An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk.
An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk.
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DOI：
10.1158/0008-5472.can-12-0010
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发表时间：
2012-12
期刊：
影响因子：
11.2
通讯作者：
Zhansheng Zhu;Xueren Gao;Yan He;Hua Zhao;Qiang Yu;D. Jiang;Pingzhao Zhang;Xiaopin Ma;Huixing H
中科院分区：
文献类型：
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作者：
Zhansheng Zhu;Xueren Gao;Yan He;Hua Zhao;Qiang Yu;D. Jiang;Pingzhao Zhang;Xiaopin Ma;Huixing H
脯氨酰羟化酶1（EGLN 2）已知通过调节缺氧诱导因子的降解来影响肿瘤发生。EGLN 2的多态性可能促进癌细胞在缺氧条件下的存活，并与癌症易感性直接相关。在这里，我们研究了一个4-bp的插入/缺失多态性（rs 10680577）的远端启动子EGLN 2的肝细胞癌（HCC）的风险在中国人群中的贡献。在623例HCC病例和1，242例对照中研究了rs 10680577对HCC风险的贡献，并在一项由444例HCC病例和450例对照组成的独立病例对照研究中重复。Logistic回归分析显示rs 10680577缺失等位基因与两项病例对照研究中HCC发生风险增加显著相关[OR = 1.40; 95%CI = 1.18-1.66，P < 0.0001; OR = 1.49; 95%CI = 1.18-1.88，P = 0.0007]。这种正相关性在目前吸烟者中（OR = 3.49，95%CI = 2.24-5.45）比非吸烟者（OR = 1.24，95%CI = 1.03-1.50;异质性P = 0.0002）更明显。基因型-表型相关性研究表明，在体内和体外，缺失等位基因与EGLN 2和RERT-lncRNA（一种长的非编码RNA，其序列与Ras相关GTP结合蛋白4 b（RAB 4 B）和EGLN 2）的高表达显著相关。此外，RERT-lncRNA表达也与体内EGLN 2表达显着相关，这与体外功能获得研究一致，表明过表达RERT-lncRNA上调EGLN 2。最后，计算机预测表明插入等位基因可以破坏RERT-lncRNA的结构。总之，我们的研究结果为rs 10680577可能通过影响RERT-lncRNA结构和随后的EGLN 2表达而促进肝癌发生的假设提供了强有力的证据，使其成为HCC早期诊断的有希望的生物标志物。
The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxia-inducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case-control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case-control studies [OR = 1.40; 95% confidence interval (CI) = 1.18-1.66, P < 0.0001; OR = 1.49; 95% CI = 1.18-1.88, P = 0.0007]. Such positive association was more pronounced in current smokers (OR = 3.49, 95% CI = 2.24-5.45) than nonsmokers (OR = 1.24, 95% CI = 1.03-1.50; heterogeneity P = 0.0002). Genotype-phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-of-function study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC.