Pin1/ERK1/FBW7功能轴影响胰腺癌糖酵解及恶性生物学行为的实验研究

Glycolysis has been found to be closely related to the malignancy of pancreatic cancer. Previously, we found that protein FBW7 played a key role of glycolysis in pancreatic cancer.We also found that protein FBW7 was downregulated in panceatic cancer. Next we reported that MEK-ERK could destabilizes FBW7 significantly. Then, we found that Pin1 was the co-activator in the regulation of FBW7 by ERK1. We speculated that the stability of FBW7 depends on the phosphorylation of ERK1 kinase and comformational switch of Pin1. And we proposed a new molecular mechanism regulated by Pin1/ERK1/FBW7 axis in the regulation of glycolysis in pancreatic cancer. This study would be carried out around the new axis on the basis of previous work, 1. Verify the existence of the axis, 2.Detet the effect on the glycolysis and malignancy of pancreatic cancer by intervening the axis via in vitro and in vivo assay, 3.Providing the potential target for the treatment of pancreatic cancer.

糖酵解与胰腺癌的恶性生物学行为密切相关。我们前期研究首先发现FBW7是影响胰腺癌糖酵解的关键分子，而同时也发现FBW7在胰腺癌中表达缺失；实验证实胰腺癌中MEK-ERK通路活化是FBW7降解的重要机制；接着我们又发现异构酶Pin1是ERK1调控FBW7表达的共同作用分子。我们推测FBW7的降解同时需要ERK1激酶依赖的磷酸化和异构酶Pin1依赖的构象转换两个步骤。由此提出“Pin1/ERK1/FBW7”功能轴这一新的调控胰腺癌糖酵解分子机制。本课题拟围绕此功能轴进一步开展以下研究：1.验证此功能轴；2.通过体内外实验干预此功能轴，明确其对胰腺癌糖酵解及恶性生物学行为的影响；3.为临床上胰腺癌的治疗提供潜在靶点。

有氧糖酵解与胰腺癌的恶性生物学行为密切相关。我们前期研究发现FBW7是影响胰腺癌糖酵解的关键分子，实验证实胰腺癌中MEK-ERK通路活化是FBW7降解的重要机制；接着我们又发现异构酶Pin1是ERK1调控FBW7表达的共同作用分子。我们推测FBW7的降解同时需要ERK1激酶依赖的磷酸化和异构酶Pin1依赖的构象转换两个步骤。.由此提出“Pin1/ERK1/FBW7”功能轴这一新的调控胰腺癌糖酵解分子机制。本课题以此功能轴为主要研究内容，得出了以下结果：1.Pin1与ERK1和FBW7存在相互作用；2.PIN1 影响胰腺癌细胞的糖代谢重塑 ；3.探寻了FBW7下游新的底物FGFBP1。较全面地认识FBW7作为新靶点在调控胰腺癌糖酵解中的作用，为潜在靶点药物的研发及胰腺癌个体化治疗提供了新的理论基础和探索途径。