Ali Nermin A, Hamdy Nadia M, Gibriel Abdullah A, El Mesallamy Hala O
Biochemistry and Molecular Biology Department, Faculty of Pharmacy, The British University in Egypt (BUE), El Sherouk, Cairo, Egypt.
Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
Arch Virol. 2021 Jun;166(6):1643-1651. doi: 10.1007/s00705-021-04981-8. Epub 2021 Apr 1.
The Ras association domain family 1 isoform A (RASSF1A), cytotoxic T lymphocyte antigen 4 (CTLA-4), and signal transducer and activator of transcription 4 (STAT4) genes play a role in regulating the cell cycle, apoptosis, and the autoimmune response against cancer. We investigated the genotype frequency and the possible association of the rs2073498 (RASSF1A), rs5742909 (CTLA-4) and rs7574865 (STAT4) genetic variants with hepatitis C virus (HCV)-G4-mediated hepatocellular carcinoma (HCC) progression in Egyptian patients. Fifty patients with HCV infection, 50 patients with HCV-mediated HCC, and 50 age- and sex-matched healthy controls were recruited. The investigated variants were genotyped based on polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The Ser133 mutant G4 variant of the rs2073498 SNP in RASSF1A exhibited a positive correlation with HCC incidence risk (OR = 0.571, 95% CI = 0.175-1.865, P < 0.001). The rs7574865 variant in STAT4 (G/T) occurred frequently in both HCV groups, with a significant incidence risk (OR = 1.583, 95% CI = 1.123-2.232, P = 0.005). The rs5742909 change in CTLA4 (C/T) did not show a significant difference between HCV-mediated HCC cases and the control group (OR = 4.5, 95% CI = 1.326-15.277, P > 0.001). Activation of the immune checkpoint gene CTLA4 or polymorphism in the encoded CTLA4 protein causes phosphorylation of kinases needed for RAS gene activation. This in turn downregulates the tumor suppressor RASSF1, inhibiting apoptosis and leading to HCC development, indicating a negative impact of CTLA4 gene polymorphism on HCV-mediated HCC cases. A major determinant of disease progression could be immune system genetic variants, together with the presence of costimulatory factors. The rs2073498 and rs7574865 variations in the RASSF1A and STAT4 genes, respectively, could be genetic susceptibility factors for Egyptian patients with HCV-mediated HCC.
Ras关联结构域家族1亚型A（RASSF1A）、细胞毒性T淋巴细胞抗原4（CTLA-4）和信号转导及转录激活因子4（STAT4）基因在调节细胞周期、细胞凋亡以及针对癌症的自身免疫反应中发挥作用。我们调查了埃及患者中rs2073498（RASSF1A）、rs5742909（CTLA-4）和rs7574865（STAT4）基因变异的基因型频率以及它们与丙型肝炎病毒（HCV）-G4介导的肝细胞癌（HCC）进展的可能关联。招募了50例HCV感染患者、50例HCV介导的HCC患者以及50例年龄和性别匹配的健康对照。基于聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对所研究的变异进行基因分型。RASSF1A中rs2073498 SNP的Ser133突变G4变异与HCC发病风险呈正相关（OR = 0.571，95% CI = 0.175 - 1.865，P < 0.001）。STAT4中的rs7574865变异（G/T）在两个HCV组中均频繁出现，具有显著的发病风险（OR = 1.583，95% CI = 1.123 - 2.232，P = 0.005）。CTLA4中的rs5742909变化（C/T）在HCV介导的HCC病例与对照组之间未显示出显著差异（OR = 4.5，95% CI = 1.326 - 15.277，P > 0.001）。免疫检查点基因CTLA4的激活或编码的CTLA4蛋白中的多态性会导致RAS基因激活所需激酶的磷酸化。这反过来会下调肿瘤抑制因子RASSF1，抑制细胞凋亡并导致HCC发展，表明CTLA4基因多态性对HCV介导的HCC病例有负面影响。疾病进展的一个主要决定因素可能是免疫系统基因变异以及共刺激因子的存在。RASSF1A和STAT4基因中的rs2073498和rs7574865变异分别可能是埃及HCV介导的HCC患者的遗传易感性因素。
