title: Restricted expression of miR-30c-2-3p and miR-30a-3p in clear cell renal cell carcinomas enhances HIF2α activity.
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.
authors.affiliation: 1Abramson Family Cancer Research Institute; 2Howard Hughes Medical Institute; 3Department of Cell and Developmental Biology; 4Penn Molecular Profiling Facility, Bioinformatics Group; 5Department of Pathology and Laboratory Medicine; 6Department of Cancer Biology; 7Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and 8INSERM U1037, Institut Claudius Regaud, Rue du Pont St Pierre, Toulouse, France.
authors.forename: Lijoy K
authors.initials: LK
authors.lastname: Mathew
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Lee
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.forename: Shilpa
authors.initials: S
authors.lastname: Rao
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C546086:MIRN30b microRNA, human; C497446:VHL protein, human