Restricted expression of miR-30c-2-3p and miR-30a-3p in Clear Cell Renal Carcinomas enhances HIF2 activity

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract 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 HIF1Į and HIF2Į. The constitutive expression of HIF1Į in a majority of VHL-deficient tumors is counterintuitive, given that HIF1Į functions as a tumor suppressor in ccRCC, whereas HIF2Į clearly enhances tumor growth. We demonstrate here that miR-30c-2-3p and miR-30a-3p specifically bind and inhibit expression of HIF2Į transcripts, and that the locus encoding miR-30c-2-3p and miR-30a-3p is selectively repressed in " H1H2 " VHL-deficient tumors expressing both HIF1Į and HIF2Į proteins. Inhibiting miR-30a-3p expression increases HIF2Į 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 HIF2Į expression, and suggest a mechanism whereby the tumor suppressive effects of constitutive HIF1Į expression are attenuated in VHL-deficient H1H2 tumors. Significance HIF1Į 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 HIF2Į levels to promote tumor growth, thereby ameliorating the inhibitory effects of HIF1Į in ccRCCs.