Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinoma.
Ror2 is an orphan receptor tyrosine kinase with expression normally restricted to early stages of development. However, emerging evidence has placed aberrantly expressed Ror2, leading to an invasive phenotype, in several cancers including renal cell carcinoma (RCC). Although Ror2 is currently identified as up-regulated in an assortment of cancers, neither the regulatory role or mechanism of action have been delineated. We sought to place Ror2 in the most commonly mutated pathway of RCC, the loss of the tumor suppressor von Hippel-Lindau (VHL), which causes hypoxia-inducible factor (HIF)-1alpha and -2alpha stabilization and the transcriptional activation of a broad repertoire of response genes. We found that Ror2 was indeed associated with the pVHL loss in RCC as well as with VHL somatic mutations tightly coordinated with the induction of RCC. Additionally, knockdown and rescue analysis of HIF expression suggests that Ror2 is dependent on pathologic stabilization of either HIF-1alpha or HIF-2alpha. Subsequent evaluation of the ROR2 promoter suggests that HIF-2alpha and its dimerization partner, aryl hydrocarbon nuclear transferase localize to the ROR2 promoter via a cryptic transcriptional element. This data substantiates a unique regulation pattern for Ror2 in the VHL-HIF axis that has the potential to be applied to other cancer etiologies.
Wright
Tricia M
TM
Department of Genetics, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Rathmell
W Kimryn
WK
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C078717:ROR2 protein, human; C497446:VHL protein, human