The rs391957 variant cis-regulating oncogene GRP78 expression contributes to the risk of hepatocellular carcinoma
The rs391957 variant cis-regulating oncogene GRP78 expression contributes to the risk of hepatocellular carcinoma
复制标题
rs391957 变异顺式调节癌基因 GRP78 的表达会增加患肝细胞癌的风险。
DOI：
10.1093/carcin/bgt061
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发表时间：
2013-06-01
期刊：
影响因子：
4.7
通讯作者：
Li, Dongpei
中科院分区：
文献类型：
--
作者：
Zhu, Xiao;Zhang, Jinfang;Li, Dongpei
葡萄糖调节蛋白78（GRP 78）是对疾病相关应激最重要的反应者之一。我们评估了中国人群中GRP 78启动子多态性与肝细胞癌（HCC）风险和GRP 78表达的相关性。我们检查了1007例诊断性HCC患者和810例无关的健康对照。GRP 78启动子多态性调节HCC风险和GRP 78水平的机制进行了分析。携带rs391957（-415bp）等位基因G和GG基因型的启动子单倍型和双倍型与HCC的危险性密切相关。荧光素酶报告基因检测结果表明，携带rs391957等位基因G（单倍型GCCd）的启动子在HepG 2细胞和Hela细胞中显示出增加的活性。rs391957还显示出增加转录激活因子Ets-2的亲和力、对凋亡的抗性以及应激微环境中的细胞不稳定性。与等位基因A相比，rs391957等位基因G与肝癌组织中GRP 78 mRNA和蛋白水平升高相关。这些发现为HCC的发病机制提供了新的见解，并为rs391957和Ets-2之间的相互作用在肝癌发生中的意想不到的效果提供了新的见解，特别是支持了影响转录调控的应激相关和进化保守的遗传变异可以预测易感性的假设。
Glucose-regulated protein 78 (GRP78) is one of the most important responders to disease-related stress. We assessed the association of the promoter polymorphisms of GRP78 with risk of hepatocellular carcinoma (HCC) and GRP78 expression in a Chinese population. We examined 1007 patients undergoing diagnostic HCC and 810 unrelated healthy controls. Mechanisms by which the GRP78 promoter polymorphism modulates HCC risk and GRP78 levels were analyzed. The promoter haplotype and diplotype carrying rs391957 (-415bp) allele G and genotype GG was strongly associated with HCC risk. Luciferase reporter assays indicated that the promoter carrying rs391957 allele G (haplotype GCCd) showed increased activity in HepG2 cells and Hela cells. rs391957 was also shown to increase the affinity of the transcriptional activator Ets-2, the resistance to apoptosis, as well as cell instability in stressful microenvironment. Furthermore, compared with allele A, rs391957 allele G was associated with higher levels of GRP78 mRNA and protein in HCC tissues. These findings provided new insights into the pathogenesis of HCC and an unexpected effect of the interaction between rs391957 and Ets-2 on hepatocarcinogenesis, and especially supported the hypothesis that stress-related and evolutionarily conserved genetic variant(s) influencing transcriptional regulation could predict susceptibilities.