title: Poor prognosis and advanced clinicopathological features of clear cell renal cell carcinoma (ccRCC) are associated with cytoplasmic subcellular localisation of Hypoxia inducible factor-2α.
abstract: BACKGROUND
  Pre-clinical studies have implicated hypoxia inducible factor (HIF)-2α as an important oncogene for clear cell renal cell carcinoma (ccRCC). Generally considered to act as a nuclear transcription factor, a recent study has also implicated HIF-2α as a protein translational initiation complex function within the cytoplasm (Uniacke et al., 2012). We hypothesised that both the absolute expression as well as the sub-cellular localisation of HIF-2α would predict clinicopathological features and cancer specific survival (CSS) in ccRCC.
  
  
  METHODS
  A tissue microarray (TMA) study was conducted on three hundred and eight ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values.
  
  
  RESULTS
  High HIF-2α nuclear (N) (cutoff >32%) expression was associated with smaller tumour sizes (p=0.002) and lower Fuhrman grades (p=0.044), whereas tumours 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). After adjustment for TNM stage, Eastern Cooperative Oncology Group performance status (ECOG PS), and Fuhrman grade, both continuous (p<0.0001) and dichotomised (p<0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained.
  
  
  CONCLUSIONS
  Our investigation supports that HIF-2α may have a unique tumour promoter role in the cytoplasm. This preliminary finding justifies further experimental and mechanistic studies that examine the biological functions of HIF-2α when located in the cytoplasm.
authors.affiliation: Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University Medicine Greifswald, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Kroeger
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles,CA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Seligson
authors.affiliation: Department of Pathology, Dana Farber Cancer Institute, Harvard School of Medicine, Boston, MA, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles,CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles,CA, USA.
authors.forename: Clara E
authors.initials: CE
authors.lastname: Magyar
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles,CA, USA.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
authors.affiliation: Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. Electronic address: apantuck@mednet.ucla.edu.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002140:California; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D046888:Tissue Array Analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: CA-IX; Cancer specific survival; HIF-1; HIF-2; Renal cell carcinoma; Tumour promotor; Tumour suppressor; VEGF; mTOR