title: Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival.
abstract: OBJECTIVE
  Tumor hypoxia is known to be associated with resistance to chemotherapy, radiotherapy, and poorer survival. Recently, it is shown that hypoxia induces the expression of hypoxia-inducible factor-1alpha and 2alpha (HIF-1alpha and HIF-2alpha), which then up-regulates the expression of downstream genes such as carbonic anhydrase IX (CA IX) and vascular endothelial growth factor (VEGF).
  
  
  METHODS
  We examined the expression of HIF-1alpha, HIF-2alpha, CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma (NPC) biopsies from 90 consecutive patients recruited between 1994 and 1997 in a randomized controlled trial of chemoradiation in locally advanced NPC and investigated their relationship with survival.
  
  
  RESULTS
  HIF-1alpha was expressed in 52 of 90 (58%), HIF-2alpha in 6 of 89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%) of tumors. Tumor HIF-1alpha expression correlated significantly with that of CA IX (P = 0.008) and VEGF (P = 0.003). High tumor HIF-1alpha expression was associated with a trend for poor overall survival (P = 0.06). Tumors with a positive hypoxic profile (defined as high expression of both HIF-1alpha and CA9) were associated with worse progression-free survival (P = 0.04). Tumors with both hypoxic and angiogenic profile (defined as high VEGF expression) were associated with a worse progression-free survival (P = 0.0095).
  
  
  CONCLUSIONS
  Overexpression of HIF-1alpha, CA IX, and VEGF is common in NPC, which is probably related to hypoxia up-regulated expression involving a HIF-dependent pathway, and is associated with poor prognosis. Targeting the hypoxia pathway may be useful in the treatment of NPC.
authors.affiliation: Departments of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Francesco
authors.initials: F
authors.lastname: Pezzella
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Terence C W
authors.initials: TC
authors.lastname: Poon
authors.forename: Benny
authors.initials: B
authors.lastname: Zee
authors.forename: Frankie
authors.initials: F
authors.lastname: Mo
authors.forename: Peter M L
authors.initials: PM
authors.lastname: Teo
authors.forename: Dolly P
authors.initials: DP
authors.lastname: Huang
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Gatter
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Johnson
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis*; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality*; D015331:Cohort Studies; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008222:Lymphokines / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000401:mortality*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011379:Prognosis; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D016228:Endothelial Growth Factors; D005819:Genetic Markers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C089226:CA9 protein, human