Abstract
Cervical intraepithelial neoplasia (CIN) is caused by human papillomavirus (HPV) infection and is the precursor to cervical carcinoma. The completion of the HPV productive life cycle depends on the expression of viral proteins which further determines the severity of the cervical neoplasia. Initiation of the viral productive replication requires expression of the E2 viral protein that cooperates with the E1 viral DNA helicase. A decrease in the viral DNA replication ability and increase in the severity of cervical neoplasia is accompanied by simultaneous elevated expression of E6 and E7 oncoproteins. Here we reveal a novel and important role for the HPV16-E2 protein in controlling host cell cycle during malignant transformation. We showed that cells expressing HPV16-E2 in vitro are arrested in prophase alongside activation of a sustained DDR signal. We uncovered evidence that HPV16-E2 protein is present in vivo in cells that express both mitotic and DDR signals specifically in CIN3 lesions, immediate precursors of cancer, suggesting that E2 may be one of the drivers of genomic instability and carcinogenesis in vivo.
Highlights
Cervical cancer is the second most common cause of cancer-related death in women worldwide and arises through a progressive graded dysplasia of the cervical epithelium, pathologically termed cervical intraepithelial neoplasia (CIN) [1, 2]
In the present study we demonstrated that human papillomavirus (HPV)-E2 protein induces a prolonged host cell cycle arrest in prophase and elicits a DNA damage response (DDR) signal in vitro in cell lines independent of their association with HPV
In patient’s samples, expression of E2 coincides with activation of markers of both mitosis and DDR signal associated with low levels of viral DNA replication mainly seen in HPV16-associated pre-malignant CIN3 lesions of the cervix
Summary
Cervical cancer is the second most common cause of cancer-related death in women worldwide and arises through a progressive graded dysplasia of the cervical epithelium, pathologically termed cervical intraepithelial neoplasia (CIN) [1, 2]. The productive phase usually prevails during the milder stages of cervical dysplasia, graded CIN1 or CIN2, where viral genomes are maintained as low-copynumber episomes in cells of the lower epithelial layers, becoming amplified as the infected cell migrates towards the epithelial surface during cellular differentiation [4, 5]. E2 expression is evident in the intermediate and/or upper layers of low grade CIN, and occurs alongside initiation of viral replication and productive amplification of the HPV genome [6]. While the majority of low grade CIN can regress together with viral clearance, 30–50% of CIN3 lesions will progress to invasive cervical cancer with integration of part of the viral genome in the cellular genome [8]
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