title: Expression of hypoxic-inducible factor 1alpha predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma.
abstract: OBJECTIVE
  Hypoxia-inducible factor-1alpha (HIF-1alpha) is an intrinsic marker of tumor hypoxia. It has been considered that the hypoxic status reduces radiosensitivity, but the role of HIF-1alpha in advanced cervical carcinoma is still unclear. The objective of this study was to clarify the impact of HIF-1alpha, human papillomavirus (HPV), and other molecular factors, such as p53, bax, bcl-2, and their correlations on the outcome of patients with Stage IIIB cervical carcinoma in radiation therapy.
  
  
  METHODS
  We analyzed 38 patients with FIGO Stage IIIB squamous cell carcinoma of the cervix treated with radiation therapy alone. All patients received the combination therapy of external beam irradiation and low-dose-rate intracavity brachytherapy. The tumor expressions of HIF-1alpha, p53, bax, and bcl-2 were examined by immunohistochemical staining of the pretreatment paraffin embedded specimens. HPV infection was also detected by polymerase chain reaction. The effects of these parameters on clinical outcomes were analyzed by univariate analysis.
  
  
  RESULTS
  Of 38 patients, high expression of HIF-1alpha, p53, bax, and bcl-2 were seen in 17 (45%), 22 (58%), 15 (39%), and 15 (39%) patients, respectively, and 28 patients (74%) showed positive infection with HPV. There was a significant positive correlation between high HIF-1alpha expression and disease recurrence (p < 0.05). Furthermore, HIF-1alpha had a significant correlation with the recurrence-free survival rate (p = 0.04). No statistical correlation was noted between high HIF-1alpha expression and the local control rate (p = 0.17), whereas the HIF-1alpha status predicted distant metastasis with strong significance (p = 0.03). Conversely, other factors demonstrated no impact on the clinical outcome.
  
  
  CONCLUSIONS
  The present results suggest that HIF-1alpha is an important prognostic factor, especially for predicting future metastasis after radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix.
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Norio
authors.initials: N
authors.lastname: Mitsuhashi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takahashi
authors.forename: Norihiro
authors.initials: N
authors.lastname: Masuda
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nakajima
authors.forename: Yoshizumi
authors.initials: Y
authors.lastname: Kitamoto
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Saitoh
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000532:radiotherapy / Q000556:secondary / Q000821:virology; D015687:Cell Hypoxia; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000532:radiotherapy / Q000821:virology; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein