一个新克隆的长链非编码RNA调控肝细胞癌增殖的机制研究

Hepatocellular carcinoma (HCC) is one of the most common and lethal types of malignant tumors in China. Recently, using RNA-Sequencing (RNA-Seq) strategies based on next-generation sequencing (NGS) technologies, we sequenced the transcriptome of HCC cells and cloned a new long non-coding RNA (lncRNA) gene located on chromosome 11q13.1. This lncRNA is up-regulated in HCC cells and is associated with poor HCC prognosis. Inhibition of this lncRNA in HCC cells using shRNAs could suppress the proliferation of these tumor cells. Furthermore, this lncRNA is located in a high-frequency amplification region of the HCC genome and is only 150 kb from the important oncogene CCND1, which encodes the cyclin D1 protein. Preliminary data show that expression of this lncRNA is positively correlated with expression of CCND1. In the proposed project, we will explore potential causes for the up-regulation of this novel lncRNA in HCC cells, we will examine the regulatory relationship between this lncRNA and CCND1, and we will identify the downstream signaling pathways that affect HCC proliferation. Together, these experiments will help elucidate the molecular mechanisms linking this novel lncRNA to HCC initiation and development. Achieving the goals in this proposal will provide new experimental data for etiological studies, new molecules for use as prognostic and diagnostic markers, and new targets for novel HCC therapies.

肝细胞癌是我国发病率和病死率最高的恶性肿瘤之一。最近我们通过新一代测序技术对肝细胞癌的RNA进行大规模测序（RNA-Seq）在染色体11q13.1区域发现并克隆了一个新的长链非编码RNA（lncRNA）基因，已初步证实该lncRNA在肝癌中表达上调，且与肝癌预后相关。利用shRNA在肝癌细胞中干扰该lncRNA的表达可抑制肝癌细胞的增殖。该lncRNA位于肝癌基因组高频扩增区域，距重要瘤基因CCND1（编码cyclinD1）仅150Kb，我们初步证实该lncRNA与CCND1的表达相关。本项目拟进一步探讨该lncRNA在肝癌中表达上调的可能原因，它与CCND1间的调控关系及它调控肝癌细胞增殖所涉及的下游信号通路，从而初步阐明这一新克隆lncRNA分子在肝癌发生发展中的作用机制。本项目的完成将为肝癌的病因发病学提供新的实验资料，并提供新的肝癌治疗靶点及诊断和预后分子标记。

肝细胞癌是我国发病率和病死率最高的恶性肿瘤之一。我们通过新一代测序技术对肝细胞癌的RNA进行大规模测序（RNA-Seq）在染色体11q13.1区域发现并克隆了一个新的长链非编码RNA（lncRNA）基因，已初步证实该lncRNA在肝癌中表达上调，且与肝癌预后相关。利用shRNA在肝癌细胞中干扰该lncRNA的表达可抑制肝癌细胞的增殖。该lncRNA位于肝癌基因组高频扩增区域，距重要瘤基因CCND1（编码cyclinD1）仅150Kb，我们初步证实该lncRNA与CCND1的表达相关，并初步探讨了该lncRNA在肝癌中表达上调的可能原因，它与CCND1间的调控关系及它调控肝癌细胞增殖所涉及的下游信号通路，从而初步阐明了这一新克隆lncRNA分子在肝癌发生发展中的作用机制。本项目的完成为肝癌的病因发病学提供新的实验资料，并提供了新的肝癌治疗靶点及诊断和预后分子标记。