title: Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival.
abstract: BACKGROUND
  Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC.
  
  
  METHODS
  Tumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry.
  
  
  RESULTS
  There was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20-3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01-2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23-18.8, P = 0.001).
  
  
  CONCLUSIONS
  HIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases.
authors: Institute of Clinical Medicine, University of Tromso, Tromso, Norway. sigve.andersen@uit.no
authors: Sigve
authors: S
authors: Andersen
authors: Tom
authors: T
authors: Donnem
authors: Helge
authors: H
authors: Stenvold
authors: Samer
authors: S
authors: Al-Saad
authors: Khalid
authors: K
authors: Al-Shibli
authors: Lill-Tove
authors: LT
authors: Busund
authors: Roy M
authors: RM
authors: Bremnes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000473:pathology*; D049308:Dioxygenases / Q000032:analysis* / Q000096:biosynthesis; D005260:Female; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000032:analysis* / Q000096:biosynthesis; D011237:Predictive Value of Tests; D011393:Procollagen-Proline Dioxygenase / Q000032:analysis* / Q000096:biosynthesis; D011379:Prognosis; D012097:Repressor Proteins / Q000032:analysis* / Q000096:biosynthesis; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; D049308:Dioxygenases; C439790:HIF1AN protein, human; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases