A Novel Tetranucleotide Repeat Polymorphism Within KCNQ1OT1 Confers Risk for Hepatocellular Carcinoma
A Novel Tetranucleotide Repeat Polymorphism Within KCNQ1OT1 Confers Risk for Hepatocellular Carcinoma
复制标题
KCNQ1OT1 内的新型四核苷酸重复多态性会增加肝细胞癌的风险
DOI：
10.1089/dna.2013.2118
复制
发表时间：
2013-11-01
影响因子：
3.1
通讯作者：
Gao, Yuzhen
中科院分区：
文献类型：
--
作者：
Wan, Jiao;Huang, Moli;Gao, Yuzhen
KCNQ1重叠转录本1（KCNQ1OT1）是一种长链非编码RNA，负责顺式沉默一组基因，已被证明与多种癌症有关。然而，KCNQ1OT1如何促进癌症发生仍有很多不清楚的地方。通过对中国人群中的510例肝细胞癌（HCC）病例和1014例健康对照进行全面分析，我们在KCNQ1OT1编码区发现了一种新的短串联重复（STR）多态性（rs35622507），并评估了其与HCC易感性的关联。逻辑回归分析表明，与携带纯合子10 - 10基因型的个体相比，仅携带一个10等位基因的杂合子个体患HCC的风险显著降低（调整后的优势比[OR]=0.67，95%置信区间[CI]=0.53 - 0.86，p = 0.0009），而不携带10等位基因的个体风险降低更显著（调整后的OR = 0.38，95% CI = 0.21 - 0.69，p = 0.0005）。此外，使用四种肝癌细胞系进行的基因型 - 表型相关性研究支持STR基因型与KCNQ1OT1表达之间存在显著关联。不携带10等位基因的细胞系中KCNQ1OT1的表达量高20.9 - 33.3倍。同时，在三种肝癌细胞系中，KCNQ1OT1的表达与细胞周期蛋白依赖性激酶抑制剂1C（CDKN1C）的表达呈负相关，CDKN1C是位于CDKN1C/KCNQ1OT1印记区域的一种肿瘤抑制基因。最后，计算机预测表明不同的等位基因可能改变KCNQ1OT1的局部结构。综上所述，我们的研究结果表明KCNQ1OT1内的STR多态性可能通过一种结构依赖机制影响KCNQ1OT1和CDKN1C的表达，从而促进肝癌的发生。我们的研究需要重复验证，并且需要进一步的功能研究来验证我们的假设，并了解KCNQ1OT1多态性在HCC易感性中的作用。
KCNQ1 overlapping transcript 1 (KCNQ1OT1), a long noncoding RNA responsible for silencing a cluster of genes in cis, has been shown to be involved in multiple cancers. However, much remains unclear of how KCNQ1OT1 contributes to carcinogenesis. By thoroughly analyzing 510 hepatocellular carcinoma (HCC) cases and 1014 healthy controls in a Chinese population, we identified a novel short tandem repeat (STR) polymorphism (rs35622507) within the KCNQ1OT1 coding region and evaluated its association with HCC susceptibility. Logistic regression analysis showed that compared with individuals carrying the homozygote 10-10 genotype, those heterozygote subjects who carry only one allele 10 had a significantly decreased risk of HCC (adjusted odds ratio [OR]=0.67, 95% confidence interval [CI]=0.53-0.86, p=0.0009), with the risk decreased even further in those without allele 10 (adjusted OR=0.38, 95% CI=0.21-0.69, p=0.0005). Furthermore, genotype-phenotype correlation studies using four hepatoma cell lines support a significant association between STR genotypes and the expression of KCNQ1OT1. Cell lines without allele 10 conferred a 20.9-33.3-fold higher expression of KCNQ1OT1. Meanwhile, KCNQ1OT1 expression was reversely correlated with the expression of the cyclin-dependent kinase inhibitor 1C (CDKN1C), a tumor suppressor gene located within the CDKN1C/KCNQ1OT1 imprinted region, in three hepatoma cell lines. Finally, in silico prediction suggested that different alleles could alter the local structure of KCNQ1OT1. Taken together, our findings suggest that the STR polymorphism within KCNQ1OT1 contributes to hepatocarcinogenesis, possibly by affecting KCNQ1OT1 and CDKN1C expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our hypothesis and understand the roles of KCNQ1OT1 polymorphisms in predisposition for HCC.