The Role Of Cross Talk Between Notch And STAT3 Pathways In The Angiogenesis And Prognosis Of The Primary Glioblastoma

Tumor development depends on interaction between tumor cells and other cells and the network control of different signaling pathways in the tumor microenvironment.Studies have shown that STAT3 activation depends on the endogenous activation of Notch,the target product of Notch signal(namely,Notch effector protein)-HES(Hairy/enhancer of split)family proteins through combining STAT3 to regulate the crosstalk between Notch and JAK-STAT signaling pathway.In addition,increased STAT3 phosphorylation can improve the activation Notch signaling pathway,and promote cell growth,differentiation and apoptosis.However,To occur two signaling pathway cross talk in which cells are not clear in the primary glioblastoma(GBM)tissue.In this study,to express VEGF,Notch1-4,HES1,pSer727/pTyr705-STAT3,CD34 and DLL4 in vascular endothelial cells and tumor cells by immunohistochemistry in primary GBM tissues,and analyze the correlation between the main parts of each signal pathway to speculate cross talk between Notch signal pathway and STAT3 signal pathway.At the same time,the K-M curves and COX proportional hazards regression models assess the impact of the progression-free survival(PFS)and overall survival(OS).This experimental results show that(1)DLL4,Notch1-4,HES1,pSer727/pTyr705-STAT3 and VEGF have different degrees of expression in the primary GBM tissues,compared with normal brain tissue;(2)HES1 associated with elevated expression of pTyr705-STAT3 in the primary glioblastoma tumor cells(P < 0.05).Simultaneously,the elevated expression of pSer727-STAT3 in vascular endothelial cells is consistent with the high expression of Notch3 and HES1 in tumor cells(P < 0.05).Further analysis showed that Notch3 was positively correlated with tumor cell pSer727-STAT3(P < 0.05).The elevated positive rate of signals was consistent with the increase of MVD expression in primary GBM tissue;(3)Univariate analysis showed that to improve the positive rate of HES1 in tumor cells and pSer727-STAT3 in tumor vascular endothelial cells were related to brief PFS(both P< 0.001)and short OS(both P < 0.001)in primary glioblastoma.The results of multivariate analysis proved the elevated expression of HES1 in tumor cells and pSer727-STAT3 in tumor vascular endothelial cells were the prognostic reasons for brief PFS(HR 3.516,P=0.019;HR 3.424,P=0.038,respectively)and brief OS(HR3.244,P=0.02;HR 4.158,P= 0.03,respectively).Conclusion,the crosstalk between STAT3 signaling pathway and Notch signaling pathway occurred in the tumor cells,tumor cells and vascular endothelial cells of primary GBM,together regulating tumor angiogenesis and resulting in bad prognosis.