REV7 is a multitasking protein involved in replication past DNA lesions, cell cycle regulation, and gene expression. REV7 is highly expressed in the adult testis and plays an essential role in primordial germ cell maintenance in mice. In this study, we analyzed whether REV7 can be a molecular target for the treatment of testicular germ cell tumors (TGCTs), in which acquired chemoresistance is a major cause of treatment failure. Strong expression of REV7 was detected in human TGCT tissues by immunohistochemistry. REV7 depletion in the TGCT cell lines suppressed cell proliferation and increased sensitivity to cisplatin and doxorubicin. cDNA microarray analysis revealed that REV7 depletion downregulated genes in the DNA repair gene set and upregulated genes in the apoptosis gene set. REV7 depletion-provoked chemosensitivity was associated with DNA double-strand break accumulation and apoptosis activation. In addition, inactivation of REV7 in cisplatin-resistant TGCT cells recovered chemosensitivity at almost equal levels as parental cells in vitro and in vivo. Our results indicate that inactivation of REV7 enhances chemosensitivity and overcomes chemoresistance in TGCT cells, suggesting REV7 as a potential therapeutic target in chemoresistant TGCTs.

REV7是一种多任务蛋白，涉及DNA损伤后的复制，细胞周期调控和基因表达。REV7在成年睾丸中高表达，并在小鼠原始生殖细胞维持中起重要作用。在这项研究中，我们分析了REV7是否可以作为睾丸生殖细胞肿瘤（TGCT）治疗的分子靶标，其中获得性化学耐药是治疗失败的主要原因。通过免疫组织化学在人TGCT组织中检测到REV7的强表达。TGCT细胞系中的REV7耗竭抑制了细胞增殖，并增加了对顺铂和阿霉素的敏感性。cDNA芯片分析显示，REV7耗竭可降低DNA修复基因组中的基因，而上调其凋亡基因组中的基因。REV7耗竭引起的化学敏感性与DNA双链断裂积累和凋亡激活相关。此外，对顺铂耐药的TGCT细胞中REV7的失活恢复了与亲代细胞几乎相同的化学敏感性。体外和体内。我们的结果表明，REV7的失活增强了TGCT细胞的化学敏感性并克服了其化学抗性，这表明REV7是抗化学性TGCTs的潜在治疗靶标。