S－腺苷蛋氨酸对肝细胞生长因子促肝癌细胞增殖效应的影响

项目名称： S－腺苷蛋氨酸对肝细胞生长因子促肝癌细胞增殖效应的影响

项目编号： No.30872491

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 刘志苏

作者单位： 武汉大学

项目金额： 32万元

中文摘要： 稳态的SAM浓度在维持肝细胞分化状态中起中心事件作用。我们探讨了与肝癌发生、发展密切相关的三个因素对肝癌细胞稳态SAM浓度的影响。首先，我们构建不同稳态SAM浓度的细胞体系，检测不同稳态SAM浓度中，HGF对肝癌细胞促有丝分裂效应的影响。我们发HGF对肝细胞促有丝分裂效应取决于细胞内稳态SAM浓度。其次，我们探讨了HBV对肝癌细胞中稳态SAM浓度的影响。我们发现HBV感染诱发肝癌的发生与激活下游靶基因MAT2A有关，其机制归因于其结构基因中X基因通过NF-kB、CREB信号通路上调MAT2A表达，从而调节肝癌细胞中稳态SAM浓度，抑制肝癌细胞凋亡。同时，我们发现HBx抑制正常肝细胞MAT1A表达，导致MAT表达由MAT1A转变成MAT2A，最终引起肝癌的发生、发展。最后，我们探讨了缺氧应激对细胞稳态SAM浓度的影响。我们发现肝癌细胞快速生长引起的缺氧微环境通过降低细胞稳态SAM浓度诱导肝癌细胞基因组CpG岛发生去甲基化，其机制归因于HIF-1α19982;MAT2A的正相关作用。我们首次鉴定了MAT2A基因是受转录因子HIF-1α35843;控的一个新靶基因。

中文关键词： S-腺苷蛋氨酸;肝细胞生长因子;乙肝病毒X蛋白;肝癌;缺氧应激

英文摘要： S-adenosylmethionine (SAM) should not be viewed only as an intermediate metabolite in methionine catabolism, but also as an intracellular control switch that regulates essential hepatic functions such as regeneration, differentiation。We have first studied the effects of hepatocyte growth factor (HGF) on hepatoma cell mitogen in diferent level of SAM homeostasis. We found that the level of SAM homeostasis was the key in the process of HGF promoting proliferation of hepatoma cells. We have also studied the effects of HBx on SAM homeostasis during hepatocarcinogenesis.Our results indicate that HBx activates MAT2A expression through NF-kB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. This finding should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC. Furthmore, we have studied the effect of hypoxia on SAM homeostasis. We show for the first time that hypoxia induces genomicDNA demethylation through the activation of HIF-1a and transcriptional upregulation of MAT2A in hepatoma cells. This finding provide new insights into our understanding of the molecular link between genomic DNA methylation and tumor hypoxia in HCC.

英文关键词： S-adenosylmethionine;Hepatocyte growth factor;Hepatitis B virus X protein; liver cancer; Hypoxia