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Figure S6 from Restricted Expression of miR-30c-2-3p and miR-30a-3p in Clear Cell Renal Cell Carcinomas Enhances HIF2α Activity

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posted on 2023-04-03, 20:40 authored by Lijoy K. Mathew, Samuel S. Lee, Nicolas Skuli, Shilpa Rao, Brian Keith, Katherine L. Nathanson, Priti Lal, M. Celeste Simon

PDF file 463K, Cell survival is reduced upon increased miR-30c-2-3p expression in RCC cells

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ARTICLE 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 HIF1α and HIF2α. The constitutive expression of HIF1α in a majority of VHL-deficient tumors is counterintuitive, given that HIF1α functions as a tumor suppressor in ccRCC, whereas HIF2α 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 HIF1α and HIF2α proteins. Inhibiting miR-30a-3p expression increases HIF2α 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 HIF2α expression and suggests a mechanism whereby the tumor-suppressive effects of constitutive HIF1α expression are attenuated in VHL-deficient H1H2 tumors.Significance: HIF1α 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 HIF2α levels to promote tumor growth, thereby ameliorating the inhibitory effects of HIF1α in ccRCCs. Cancer Discov; 4(1); 53–60. ©2013 AACR.See related commentary by Moch and Lukamowicz-Rajska, p. 22This article is highlighted in the In This Issue feature, p. 1

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