Expression of the cellular oxygen sensor PHD2 (EGLN-1) predicts radiation sensitivity in squamous cell cancer of the head and neck

Abstract

Purpose: Prolyl hydroxylase domain proteins constitute a family of oxygen sensors that regulate the expression of hypoxia-inducible factor-1 alpha (HIF-1α), which mediates transcription of many genes under low oxygen concentration. PHD2 (Prolyl hydroxylase domain protein 2) isoform is the main regulator of HIF-1α degradation in normoxia and mild hypoxia. The aim of our study was to evaluate the relationship between expression of PHD2 and radiosensitivity in squamous cell cancer of the head and neck (HNSCC).

Patients and methods: Paraffin embedded sections from untreated primary tumours were obtained for immunohistochemistry in 48 HNSCC patients scheduled for preoperative radiotherapy (RT). Nuclear expression of PHD2 was evaluated as a percentage of tumour cells showing positively stained nucleus. RT was a split-course accelerated hyperfractionated regimen (1.6 Gy twice a day) in 15 patients and standard in 33 patients. Viability of cancer cells was routinely evaluated histologically from resected tumours at planned surgery 3–4 weeks after RT. The follow-up time after multimodality treatment was five years or until death.

Results: PHD2 expression was low in normal tissues and well differentiated tumours. The expression was increased and predominantly nuclear in poorly differentiated tumours. In tumours later found to be sterilised by RT, nuclear PHD2 expression was markedly lower as compared to tumours showing viable cells at surgery (p = 0.04). A low nuclear staining of PHD2 (<10% of PHD2-positive nuclei) in the primary tumour was found to associate with good radiation response (p = 0.005).

Conclusions: We found low PHD2 expression and in particular low nuclear expression to predict a favourable response to RT. Therefore, nuclear PHD2 expression may act as a surrogate marker for radiation resistance in HNSCC.

Keywords:

• head/neck squamous cell carcinoma
• radiotherapy
• hypoxia
• HIF hydroxylases
• prolyl hydroxylase
• prognostic factors