is known about FEV gene and its involvement in PCa. Methods: FEV mRNA expression was analyzed and correlated to clinical outcomes in PCa patients who underwent prostatectomy in Massachusetts General Hospital. FEV expression level was also detected in PCa cell lines and an immortalized prostate epithelial cell line BPH-1 by Western blot and qRT-PCR. Furthermore, we established stable cell lines (LNCaP and PC-3) transfected with either empty vector or the full-length FEV gene and conducted cell function assays in vitro. The role of FEV in tumor xenografts growth was also determined in vivo Finding: Of 191 patients who enrolled in this study, 77 (40.3%) and 24 (13.6%) developed prostate-specific antigen (PSA) relapse and metastasis respective after radical prostatectomy. FEV was significantly downregulated in PCa patients with PSA failure and metastasis. FEV expression was significantly reduced in all PCa cell lines compared to BPH-1 (all P<0.05). Functionally, the enforced expression of FEV markedly inhibited cell growth, migration and invasion efficacies in PCa cells and led to a significant repression of tumor xenografts growth in vivo. Interpretation: Our data indicate that FEV downregulation may be potentially associated with PSA relapse in PCa patients. Functionally, FEV may act as a tumor suppressor in PCa. Funding Statement: This work was supported by grants from National Key Basic Research Program of China (2015CB553706), National Natural Science Foundation of China (81874099, 81571 427, 81802555), the Fundamental Research Funds for the Central Universities(2018MS 18), Natural Science Foundation of Guangdong Province (2018A030313668, 2017A030 310149), Guangzhou Municipal Science and Technology Project (201710010081, 20180 3040001, 201707010291), Projects of Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou Medical University Initiation Project for PHD (201 6C12), General Research Projects of Guangzhou Science and Technology Department (201804010053). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: The study was approved by the human study ethics committees at Massachusetts General Hospital (MGH; Boston, MA). All specimens were handled and made anonymous according to the ethical and legal standards.