长链非编码RNA lncLCSC调控肝癌干细胞自我更新的分子机制研究

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide. The molecular basis for this clinical.heterogeneity remains incompletely understood. Long noncoding RNAs (lncRNAs) are transcribed from thousands of loci in mammalian genomes and might play widespread roles in gene regulation and other cellular processes. LncRNAs have become the forefront and hotspot in cancer research, and play important roles in cancer progression, invasiveness and metastasis. So far, however, little is known about the function and mechanism of lncRNA in cancer stem cells. This project is therefore aiming to explore the self-renewal regulation of lncRNA in liver cancer stem cells. By the whole transcriptome microarray and bioinformatics analyses, differential lncRNAs were co-expressed with genes related to transcriptional regulation, cell cycle, and chromatin remolding complexes. Here we characterize a lncRNA termed lncLCSC that is overexpressed in liver cancer stem cells and a subset of HCC cancer patients. Knockdown of lncLCSC caused smaller numbers of HCC cell spheres, significant down-expression of SOX2, NANOG, and a neighbored gene TCF7 compared with controls. This study will further investigate the self-renewal roles and mechanisms of lncLCSC in liver cancer stem cells. We will identify lncLCSC downstream target genes and elucidate the interacting proteins regulating lncLCSC expression. We will further elucidate the regulating mechanisms of lncLCSC on TCF7. Then, we will examine the relationship between lncLCSC and prognosis of HCC patients. Taken together, this study will systematically provide new insights into the molecular mechanism for the function of lncLCSC in self-renewal of liver cancer stem cells, and help to provide theoretical foundations and reveal the more effective treatment targets for liver cancer.

近年来，长链非编码RNA（lncRNA）已成为生命科学研究的前沿和热点。lncRNA在肿瘤发生发展中亦发挥着重要作用，但是在肿瘤干细胞中的研究还未见报道。因此，本课题将深入研究lncRNA对肝癌干细胞自我更新的调控及机制。通过全转录组芯片分析，差异的lncRNA与转录调控、细胞周期及染色质修饰等相关的mRNA共表达。我们研究发现lncLCSC在肝癌干细胞中显著高表达，其缺失导致干细胞小球数量显著减少，干细胞中SOX2和NANOG的表达显著下调，其相邻基因TCF7的表达显著下调。在此基础上，本课题将深入研究lncLCSC在肝癌干细胞自我更新的作用，鉴定lncLCSC的下游靶基因及相互作用蛋白，阐明lncLCSC对TCF7调控的分子机制，揭示lncLCSC通过调控TCF7进而对肿瘤干细胞自我更新调控的分子机理，为肝癌的治疗提供新的理论基础和干预靶点。

深入研究肝癌发生发展的分子机制对于肝癌的有效治疗是至关重要的。近年来，长链非编码RNA（lncRNA）已成为肿瘤学研究的前沿和热点，在多种肿瘤发生发展中发挥着重要作用，但是在肿瘤干细胞中的研究报道较少。本课题研究发现长链非编码RNA lncTCF7在肝癌干细胞和肝癌组织中高表达，lncTCF7主要定位在细胞核中，Northern结果显示其在肝癌细胞中只有1个转录本。lncTCF7的低表达抑制了肝癌干细胞小球形成、皮下肿瘤形成等肝癌干细胞的自我更新，lncTCF7的高表达促进了肝癌干细胞的自我更新。lncTCF7可以通过招募SWI/SNF复合物到其相邻基因TCF7的启动子区，调控TCF7的表达，进而调控Wnt信号通路，促进肝癌干细胞的自我更新。为肝癌的治疗提供新的理论基础和干预靶点。