Liu Fei, Li Fuqiang, Luo Limei, Yang Hanteng, Wei Yonggang, Wang Wentao, Yan Lvnan, Wen Tianfu, Yang Jiayin, Li Bo
Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, 37 Guo Xue Road, Chengdu, 610041, Sichuan, China.
Department of General Surgery, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, 310003, Zhejiang, China.
Apoptosis. 2017 Aug;22(8):1035-1047. doi: 10.1007/s10495-017-1385-z.
Cell death pathway plays an important role in apoptosis, and corruption of this signaling pathway has been shown to participate in carcinogenesis. We aimed at determining whether genetic variants in CASP8, CASP10 and CFLAR influence the development and clinical outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). A hospital-based case-control study, including 600 HCC cases and 600 HBsAg positive controls without HCC, was conducted to assess the relationship between 11 tagging SNPs in CASP8, CASP10 and CFLAR and HBV-related HCC risk and prognosis in a Chinese Han population. Among the 11 polymorphisms, only CASP8 rs3834129 (-652 6N ins/del) modified HCC risk. Compared with CASP8 -652 insins genotype, the deldel (adjusted OR 0.717, 95% CI 0.553-0.930) and insdel (adjusted OR 0.731, 95% CI 0.554-0.964) genotypes had a significantly decreased HCC risk. Furthermore, this polymorphism was significantly associated with decreased portal vein tumor thrombosis (adjusted OR 0.554; P = 0.044) and reduced postoperative recurrence (adjusted OR 0.356; P < 0.001) of resected HCC. In addition, the multivariate analysis showed that the -652 6N ins/del polymorphism was significantly associated with improved overall survival and recurrence-free survival of resected HCC patients. The expression levels of CASP8 in HCC tumor tissues were significantly lower than those in paracancerous liver tissues, although no significant association between -652 6N ins/del genotypes and the expression levels of CASP8 were observed in these tissues. These results suggest that the CASP8 -652 6N ins/del polymorphism may play a protective role in the development, progression, and survival of HBV-related HCC among the Chinese Han population.
细胞死亡途径在细胞凋亡中起重要作用，并且已表明该信号通路的破坏参与致癌作用。我们旨在确定半胱天冬酶8（CASP8）、半胱天冬酶10（CASP10）和含半胱氨酸的天冬氨酸蛋白水解酶8相关蛋白（CFLAR）中的基因变异是否影响乙型肝炎病毒（HBV）相关肝细胞癌（HCC）的发生发展及临床结局。开展了一项基于医院的病例对照研究，纳入600例HCC病例和600例无HCC的HBsAg阳性对照，以评估CASP8、CASP10和CFLAR中11个标签单核苷酸多态性（SNP）与中国汉族人群中HBV相关HCC风险及预后的关系。在这11个多态性中，只有CASP8 rs3834129（-652 6N插入/缺失）改变了HCC风险。与CASP8 -652插入/插入基因型相比，缺失/缺失（校正比值比[OR]0.717，95%可信区间[CI]0.553 - 0.930）和插入/缺失（校正OR 0.731，95%CI 0.554 - 0.964）基因型的HCC风险显著降低。此外，这种多态性与门静脉癌栓形成减少（校正OR 0.554；P = 0.044）及切除的HCC术后复发减少（校正OR 0.356；P < 0.001）显著相关。另外，多因素分析显示，-652 6N插入/缺失多态性与切除的HCC患者总生存期和无复发生存期改善显著相关。HCC肿瘤组织中CASP8的表达水平显著低于癌旁肝组织，尽管在这些组织中未观察到-652 6N插入/缺失基因型与CASP8表达水平之间存在显著关联。这些结果表明，CASP8 -652 6N插入/缺失多态性可能在中国汉族人群HBV相关HCC的发生、发展及生存中起保护作用。
