乏氧应激上调GOLM1促进肝细胞癌恶性潜能的作用及其机制研究

项目名称： 乏氧应激上调GOLM1促进肝细胞癌恶性潜能的作用及其机制研究

项目编号： No.81472677

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 朱文伟

作者单位： 复旦大学

项目金额： 72万元

中文摘要： 乏氧应激与肝癌侵袭、转移及治疗抵抗等恶性潜能密切相关。我们前期通过高通量基因组学筛选技术发现，GOLM1与肝癌乏氧相关恶性潜能密切联系；深入研究证实，GOLM1在肝癌乏氧应激环境中显著上调，并促进肝癌乏氧相关侵袭、转移及治疗抵抗恶性潜能；基于蛋白-蛋白相互作用分析及前期研究提示，我们又推测HIF1A是GOLM1调控肝癌乏氧应激相关恶性潜能的关键中间衔接分子，由此提出GOLM1-HIF1A-乏氧应激-恶性潜能功能轴这一新的分子机制。本课题拟在前期研究基础上，进一步围绕此功能轴展开以下研究：①分析肝癌细胞中GOLM1、HIF1A在表达和功能上的联系，对此功能轴进行验证；②在肝癌临床样本中检测GOLM1、HIF1A的表达，探讨此功能轴与肝癌患者转移复发及预后的关系；③通过体内、体外实验，干预此功能轴，明确其对肝癌侵袭转移及治疗抵抗的影响；为肝癌转移复发提供有效的预测模型和干预靶点。

中文关键词： C09_肝和肝内胆管肿瘤；GOLM1；肿瘤转移；乏氧应激；治疗抵抗

英文摘要： It is well acknowledged that hypoxic stress and malignant phenotype such as invasion, metastasis as well as therapy resistance are closely related in hepatocellular carcinoma(HCC).Previously,we had demonstrated that expression of GOLM1 was closely correlated with hypoxia-associated malignant phenotype in HCC by means of a high-throughput genomic filtering technology. In-depth study, we found that GOLM1 was significantly up-regulated in hypoxic environment which in turn regulated hypoxia-related malignant phenotype such as invasion, metastasis, angiogenesis and threapy resistance of HCC cells. Based on our previous study about the protein interactions, we speculated that HIF1A may have an important role as a connected molecular between GOLM1 and hypoixa-related invasion, metastasis, angiogenesis and treatment resistance. So we suggest that there is a new molecular mechanism as an axis of GOLM1-HIF1A-hypoxia-malignant potential to take effect and we are going to carry out some researches on this functional axis as below: 1. Analyze the connection between the GOLM1,HIF1A both structurally and functionally in HCC for the confirmation of this axis. 2. Determinate the expression of these molecular in clinical specimens to investigate the correlation between this axis and recurrence ，metastasis and poor prognosis of HCC patients. 3. Disturb this functional axis by some in vitro and in vivo assays for further validation that it can effectively predict the recurrence and serve as a potential therapeutic target in HCC.

英文关键词： hepatocellular carcinoma;GOLM1;cancer metastasis;hypoixa stress;therapy resistance