Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86

BACKGROUND: Radiotherapy is central in the treatment of cervical cancer. The formation of DNA double-strand breaks is considered to be critical for the radiotherapeutic effect. The non-homologous end joining (NHEJ) proteins DNA-PKcs, Ku70 and Ku86 have a major role in repairing DNA lesions. The objective of this study was to analyse if the expression of DNA-PKcs, Ku70 and Ku86 and their downstream signalling molecules p53, p21 and Mdm-2 are altered in residual cervical tumours after radiotherapy. METHODS: Retrospective analysis of 127 patients with cervical cancer stage IB-IIA treated with preoperative radiotherapy and radical surgery, revealed residual tumour in the cervical specimen in 30 patients. In 22 cases tumour material from residual and corresponding primary tumour were retrieved and the expression of DNA-PKcs, Ku86, Ku70, p53, p21 and Mdm- 2 were assessed by immunohistochemistry. RESULTS: Residual tumours showed increased frequency of DNA-PKcs (P = 0.037), Ku70 (P = 0.018), Ku86 (P = 0.008) positive cells. A correlation in DNA-PKcs expression between primary and residual tumours was found. The frequency of p21-positive cells was decreased ( P = 0.007) in residual tumours whereas no change in p53 or Mdm-2-positive cells were observed. CONCLUSION: Our results show that cervical carcinoma surviving radiotherapy have an increased DNA-PK expression. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of DNA-PK function may be part of a radioresistance mechanism within this tumour type. British Journal of Cancer (2009) 101, 816-821. doi:10.1038/sj.bjc.6605201 www.bjcancer.com Published online 11 August 2009 (C) 2009 Cancer Research UK