The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer.
BACKGROUND
Hypoxia promotes tumorigenesis through the hypoxia-inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF-1alpha and HIF-2alpha, which have different effects in genetic knock-out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF-alpha expression in tumors.


METHODS
The expression of HIF-1alpha, HIF-2alpha, carbonic anhydrase-9 (CA-9), and peripheral hemoglobin (Hb) levels in 151 patients who underwent surgery for head and neck squamous cell carcinoma (HNSCC) were analyzed and related to outcome.


RESULTS
High HIF-1alpha was expressed in 45 of 140 tumors (30%), HIF-2alpha was expressed in 21 of 139 tumors (14%), and CA-9 was expressed in 56 of 149 tumors (62%). There was a positive correlation between HIF-1alpha expression and HIF-2alpha expression (P =.0001). HIF-1alpha alone was associated with a worse disease-specific survival (DSS) (P =.05) and disease-free survival (DFS) (P = .03) in multivariate analyses. Nine percent of tumors expressed both high HIF-1alpha and high HIF-2alpha. High HIF-1alpha/high HIF-2alpha expression was an independent prognostic factors in DSS (P = .04) and DFS (P =.005) in multivariate analyses. There was no correlation noted between Hb and HIF-1alpha, HIF-2alpha, or CA-9.


CONCLUSIONS
HIF-1alpha alone was correlated with DSS and DFS. The additive effect of HIF-2alpha on poor prognosis suggested that different pathways may be regulated by HIF-2alph. Anemia that was not related to HIF-alpha expression suggests that tumor intrinsic factors regulate HIF-alpha therefore, anemia may be a surrogate marker for other factors that affect outcome.
Winter
Stuart C
SC
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Shah
Ketan A
KA
Han
Cheng
C
Campo
Leticia
L
Turley
Helen
H
Leek
Russell
R
Corbridge
Rogan J
RJ
Cox
Graham J
GJ
Harris
Adrian L
AL
D000951:Antigens, Neoplasm / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015331:Cohort Studies; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D011379:Prognosis; D015996:Survival Rate; D013997:Time Factors; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D006454:Hemoglobins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C089226:CA9 protein, human