LncRNA GAS5启动子区插入/缺失多态与肝细胞肝癌发病的关联研究

Long noncoding RNA is one kind of RNA that with little or without open reading frame, which plays its role in regulating gene expression in multilayer as RNA. Recent studies have suggested that the dysregulated expression of lncRNA GAS5 was involved in many cancers including hepatocellular carcinoma (HCC), however, researches were mainly on the role it played in cancers, only few studies on the regulation mechanism of itself in cancers. Our preliminary study showed that an indel polymorphism rs145204276 in the upstream of GAS5 transcriptional start point was associated with the susceptibility to HCC, and the expression level of GAS5 in HCC tissues with different genotypes was significant different, later experiment demonstrated that the region indel rs145204276 located in was the promoter region of GAS5. To further reveal the mechanism of the association between the indel polymorphism and HCC, we will adopt double center large samples case-control study combined with multiple system function study, which will supply valuable theoretical foundation for the risk prediction、community prevention and individual therapy of HCC.

长链非编码RNAs（lncRNAs）是无或少有蛋白编码能力的长链非编码RNA，以RNA 形式在多层面调控基因表达。近期研究表明lncRNA GAS5的异常表达与包括肝细胞肝癌（Hepatocellular carcinoma，HCC）在内的多种肿瘤有关，但研究多集中于GAS5在肿瘤中发挥作用的机制，对其自身在肿瘤中表达失调的原因较少涉及。我们前期研究发现位于GAS5转录起始点上游的插入缺失（indel）多态rs145204276与HCC的易感性有关，不同基因型的HCC组织GAS5的表达水平存在显著差异，并证实indel所在区域为GAS5的启动子区。本项目拟在前期工作基础上，采用双中心大样本量病例对照研究模式结合多系统功能研究，进一步探讨indel多态与HCC发生发展的关系，以期阐明遗传多态参与调控GAS5表达的分子机制。为HCC发生的风险预测、人群的预防及个体化防治提供有价值的理论依据。

长链非编码RNAs（lncRNAs）是无或少有蛋白编码能力的长链非编码RNA，以RNA 形式在多层面调控基因表达。近期研究表明lncRNA GAS5的异常表达与包括肝细胞肝癌（Hepatocellular carcinoma，HCC）在内的多种肿瘤有关，但研究多集中于GAS5在肿瘤中发挥作用的机制，对其自身在肿瘤中表达失调的原因较少涉及。我们近期的研究表明位于lncRNA GAS5启动子区的插入缺失多态与HCC的发生发展显著相关，并获得了其参与HCC发生发展的可靠证据。本项目采用生物信息学方法筛选出位于GAS5潜在功能区内的候选Indel（rs145204276），然后先后通过病例对照研究、基因型表型关联研究、双荧光素酶报告基因系统及焦磷酸测序等方法深入研究了该Indel在HCC发生发展过程中的分子机制。实验结果表明，该Indel可能通过影响GAS5启动子区的甲基化状态进而影响GAS的转录活性，从而参与HCC的发生发展，为HCC 发生的风险预测、人群的预防及个体化防治提供有价值的理论依据。