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Crosstalk between high-risk human papillomavirus E7 and p63 in cervical cancer
[Thesis]. Manchester, UK: The University of Manchester; 2018.
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Abstract
Abstract Crosstalk between high-risk human papillomavirus E7 and p63 in cervical cancer Sahar Eldakhakhny The University of Manchester, Doctor of Philosophy (PhD), August 2018 Introduction: Cervical cancer is the fourth most common malignancy diagnosed in women worldwide. It results from cellular transformation by the high-risk human papillomavirus (HPV) oncogenes E6 and E7, which accounts for more than 99% of diagnosed cases. HPV links its life cycle to epithelial proliferation and differentiation, which requires the cells to remain active in cell cycle. p63 modulates epithelial development as well as proliferation, differentiation and DNA damage response (DDR), which makes it an important target for HPV oncoproteins to allow viral replication and survival in infected cells. Methods: In this study, small interfering RNAs targeting E7 oncoprotein and p63 in the HPV16 positive cervical cancer cell line CaSki were used. Western blotting, proliferation assays, apoptosis assays and cell cycle analysis were applied to examine the effects of E7 and p63 depletion on cell fate. Overexpression of different types of HPV-E7 was performed in the N/Tert-1 keratinocyte cell line to study the effect of E7 overexpression on p63 level. Results: E7 drives the expression of p63 at both transcript and protein levels in cervical cancer cell lines. Downregulation of E7 is accompanied by a remarkable inhibition of cell proliferation and cell cycle arrest in the G0/G1 phase. Depletion of E7 is associated with a significant reduction in p63 expression which is not due to impaired proliferation or induced differentiation. Downregulation of p63 is associated with delayed DDR in cervical cancer cells following treatment with ionising radiation. High-risk HPV E7s are more potent in inducing p63 upregulation and increasing the proliferation rates in keratinocytes. Conclusion: This work for the first time demonstrated that E7 modulates the expression of p63, which regulates DNA damage repair pathways, that promotes efficient and rapid repair of the DNA damage following ionising radiation treatment in cervical cancer cells. Tumour recurrence due to resistance to radiotherapy is common, mostly due to promoted DNA repair ability of cancer cells to reduce radiation-induced toxicity and increase cell survival in response to ionising radiation. These findings might be the key to the development of radioresistance in cervical cancer. The HPV E7-p63 axis may be a novel therapeutic target to enhance radio-sensitivity in HPV-transformed tumours.
Keyword(s)
Cervical cancer; DDR; E7; HPV-16; p63