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HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma.

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.

SUBMITTER: Xue Y

PROVIDER: S-EPMC4741503 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma.

Xue Yuezhen Y Toh Shen Yon SY He Pingping P Lim Thimothy T Lim Diana D Pang Chai Ling CL Abastado Jean-Pierre JP Thierry Françoise F

Oncotarget 20151001 33

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 s ...[more]

PMID: 26474276

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Project description:ObjectiveTo examine whether surgical procedures involving the uterine cervix were associated with pregnancy outcomes, including preterm birth, low birth weight, cesarean delivery and pregnancy loss.DesignPopulation-based observational study nested in retrospective matched cohort.SettingKaiser Permanente Northwest integrated health plan in Oregon/Washington, U.S.A.PopulationFemale health plan members age 14-53 years with documented pregnancies from 1998-2009. Women with prior excisional and ablative cervical surgical procedures (N = 322) were compared to women unexposed to cervical procedures (N = 4,307) and, separately, to those having undergone only diagnostic/biopsy procedures (N = 847).MethodsUsing log-linear regression models, we examined risk of adverse pregnancy outcomes in relation to prior excisional or ablative cervical surgical procedures. We stratified excisional procedures by excision thickness. We evaluated for confounding by age, body mass index, race, smoking history, previous preterm birth, and parity.ResultsWe found a positive association between excisional treatment > = 1.0 cm and the outcomes preterm birth and low birth weight (preterm birth unadjusted risk ratio [RR] = 2.15, 95% confidence interval [CI] 1.16-3.98 for excisions ?1.0 cm compared to unexposed women), particularly in women who delivered within one year of surgery (RR = 3.26, 95% CI 1.41-7.53). There was no clear association between excisional treatment and cesarean delivery, and treated women did not have a substantially higher risk of dysfunctional labor. Ablative treatment was not associated with low birth weight, preterm birth, or cesarean delivery but was associated with pregnancy loss (RR = 1.43, 95% CI 1.05-1.93 vs. unexposed women). Analyses using the diagnostic procedures comparison group produced similar results.ConclusionWomen with > = 1.0 cm excisional treatment had elevated risk of preterm birth and low birth weight when compared to unexposed women and women with cervical diagnostic procedures. This suggests that increased risk derives from the treatment itself, not from other characteristics. The observed association between pregnancy loss and ablative surgical treatment requires further investigation.

Dataset Information

HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma.

Publications

HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma.

Similar Datasets

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