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Effect of ionising radiation on HPV-positive and HPV-negative oropharyngeal cancer cell lines

Holzhauser, Stefan 2018. Effect of ionising radiation on HPV-positive and HPV-negative oropharyngeal cancer cell lines. PhD Thesis, Cardiff University.
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Abstract

In recent decades, the incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) has increased world-wide. Overall, HPV-positive OPSCC patients respond better to treatment (increased survival rate) compared to HPV-negative patients. This might be partially associated with a deficiency in repair of double-strand DNA breaks, and/or with residual p53 activity in HPV-positive tumours. However new studies, specific to HPV-positive OPSCC, are limited due to the low number of relevant OPSCC in-vitro models. The general aims of this study were to develop new HPV-positive OPSCC cell lines and use them, together with established OPSCC cell lines, to investigate responses to ionising radiation (IR). These experiments were intended to test that HPV-positive OPSCC cell lines were more sensitive to IR than HPV-negative OPSCC cell lines. Two novel OPSCC cell lines, one HPV-positive and one HPV-negative, were derived and characterised. The HPV-positive OPSCC cell lines demonstrated greater variation in radio-sensitivity compared to HPV-negative OPSCC cell lines. However, radio-sensitivity was not associated with p53 accumulation and/or cell cycle arrest. All HPV-positive OPSCC cell lines showed G2 arrest after IR, but so did several HPV-negative lines. The mRNA sequencing data confirmed expression of HPV oncogenes and integration of HPV DNA into the host genome, with an increase of integration sites after IR. Comparison of irradiated HPV-positive and HPV-negative cell lines did not show consistent differences in gene expression associated with DNA repair. The transcription of DNA repair factors did not correlate with radio-sensitivity within the HPV-positive cell lines. The study was successful in generating and characterising new OPSCC cell lines but did not find evidence that the better prognosis of HPV-positive tumours is associated with defects in DNA repair. This suggests that additional mechanisms may be responsible for the improved prognosis of HPV-positive OPSCC patients following treatment.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 11 March 2019
Last Modified: 11 Mar 2019 11:10
URI: http://orca-mwe.cf.ac.uk/id/eprint/120510

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