title: Preoperative radiotherapy downregulates the nuclear expression of hypoxia-inducible factor-1alpha in rectal cancer.
abstract: OBJECTIVE
  To assess the value of hypoxia-inducible factor-1alpha (HIF-1alpha) expression as a predictor of disease outcome in rectal cancer treated by preoperative radio- or chemoradiotherapy.
  
  
  METHODS
  Operative samples from 168 rectal cancer patients and 79 respective preoperative biopsies were analyzed for nuclear HIF-1alpha protein expression using immunohistochemistry by three approaches: (a) positive/negative, (b) the percentage of HIF-positive cancer cells and (c) staining intensity. The patients had received either short- (n = 75) or long-course radiotherapy with or without chemotherapy (n = 39) or no treatment preoperatively (n = 54).
  
  
  RESULTS
  HIF-1alpha staining was positive in 70% of the diagnostic biopsies but negative in most of the post-radiotherapy specimens (60%). HIF-1alpha expression in the biopsies was downregulated in 56% of samples taken after preoperative treatment, while negative HIF-1alpha expression was upregulated in 25% of samples. Patients who had HIF-negative tumours after long-course radiotherapy had significantly (P = 0.001) better disease-specific survival (DSS) in univariate analysis. In the multivariate (Cox) regression model, HIF-1alpha lost its significance and only being in the preoperative treatment group was an independent predictor of disease-free survival. In a similar Cox model, disease recurrence and the number of metastatic lymph nodes were independent predictors of DSS.
  
  
  CONCLUSIONS
  HIF-1alpha expression was positive in most of the preoperative biopsies but downregulated in most of the operative samples, implicating that preoperative radiotherapy downregulates HIF-1alpha expression in rectal cancer. Negative HIF expression after preoperative long-course radiotherapy was associated with significantly better DSS.
authors.affiliation: Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Turku, Finland. eija.korkeila@tyks.fi
authors.forename: E
authors.initials: E
authors.lastname: Korkeila
authors.forename: P M
authors.initials: PM
authors.lastname: Jaakkola
authors.forename: K
authors.initials: K
authors.lastname: Syrjänen
authors.forename: J
authors.initials: J
authors.lastname: Sundström
authors.forename: S
authors.initials: S
authors.lastname: Pyrhönen
mesh_terms: D015687:Cell Hypoxia; D015536:Down-Regulation / Q000528:radiation effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000528:radiation effects*; D008297:Male; D009367:Neoplasm Staging; D011300:Preoperative Care; D012004:Rectal Neoplasms / Q000473:pathology / Q000532:radiotherapy*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit