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Overexpression of Hypoxia-inducible Factor 1 Indicates Diminished Response to Radiotherapy and Unfavorable Prognosis in Patients Receiving Radical Radiotherapy for Cervical Cancer¹

Department of Radiotherapy and Radiobiology [B. B., R. P., B. D., T. H. K.], Department of Gynecology and Obstetrics [M. S.], Institute of Neurology [J. A. H.], and Clinical Institute of Pathology [R. H., P. B.], University of Vienna, A-1090 Vienna, Austria

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

Experimental Design: Expression of HIF-1 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-1 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-1. Nineteen samples (28.4%) were considered negative for HIF-1 expression. Strong/moderate expression of HIF-1 was associated with only partial response to radiotherapy (P = 0.037, ² test). Strong/moderate expression of HIF-1 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-1 expression and infection with different HPV types could be found.

Conclusions: Overexpression of HIF-1 has predictive and prognostic significance in cervical cancer patients receiving curative radiation therapy. Possibly, expression of HIF-1 could serve as intrinsic marker of hypoxia in cervical cancer.

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