hPOT1分子调控端粒长度影响肝癌细胞恶性生物学行为的分子作用机制

项目名称： hPOT1分子调控端粒长度影响肝癌细胞恶性生物学行为的分子作用机制

项目编号： No.81201928

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 刘寒强

作者单位： 中国人民解放军第四军医大学

项目金额： 23万元

中文摘要： 端粒长度(TL)异常所致的基因组不稳定参与了肿瘤的发生及进展。人端粒保护蛋白1(hPOT1) 是新发现的一种端粒单链DNA结合蛋白，其在TL调控及染色体稳定中起重要作用。我们前期研究发现外周血TL是影响肝癌患者预后的独立因子(Carciongenesis杂志)。预实验表明肝癌组织中hPOT1的表达显著高于癌旁，并与TL呈正相关。为进一步阐明hPOT1是否通过调控TL影响肝癌细胞的恶性生物学行为，是否与肝癌患者的临床病理学特征及预后相关，其分子机制是什么？本研究首先构建hPOT1稳定过表达/基因沉默的肝癌细胞株，试图证实通过调节hPOT1的表达，能够改变TL，继而影响肝癌细胞的增殖及侵袭等恶性生物学行为；并经荷瘤裸鼠模型加以验证；在肝癌组织标本中研究hPOT1与TL、患者临床病理学特征及预后的关系。通过上述探索性研究，将有助于阐明hPOT1在肝癌发生进展中的作用,并为肝癌的防治提供分子靶标。

中文关键词： 人端粒保护蛋白1；端粒长度；肝细胞肝癌；恶性生物学行为；上皮间质转化

英文摘要： Telomere can protect chromosome stability from nucleolytic degradation, chromosome ends infusion, and chromosome aberrant recombination. Telomeres shortening is a major mechanism leading to genetic instability that accompany the carcinogenesis and progression of tumors. The human protection of telomeres 1 (hPOT1) protein, a single-strand telomeric DNA binding protein, plays an important role in telomere length (TL) regulation and chromosome stability. In our previous study, we have reported that leukocyte TL may serve as an independent prognostic marker for hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolisation.The results have been published on Feb. 8, 2012 in Carcinogenesis. Moreover, results of our preliminary experiments showed that hPOT1 protein in HCC tissues was significantly higher than in adjacent noncancerous tissues.Further analysis showed a significant positive correlation between hPOT1 and TL(r = 0.840, P＜0.001). However, the role of hPOT1 in malignant behavior of HCC cells by regulating TL remains unclear. In this study, through transfection of pcDNA3.0-hPOT1 and/or hPOT1-shRNA into HCC cell lines, a stable expression of hPOT1 / gene silencing cell model will be constructed to confirm our hypothesis that hPOT1 can regulate the TL, then affect the malignant behavior of

英文关键词： human protection of telomeres 1 (hPOT1)；telomere length (TL)；hepatocellular carcinoma (HCC)；malignant biological behavior；epithelial-mesenchymal transition (EMT)