Restricted Expression of miR-30c-2-3p and miR-30a-3p in Clear Cell Renal Cell Carcinomas Enhances HIF2α Activity

Inactivation of the von-Hippel Lindau (VHL) tumor suppressor gene occurs in 90% of human clear cell renal cell carcinomas (ccRCC) and leads to the stable expression of the hypoxia-inducible factors HIF1 alpha and HIF2 alpha. The constitutive expression of HIF1 alpha in a majority of VHL-deficient tumors is counterintuitive, given that HIF1a functions as a tumor suppressor in ccRCC, whereas HIF2a clearly enhances tumor growth. We demonstrate here that miR-30c-2-3p and miR-30a-3p specifically bind and inhibit expression of HIF2A transcripts, and that the locus encoding miR-30c-2-3p and miR-30a-3p is selectively repressed in H1H2 VHL-deficient tumors expressing both HIF1 alpha and HIF2 alpha proteins. Inhibiting miR-30a-3p expression increases HIF2 alpha levels in H1H2 ccRCC cells and promotes cellular proliferation, angiogenesis, and xenograft tumor growth. Our results indicate that miR-30c-2-3p and miR-30a-3p repression enhances HIF2 alpha expression and suggests a mechanism whereby the tumor-suppressive effects of constitutive HIF1 alpha expression are attenuated in VHL-deficient H1H2 tumors. SIGNIFICANCE: HIF1a is constitutively expressed in a majority of VHL-deficient ccRCCs, despite its tumor suppressor activity in these malignancies. This study demonstrates that repression of miR-30c-2-3p /miR-30a-3p increases HIF2 alpha levels to promote tumor growth, thereby ameliorating the inhibitory effects of HIF1a in ccRCCs. (C) 2013 AACR.