Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Hypoxia-induced factor-1 alpha(HIF-1α)affects many effector molecules and regulates tumor lymphangiogenesis and angiogenesis during hypoxia.The aim of this study was to investigate the role of HIF-1αin the regulation of vascular endothelial growth factor C(VEGF-C)expression and its effect on lymphangiogenesis and angiogenesis in breast cancer.Lymphatic vessel density(LVD),microvessel density(MVD)and the expressions of HIF-1αand VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples.There was a significant correlation between HIF-1αand VEGF-C(P=0.014,r=0.273,Spearman's coefficient of correlation).HIF-1αand VEGF-C overexpression was significantly correlated with higher LVD(P=0.003 and P=0.017,respectively),regional lymph nodal involvement(P=0.002 and P=0.004,respectively)and advanced tumor,node,metastasis(TNM)classification(P=0.001 and P=0.01,respectively).Higher MVD was observed in the group expressing higher levels of HIF-1αand VEGF-C(P=0.033 and P=0.037,respectively).Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1αand VEGF-C.HIF-1αwas also found to be an independent prognostic factor of overall survival in multivariate analysis.The results suggest that HIF-1αmay affect VEGF-C expression,thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer.This study highlights promising potential of HIF-1αas a therapeutic target against tumor lymph node metastasis.