Department of Medical Research, Terry Fox Cancer Research Lab, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404 Taiwan.
Anticancer Res. 2013 Feb;33(2):529-35.
Hepatocellular carcinoma (HCC) is a neoplasm for which the prevalence and mortality rates are very high in Taiwan. The DNA non-homologous end-joining repair gene XRCC6/Ku70 plays an important role in the repair of DNA double-strand breaks (DSBs) induced by both exogenous and endogenous DNA-damaging agents. Defects in overall DSB repair capacity can lead to genomic instability and carcinogenesis. In this study, we investigated the contribution of variant XRCC6 in relation to the risk of HCC, from the levels of DNA, RNA and protein.
In this hospital-based case-control study, we collected 298 patients with HCC and 298 cancer-free controls, with frequency matched by age and gender. Firstly, the associations of XRCC6 promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron-3 (rs132774) polymorphisms with HCC risk in this Taiwanese population were evaluated. Secondly, 30 HCC tissue samples with variant genotypes were tested to estimate the XRCC6 mRNA expression by real-time quantitative reverse transcription. Finally, the HCC tissue samples of variant genotypes were examined by immunohistochemistry and western blotting to estimate their XRCC6 protein expression levels.
Compared with the TT genotype, the TC and CC genotypes conferred a significantly increased risk of HCC [adjusted odds ratio (aOR)=2.43 and 3.52, 95% confidence interval (CI)=1.52-4.03 and 1.18-13.36, p=0.0003 and 0.0385, respectively]. The mRNA and protein expression levels in HCC tissues revealed statistically significantly lower XRCC6 mRNA and protein expressions in the HCC samples with TC/CC genotypes compared with those with the TT genotype (p=0.0037 and 0.0003, respectively).
Our multi-approach findings at the DNA, RNA and protein levels suggested that XRCC6 may play an important role in HCC carcinogenesis in the Taiwanese population.
肝细胞癌（HCC）是一种在台湾患病率和死亡率都非常高的肿瘤。DNA 非同源末端连接修复基因 XRCC6/Ku70 在修复内外源 DNA 损伤剂诱导的 DNA 双链断裂（DSB）方面发挥着重要作用。整体 DSB 修复能力的缺陷可导致基因组不稳定和致癌作用。在这项研究中，我们从 DNA、RNA 和蛋白质水平研究了变体 XRCC6 与 HCC 风险之间的关系。
本病例对照研究以医院为基础，共收集了 298 例 HCC 患者和 298 例无癌症对照者，年龄和性别按频率匹配。首先，评估 XRCC6 启动子 T-991C（rs5751129）、启动子 G-57C（rs2267437）、启动子 A-31G（rs132770）和内含子 3（rs132774）多态性与台湾人群 HCC 风险的相关性。其次，对 30 例具有变体基因型的 HCC 组织样本进行实时定量逆转录检测 XRCC6 mRNA 表达。最后，通过免疫组织化学和蛋白质印迹法检测变体基因型的 HCC 组织样本，以评估其 XRCC6 蛋白表达水平。
与 TT 基因型相比，TC 和 CC 基因型显著增加 HCC 的发病风险[校正比值比（aOR）=2.43 和 3.52，95%置信区间（CI）=1.52-4.03 和 1.18-13.36，p=0.0003 和 0.0385]。与 TT 基因型相比，TC/CC 基因型 HCC 组织中 XRCC6 mRNA 和蛋白表达水平明显降低（p=0.0037 和 0.0003）。
在 DNA、RNA 和蛋白质水平上的多方法研究结果表明，XRCC6 可能在台湾人群的 HCC 致癌作用中发挥重要作用。
