Abstract
Cervical cancer is the third most common malignancy diagnosed in women worldwide. The major aetiological factor underlying the malignant transformation of cervical cells is the persistent infection with high-risk human papillomaviruses (HR-HPV), with more than 99% of cases expressing viral sequences. Here, we report a previously unknown mechanism driven by high-risk human papillomavirus E7 protein to modulate response to DNA damage in cervical cancer cells. Our data shows that HR-HPV E7 oncoprotein induces the transcription of the p53-family member p63, which modulates DNA damage response pathways, to facilitate repair of DNA damage. Based on our findings, we proposed a model, where HR-HPV could interfere with the sensitivity of transformed cells to radiation therapy by modulating DNA damage repair efficiency. Importantly, we have shown for the first time a critical role for p63 in response to DNA damage in cervical cancer cells.
Highlights
Cervical cancer is the third most common malignancy and the fourth leading cause of cancer-deaths among women, with less than a 50% 5-year survival rate in poor resource settings[1,2,3]
The major aetiological factor underlying the malignant transformation is the persistent infection with high-risk human papillomaviruses (HRHPV), with more than 99% of cases expressing viral sequences[2,4]
While in normal stratified epithelia the only pool of mitotically active cells is located in the basal and parabasal layers[9], in HPVinfected epithelial cells at suprabasal layers keep their proliferative capacity[10]
Summary
Cervical cancer is the third most common malignancy and the fourth leading cause of cancer-deaths among women, with less than a 50% 5-year survival rate in poor resource settings[1,2,3]. HPVs are a heterogeneous family of double-stranded DNA viruses with more than 150 different types identified so far[5] They all show tropism to cutaneous or mucosal epithelial cells, approximately one-third infect the genital tract[6,7]. While in normal stratified epithelia the only pool of mitotically active cells is located in the basal and parabasal layers[9], in HPVinfected epithelial cells at suprabasal layers keep their proliferative capacity[10] This is mostly achieved by HPV E7 protein, which binds to pRb family members and targets them for degradation, leading to release of E2F transcription factor to drive expression of S phase genes[11]. Integration typically results in the increased expression and stability of transcripts encoding the viral oncogenes E6 and E7, which is necessary for the pathogenesis of HPV12
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