Effects of HIF-1 and HIF2 on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts

Abstract

In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1 (HIF-1+), HIF-2 (HIF-2+), or empty vector (EV), no significant differences were observed in the growth ratesin vitro, but when grownin vivoas xenografts HIF-2 significantly increased, and HIF-1 significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2 in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype.