Tai Yi-Jou, Ou Cheng-Miao, Chiang Ying-Cheng, Chang Chi-Fang, Chen Chi-An, Cheng Wen-Fang
Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University Taipei, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University Taipei, Taiwan.
Am J Cancer Res. 2022 Sep 15;12(9):4211-4226. eCollection 2022.
Most ovarian cancer patients experience disease recurrence and chemotherapeutic resistance, and the underlying mechanisms are unclear. Identifying relevant pathways could reveal new therapeutic targets. Here we examined expression of transmembrane protein 102 (TMEM102), a biomarker of prognosis and chemoresistance, in epithelial ovarian cancer (EOC), and assessed its role in inhibiting tumor cell apoptosis. We performed qRT-PCR to investigate the association of TMEM102 expression with clinical outcomes in 226 EOC patients. We also conducted studies to explore possible mechanisms through which TMEM102 may influence chemoresistance, including the effects of downregulating TMEM102 expression with small interfering RNA. Serous and high-grade carcinomas expressed significantly higher TMEM102 than normal ovarian tissues. TMEM102 was also overexpressed in patients with advanced-stage disease and chemoresistance. Reduction of TMEM102 expression by small interfering RNA induced ovarian cancer cell apoptosis after cytotoxic treatment. TMEM102 overexpression enhanced chemoresistance via upregulation of heat shock proteins 27, 60, and 70; and survivin, resulting in decreased cytochrome c in the mitochondria and decreased caspase 9 expression. Our results indicate that TMEM102 overexpression may promote chemoresistance via inhibition of a mitochondria-associated apoptotic pathway.
大多数卵巢癌患者会出现疾病复发和化疗耐药，其潜在机制尚不清楚。确定相关途径可能会揭示新的治疗靶点。在此，我们检测了跨膜蛋白102（TMEM102）（一种预后和化疗耐药的生物标志物）在上皮性卵巢癌（EOC）中的表达，并评估了其在抑制肿瘤细胞凋亡中的作用。我们进行了qRT-PCR，以研究226例EOC患者中TMEM102表达与临床结局的相关性。我们还开展了研究，以探索TMEM102可能影响化疗耐药的潜在机制，包括用小干扰RNA下调TMEM102表达的作用。浆液性癌和高级别癌中TMEM102的表达明显高于正常卵巢组织。TMEM102在晚期疾病和化疗耐药患者中也过表达。用小干扰RNA降低TMEM102表达可在细胞毒性治疗后诱导卵巢癌细胞凋亡。TMEM102的过表达通过上调热休克蛋白27、60和70以及生存素增强化疗耐药性，导致线粒体中细胞色素c减少和半胱天冬酶9表达降低。我们的结果表明，TMEM102过表达可能通过抑制线粒体相关凋亡途径促进化疗耐药。
