Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity

CM Nickson, P Moori, RJ Carter, CARLOS RUBBI, JL Parsons

Research output: Contribution to journalArticle (journal)peer-review

66 Citations (Scopus)
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Abstract

Patients with human papillomavirus type 16 (HPV)-associated oropharyngeal
squamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy and
improved survival rates in comparison to HPV-negative forms of the disease. However
the cellular mechanisms responsible for this characteristic difference are unclear.
Here, we have investigated the contribution of DNA damage repair pathways to the
in vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positive
OPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, which
correlates with reduced efficiency for the repair of ionising radiation (IR)-induced
DNA double strand breaks (DSB). Interestingly, we show that HPV-positive OPSCC
cells consequently have upregulated levels of the proteins XRCC1, DNA polymerase β,
PNKP and PARP-1 which are involved in base excision repair (BER) and single strand
break (SSB) repair. This translates to an increased capacity and efficiency for the
repair of DNA base damage and SSBs in these cells. In addition, we demonstrate
that HPV-positive but interestingly more so HPV-negative OPSCC display increased
radiosensitivity in combination with the PARP inhibitor olaparib. This suggests that
PARP inhibition in combination with radiotherapy may be an effective treatment
for both forms of OPSCC, particularly for HPV-negative OPSCC which is relatively
radioresistant.
Original languageEnglish
Pages (from-to)29963-29975
JournalOncotarget
Volume8
Issue number18
Early online date16 Mar 2017
DOIs
Publication statusPublished - 16 Mar 2017

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