PGK-1通过Hsp90引起Akt/GSK-3β/β-catenin通路活化促进肝癌转移分子机制研究

The aerobic glycolysis is the typical characteristic of metabolism in cancer. Phosphoglycerate kinase 1 (PGK-1) is a major rate-limiting enzyme in mammalian glycolytic pathway. Our previous study revealed PGK-1 was the most significant up-regulated gene in hepatocellular carcinoma (HCC) tissues with lung metastasis compared with those without lung metastasis and further study indicated that the overexpression of PGK1 could promote invasion and metastasis of HCC cells through activation of Akt/GSK-3β/β-catenin signaling pathway and predict recurrence and poor clinical outcomes of patients with HCC after curative liver resection. Our co-IP results suggested a possible interaction between PGK1 and Hsp90 which proposed that Hsp90 might participate in PGK-1 induced Akt/GSK-3β/β-catenin signaling activation in HCC cells. In the present research we will explore underlying mechanism of PGK-1modulation promoting HCC metastasis including up-regulation of Hsp90 activity, activation of Akt/GSK-3β/β-catenin signaling pathway through a series of in vitro assays such as plasmid transfection, co-IP, ubiquitination analysis. Human HCC tissue samples and nude mice will be used to certify our results in vitro. The research may provide preclinical data for the novel potential therapeutic targets in the treatment of HCC．

糖酵解增强是肿瘤代谢的基本特征，磷酸甘油激酶1（PGK-1）是糖酵解过程中重要的限速酶。本课题组前期研究显示肝癌组织中PGK-1表达在有肺转移肝癌组织中显著高于未发生转移的肝癌，并与肝癌患者根治性切除术后复发转移密切相关。进一步研究发现PGK-1除了影响糖酵解外，还可促进Akt/GSK-3β/β-catenin 信号通路，免疫共沉淀发现PGK-1可与热休克蛋白90（Hsp90）相互结合，提示Hsp90可能介导了PGK-1引起的Akt/GSK-3β/β-catenin 通路的活化。本研究拟通过质粒转染、免疫共沉淀、泛素化水平检测等方法，研究PGK-1调节Hsp90分子伴侣活性，介导Akt/GSK-3β/β-catenin 信号通路的分子机制；并进一步在肝癌组织和裸鼠模型中验证其相关性。从而阐明PGK-1促进肝癌转移的分子机制，为干预肝癌转移寻找新的分子靶点，提高肝癌综合治疗效果提供理论依据。

糖酵解增强是肿瘤代谢的基本特征，磷酸甘油激酶1（PGK-1）是糖酵解过程中重要的限速酶。本课题组前期研究显示肝癌组织中PGK-1表达在有肺转移肝癌组织中显著高于未发生转移的肝癌，并与肝癌患者根治性切除术后复发转移密切相关。进一步研究发现PGK-1除了影响糖酵解外，还可促进Akt/GSK-3β/β-catenin 信号通路，免疫共沉淀发现PGK-1可与热休克蛋白90（Hsp90）相互结合，提示Hsp90可能介导了PGK-1引起的Akt/GSK-3β/β-catenin 通路的活化。本研究拟通过质粒转染、免疫共沉淀、泛素化水平检测等方法，研究PGK-1调节Hsp90分子伴侣活性，介导Akt/GSK-3β/β-catenin 信号通路的分子机制；并进一步在肝癌组织和裸鼠模型中验证其相关性。从而阐明PGK-1促进肝癌转移的分子机制，为干预肝癌转移寻找新的分子靶点，提高肝癌综合治疗效果提供理论依据。