Preoperative radiotherapy downregulates the nuclear expression of hypoxia-inducible factor-1α in rectal cancer

Abstract

Objective. To assess the value of hypoxia-inducible factor-1α (HIF-1α) expression as a predictor of disease outcome in rectal cancer treated by preoperative radio- or chemoradiotherapy. Material and methods. Operative samples from 168 rectal cancer patients and 79 respective preoperative biopsies were analyzed for nuclear HIF-1α 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-1α staining was positive in 70% of the diagnostic biopsies but negative in most of the post-radiotherapy specimens (60%). HIF-1α expression in the biopsies was downregulated in 56% of samples taken after preoperative treatment, while negative HIF-1α 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-1α 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-1α expression was positive in most of the preoperative biopsies but downregulated in most of the operative samples, implicating that preoperative radiotherapy downregulates HIF-1α expression in rectal cancer. Negative HIF expression after preoperative long-course radiotherapy was associated with significantly better DSS.

Key Words::

• Chemotherapy
• hypoxia-inducible factor-1α
• predictive factor
• prognosis
• radiotherapy
• rectal cancer

Acknowledgements

The authors are grateful to Mrs Sinikka Kollanus for her skilful help in laboratory work and Mr Jaakko Liippo for aid with the digital pictures. This research work was supported by grants from the Special Government Funding (EVO) allocated to Turku University, the Finnish Society for Therapeutic Radiology and Oncology, the Finnish Cultural Foundation, Varsinais-Suomi Regional Fund and the Finnish Cancer Institute (to P. M. J.).

Declaration of interest: The authors report no conflicts of interest.