title: Deregulation of E2-EPF ubiquitin carrier protein in papillary renal cell carcinoma.
abstract: Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Frederik C
authors.initials: FC
authors.lastname: Roos
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Evans
authors.forename: Walburgis
authors.initials: W
authors.lastname: Brenner
authors.forename: Bill
authors.initials: B
authors.lastname: Wondergem
authors.forename: Jeffery
authors.initials: J
authors.lastname: Klomp
authors.forename: Pardeep
authors.initials: P
authors.lastname: Heir
authors.forename: Olga
authors.initials: O
authors.lastname: Roche
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.forename: Heiko
authors.initials: H
authors.lastname: Schimmel
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Thüroff
authors.forename: Christian
authors.initials: C
authors.lastname: Hampel
authors.forename: Michael
authors.initials: M
authors.lastname: Ohh
mesh_terms: D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000201:enzymology / Q000473:pathology; D015687:Cell Hypoxia; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D020218:Response Elements / Q000235:genetics; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C046288:ubiquitin carrier proteins; C544962:Ube2S protein, human; D044763:Ubiquitin-Conjugating Enzymes; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human