1071 POOR PROGNOSIS AND ADVANCED CLINICOPATHOLOGICAL FEATURES OF CLEAR CELL RENAL CELL CARCINOMA (CCRCC) ARE ASSOCIATED WITH CYTOPLASMIC SUBCELLULAR LOCALIZATION OF HIF-2α (2013)

You have accessJournal of UrologyKidney Cancer: Evaluation & Staging (III)1 Apr 20131071 POOR PROGNOSIS AND ADVANCED CLINICOPATHOLOGICAL FEATURES OF CLEAR CELL RENAL CELL CARCINOMA (CCRCC) ARE ASSOCIATED WITH CYTOPLASMIC SUBCELLULAR LOCALIZATION OF HIF-2α Nils Kroeger, David Seligson, Sabina Signoretti, Hong Yu, Joshua Logan, Frédéric Birkhäuser, Clara Magyar, Jiaoti Huang, Joseph Riss, Fairooz Kabbinavar, Arie Belldegrun, and Allan Pantuck Nils KroegerNils Kroeger Los Angeles, CA More articles by this author , David SeligsonDavid Seligson Los Angeles, CA More articles by this author , Sabina SignorettiSabina Signoretti Boston, MA More articles by this author , Hong YuHong Yu Los Angeles, CA More articles by this author , Joshua LoganJoshua Logan Los Angeles, CA More articles by this author , Frédéric BirkhäuserFrédéric Birkhäuser Los Angeles, CA More articles by this author , Clara MagyarClara Magyar Los Angeles, CA More articles by this author , Jiaoti HuangJiaoti Huang Los Angeles, CA More articles by this author , Joseph RissJoseph Riss Los Angeles, CA More articles by this author , Fairooz KabbinavarFairooz Kabbinavar Los Angeles, CA More articles by this author , Arie BelldegrunArie Belldegrun Los Angeles, CA More articles by this author , and Allan PantuckAllan Pantuck Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.660AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Pre-clincal studies have implicated HIF-2α as an important tumor promotor for ccRCC. Generally considered to act as a nuclear transcription factor, a recent study has also implicated HIF-2α to have a protein translational initiation complex function within the cytoplasm (Uniacke et al.Nature. 2012 May 6; 486(7401):126-9). We hypothesized that both the absolute expression as well as the sub-cellular localization of HIF-2α would predict clinicopathological features and CSS in ccRCC. METHODS A tissue microarray (TMA) study was conducted on three hundred-eight ccRCC patients. The nuclear and cytoplasmic expression of HIF-2α were correlated for their association with survival outcome and clinicopathological features ccRCC. RESULTS High HIF-2α nuclear (N) (cutoff>32%) expression was associated with smaller tumor sizes (p=0.002) and lower Fuhrman grades (p=0.044), whereas tumors with high cytoplasmic (C) HIF-2α (>0%) more often had positive lymph nodes (p=0.004), distant metastases (p=0.021), and higher Fuhrman grades (p<0.0001). HIF-2α C was closely correlated to markers of proliferation (pS6 p<0.0001; Ki67 p=0.011) and low CAIX (p<0.0001). There was a trend for an opposite correlation with members of the VEGF-pathway in the tumor epithelium (high expression) and endothelium (low expression). Univariate analyses showed an association between high HIF-2α N (p=0.035) and better CSS. In contrast, HIF-2α C demonstrated an association with CSS when examined as both a continuous (p<0.0001) and as a dichotomized variable (p<0.0001). After adjustment for TNM stage, ECOG PS, and Fuhrman grade, both continuous (p<0.0001) and dichotomized (p<0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained. The ratio of HIF-2α C/N was the strongest predictor of CSS in multivariate analysis (p=0.001; HR 4.83 (95% CI: 1.99 - 11.76)). CONCLUSIONS HIF-2α may possess unique cytoplasmic and nuclear biological functions that impact upon ccRCC tumor progression. These preliminary findings warrant molecular and mechanistic studies that investigate the cytoplasmic role of HIF-2α. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e439-e440 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nils Kroeger Los Angeles, CA More articles by this author David Seligson Los Angeles, CA More articles by this author Sabina Signoretti Boston, MA More articles by this author Hong Yu Los Angeles, CA More articles by this author Joshua Logan Los Angeles, CA More articles by this author Frédéric Birkhäuser Los Angeles, CA More articles by this author Clara Magyar Los Angeles, CA More articles by this author Jiaoti Huang Los Angeles, CA More articles by this author Joseph Riss Los Angeles, CA More articles by this author Fairooz Kabbinavar Los Angeles, CA More articles by this author Arie Belldegrun Los Angeles, CA More articles by this author Allan Pantuck Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...