ENO1通过HIF-1α调控PLOD2的表达从而促进胶质瘤细胞糖酵解介导的侵袭作用

Aberrant glucose metabolism is one of the ten characteristics of the tumor, thereby cutting off the tumor cells’ energy supply by interfere with glycolysis may be a key way for cancer treatment . ENO1 is one of the reaction rate-limiting enzymes of glycolysis. Our previous study showed that ENO1 was downregulated iin normal brain tissues compared to glioma tissues at the mRNA and protein levels. Furthermore, increased ENO1 was associated disease progression of glioma samples. Knocking down ENO1 expression not only significantly decreased cell proliferation, but also markedly inhibited the ability of cell migration and invasion as well as iin vivo tumorigenesis. In preliminary experiments, we have built models of hypoxic enviroment of glioma cells by physical and chemical methods, and found that the expression of HIF-1α, as a key factor of glycolysis , was a positive correlation among the expression of ENO1 and PLOD2. Further, the expression of Akt phosphorylation and PLOD2 were significantly suppressed after knocking down the expression of ENO1 by real-time PCR in glioma cells. Furthermore, downregulation of PLOD2 using siRNA-PLOD2 also inhibited cell migration and invasion in U251 and U87 cells. In this study, using gene transfection, ChIP, luciferase reporter system, functional experiment in vivo and in vitro, we attempt to explore a novel regulatory mechanism of ENO1, promots the glycolysis mediated invasion progression by activating the PI3K/Akt pathway and regulating the expression of PLOD2 thougt HIF-1α in glioma.We anticipate that our results will provide new insight into the molecular mechanism for glioma, and this will be helpful in identifying potential candidates for intervention aerobic glycolysis to block glioma cell energy supply and targeting acidic microenvironment to inhibit tumor invasion.

糖代谢异常是肿瘤的十大特征之一，干扰糖酵解从而切断肿瘤细胞的能量供应可能是治疗恶性肿瘤的一个关键途径。ENO1是一种糖酵解反应限速酶，我们前期研究发现，ENO1在胶质瘤中高表达，并促进胶质瘤细胞增殖、侵袭及促进细胞体内成瘤能力。在预实验中，干扰ENO1表达后能抑制Akt磷酸化及糖酵解过程中关键因子HIF-1α的表达，而PI3K/Akt信号通路可以调控HIF-1α，同时在缺氧条件下HIF-1α能诱导PLOD2的表达，干扰胶质瘤细胞PLOD2表达后，细胞的侵袭能力减弱。本项目拟利用基因转染、ChIP、荧光素酶报告系统、体内外功能实验验证一个新的ENO1表达调控的机制，即ENO1通过PI3K/Akt信号通路调控HIF-1α并诱导PLOD2的表达，进而促进胶质瘤细胞糖酵解介导的侵袭作用。如本项目顺利开展，将为干预有氧糖酵解以阻断胶质瘤细胞能量供应和靶向酸性微环境以抑制肿瘤的侵袭提供供新的基因靶点。

糖代谢异常是肿瘤的十大特征之一，干扰糖酵解从而切断肿瘤细胞的能量供应可能是治疗恶性肿瘤的一个关键途径。ENO1是一种糖酵解反应限速酶，我们研究发现，ENO1在胶质瘤中高表达，并促进胶质瘤细胞增殖、侵袭及促进细胞体内成瘤能力。干扰ENO1表达后能抑制Akt磷酸化及糖酵解过程中关键因子HIF-1α的表达，而PI3K/Akt信号通路可以调控HIF-1α，同时在缺氧条件下HIF-1α能诱导PLOD2的表达，干扰胶质瘤细胞PLOD2表达后，细胞的侵袭能力减弱。本项目利用基因转染、ChIP、荧光素酶报告系统、体内外功能实验验证一个新的ENO1表达调控的机制，即ENO1通过PI3K/Akt信号通路调控HIF-1α并诱导PLOD2的表达，进而促进胶质瘤细胞糖酵解介导的侵袭作用。为干预有氧糖酵解以阻断胶质瘤细胞能量供应和靶向酸性微环境以抑制肿瘤的侵袭提供新的基因靶点。