title: Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways.
abstract: Hypoxia-inducible factor (HIF)-1 alpha is the regulatory subunit of HIF-1 that is stabilized under hypoxic conditions. Under different circumstances, HIF-1 alpha may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF-1 alpha as a prognostic factor. This study evaluated HIF-1 alpha expression in 172 consecutive patients with stage I-IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF-1 alpha nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut-point and 60% as a high positive cut-point. Using the low cut-point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)-9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, p53 (p = 0.008), T-stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl-2 or either N- or overall TMN stage or prognosis. When the high positive cut-point was used, HIF-1 alpha was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP-9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF-1 alpha. The association with TN and squamous-type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF-1 alpha. The prognostic data may reflect a change in the behavior of HIF-1 alpha in increasingly hypoxic environments.
authors.affiliation: Cancer Centre, Queen Elizabeth Hospital, Birmingham, United Kingdom. daniel.swinson@fsmail.net
authors.forename: Daniel E B
authors.initials: DE
authors.lastname: Swinson
authors.forename: J Louise
authors.initials: JL
authors.lastname: Jones
authors.forename: Giles
authors.initials: G
authors.lastname: Cox
authors.forename: Donna
authors.initials: D
authors.lastname: Richardson
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor; D002256:Carbonic Anhydrases / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D015687:Cell Hypoxia; D003430:Cross-Sectional Studies; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008875:Middle Aged; D009336:Necrosis; D009367:Neoplasm Staging; D011379:Prognosis; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; D002256:Carbonic Anhydrases