Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer.
OBJECTIVE
The purpose is to investigate the impact of hypoxia-inducible factor (HIF)-1alpha expression on response to radiotherapy and prognosis of patients with primary irradiated cervical cancer. Because human papillomavirus (HPV) oncoprotein E6 might interact with HIF-1alpha in various pathways, we also investigated the relation of HIF-1alpha and HPV status.


METHODS
Expression of HIF-1alpha was investigated by immunohistochemistry in 67 specimens of patients who had received radical radiotherapy for cervical cancer stages IB-IIIB. HPV analysis was performed using type-specific PCR, cloning, and sequencing. Survival analysis was performed using univariate and multivariate analysis.


RESULTS
Immunohistochemistry revealed expression of HIF-1alpha in 72.1% of the tumor samples. In 16 (23.9%) cases, there was a weak expression, in 25 (37.3%) a moderate expression, and in 7 cases (10.4%) a strong expression of HIF-1alpha. Nineteen samples (28.4%) were considered negative for HIF-1alpha expression. Strong/moderate expression of HIF-1alpha was associated with only partial response to radiotherapy (P = 0.037, chi(2) test). Strong/moderate expression of HIF-1alpha was also an independent prognostic factor for shorter progression-free survival (P = 0.036, Cox regression) and cervical cancer-specific survival (P = 0.04, Cox regression). No association between HIF-1alpha expression and infection with different HPV types could be found.


CONCLUSIONS
Overexpression of HIF-1alpha has predictive and prognostic significance in cervical cancer patients receiving curative radiation therapy. Possibly, expression of HIF-1alpha could serve as intrinsic marker of hypoxia in cervical cancer.
Bachtiary
Barbara
B
Department of Radiotherapy and Radiobiology, University of Vienna, A-1090 Vienna, Austria.
Schindl
Monika
M
Pötter
Richard
R
Dreier
Bettina
B
Knocke
Thomas Hendrik
TH
Hainfellner
Johannes A
JA
Horvat
Reinhard
R
Birner
Peter
P
D015415:Biomarkers; D015687:Cell Hypoxia; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000378:metabolism; D011379:Prognosis; D015996:Survival Rate; D014157:Transcription Factors / Q000032:analysis*; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000401:mortality / Q000532:radiotherapy*
D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors