非编码端粒RNA异常表达在肝癌恶性进展中的生物学意义及机制研究

Telomeric repeat-containing RNA (TERRA), a large non-coding RNA, has been identified in a variety of eukaryotes recently, which acts as a regulator of telomere function and telomerase activity, thus is implicated in development, aging and carcinogenesis. TERRA transcription is regulated by several mechanisms, including telomere-binding protein and subtelomeric DNA methylation status. Our preliminary study revealed that TERRA was signi?cantly down-regulated, and subtelomeric regions were hypermethylated in hepatocellular carcinoma (HCC) tissues. There was a significant negative correlation between subtelomeric methylation status and TERRA transcription in subsequent correlation analysis. These findings suggest that subtelomeric DNA hypermethylation may negatively regulate TERRA expression, resulting in telomere dysfunction, which is implicated in HCC progression. This study aims to explore potential role of down-regulated TERRA in HCC and regulation of subtelomeric methylation on TERRA expression via cell, animal model and large sample analysis of clinical tissue from HCC patients. The project will be of great signification for prevention and treatment of HCC.

端粒RNA是新发现的一种非编码RNA。最近研究表明，端粒RNA参与形成端粒结构，可通过抑制端粒酶活性参与调控端粒长度和功能，在发育、衰老和肿瘤发生中发挥重要作用。端粒RNA的表达调控受端粒结合蛋白及亚端粒区的甲基化修饰等多种因素影响。课题组前期研究表明，肝癌组织中端粒RNA表达降低，同时肝癌组织亚端粒区甲基化水平增强，进一步分析发现，亚端粒区甲基化程度与端粒RNA的表达呈显著负相关。上述研究结果提示，肝癌细胞亚端粒区的高甲基化修饰可能与端粒RNA的低表达相关，导致端粒功能异常，进而参与肝癌的恶性进展。本研究拟从细胞、整体动物和临床标本三个层次，系统分析端粒RNA表达下调在肝癌恶性进展过程中的生物学作用及其分子机制，探讨亚端粒区甲基化修饰对端粒RNA表达的调控作用，为肝癌防治提供新的理论依据。

端粒RNA是新发现的一种非编码RNA。最近研究表明，端粒RNA参与形成端粒结构，可通过抑制端粒酶活性参与调控端粒长度和功能，在发育、衰老和肿瘤发生中发挥重要作用。端粒RNA的表达调控受端粒结合蛋白及亚端粒区的甲基化修饰等多种因素影响。以往多项研究均证实端粒RNA与多种肿瘤的发生发展密切相关，但目前尚未见端粒RNA调控肝癌发生发展的具体分子机制。本研究中，我们利用免疫组化、Western Blot、MTS、EdU、流式细胞术等分子生物学技术和小鼠模型构建等技术检测端粒RNA与肝癌恶性表型相关性，分析发现端粒RNA可显著抑制肝癌细胞增殖和转移，同时促进细胞凋亡；端粒RNA与患者的预后显著相关；在体内和体外水平证实端粒RNA参与肝癌细胞增殖、凋亡和转移的调控。本项目的完成对于建立肝癌的预防、肝癌患者治疗靶点的选择和明确的分子机制具有重要的意义。