Role of HPV16 E1 in cervical carcinogenesis.

Cervical cancer is the fourth most common cancer in women worldwide. More than 90% of cases are caused by the human papillomavirus (HPV). Vaccines developed only guard against a few HPV types and do not protect people who have already been infected. HPV is a small DNA virus that infects the basal layer of the stratified epithelium of the skin and mucosa through small breaks and replicates as the cells differentiate. The mucosal types of HPV can be classified into low-risk and high-risk groups, based on their association with cancer. Among HPV types in high-risk group, HPV type 16 (HPV-16) is the most common, causing 50% of all cancer cases. HPV infection can occur as transient or persistent infections, based on the ability of immune system to clear the virus. Persistent infection is characterized by the integration of HPV genome. HPV-16 exhibits a different integration pattern, with only 50% reported to be integrated at the carcinoma stage. Replication of the HPV genome depends on protein E1, an ATP-dependent helicase. E1 is essential for the amplification of the viral episome in infected cells. Previous studies have shown that E1 does not only act as a helicase protein but is also involved in recruiting and interacting with other host proteins. E1 has also been deemed to drive host cell proliferation. Recent studies have emphasized the emerging role of HPV E1 in cervical carcinogenesis. In this review, a possible mechanism by which E1 drives cell proliferation and oncogenesis will be discussed.

HPV16 E1 dysregulated cellular genes involved in cell proliferation and host DNA damage: A possible role in cervical carcinogenesis.

HPV16 is the most prominent cause of cervical cancer. HPV16 E1, a helicase required for HPV replication exhibits increased expression in association with cervical cancer progression, suggesting that E1 has a similar effect on the host as the HPV16 E6 and E7 oncoproteins. This study aimed to determine whether expression of HPV16 E1 correlated with carcinogenesis by modulating cellular pathways involved in cervical cancer. HEK293T cells were transfected with pEGFP, pEGFPE1 or truncated forms of HPV16 E1. Cell proliferation, cell death, and the impact of HPV16 E1 on host gene expression was then evaluated. HPV16 E1 overexpression resulted in a significant reduction of cell viability and cellular proliferation (p-value<0.0001). Moreover, prolonged expression of HPV16 E1 significantly induced both apoptotic and necrotic cell death, which was partially inhibited by QVD-OPH, a broad-spectrum caspase inhibitor. Microarray, real time RT-PCR and kinetic host gene expression analyses revealed that HPV16 E1 overexpression resulted in the downregulation of genes involved in protein synthesis (RPL36A), metabolism (ALDOC), cellular proliferation (CREB5, HIF1A, JMJDIC, FOXO3, NFKB1, PIK3CA, TSC22D3), DNA damage (ATR, BRCA1 and CHEK1) and immune response (ISG20) pathways. How these genetic changes contribute to HPV16 E1-mediated cervical carcinogenesis warrants further studies.

Comparison of detection rate of high risk HPV infection between self-collected HPV testing and clinician-collected HPV testing in cervical cancer screening.

OBJECTIVE: to correlate the detection rate of high risk HPV (HR-HPV) DNA between self-collected and clinician-collected testing. MATERIALS AND METHODS: A cross-sectional analytic study was conducted in 400 women undergoing cervical cancer screening program during February and May 2015. The procedure began with self-collected method and then clinician-collected method. Then, the specimens were processed and interpreted with the same technique. If the results from either methods were positive for HPV genotype 16 or 18, colposcopy was performed. We also conducted cytology testing for the participants. If the results were abnormal (ASC-US+), colposcopy was also performed. RESULTS: The detection rate of HR-HPV DNA was 10.0% and 7.5% by self-collected and clinician-collected specimen, respectively (kappa = 0.73). HR-HPV positive rate in cytology ASC-US+ was no significantly different between groups. HR-HPV DNAs were positive in every HSIL (100% detection rate). HPV DNA test positive for detection CIN+ was not significantly different between self-collected and clinician-collected testing. CONCLUSION: self-collected HPV testing can be used as an alternative option for primary cervical screening program. Detection rate of high grade lesion is similar to clinician-collected test.

Elevated HPV16 E1 Expression Is Associated with Cervical Cancer Progression.

OBJECTIVES: The primary replication protein, HPV E1, has been shown to play a role in mitigating host defence and disrupting normal cell cycle processes, leading to the development of cancer. This study investigated the expression profile of HPV16 E1 in various stages of cervical cancer development and the factors that control E1 expression. METHODS: One hundred and twenty-four HPV16-positive cervical samples ranging from normal to CIN 1, CIN 2/3, and SCC lesions were studied. E1 mRNA expression was determined by ddPCR. Methylation of promoters p97 and p670 was quantified by pyrosequencing, while PCR, qPCR, and sequencing were used to determine the physical state and variations of the HPV16 E1 genome. RESULTS: Increased E1 mRNA expression related to disease progression (normal 0.18, CIN 1 0.41, CIN 2/3 0.65, and SCC 0.79) was demonstrated with a significant positive correlation (r = 0.661, p = 0.019). No association between physical state and E1 expression was found. Methylation of p97 and p670 promoters showed significant elevation in SCC compared to normal samples. Only 4.2% showed genomic variations of HPV16 E1 63-bp duplication. CONCLUSION: E1 may play a role in cancer development. The detection of E1 mRNA and promoter methylation may be useful as cancer prognostic markers.