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Investigating the association between serum human papillomavirus type 16 E7 antibodies and risk of head and neck cancer.

ABSTRACT: Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital-based case-control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non-OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV-positive OPC.

SUBMITTER: Huang CC

PROVIDER: S-EPMC8209620 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Human papillomavirus type 16 E7 oncoprotein mediates CCNA1 promoter methylation.

Project description:Human papillomavirus (HPV) oncoproteins drive distinctive promoter methylation patterns in cancer. However, the underlying mechanism remains to be elucidated. Cyclin A1 (CCNA1) promoter methylation is strongly associated with HPV-associated cancer. CCNA1 methylation is found in HPV-associated cervical cancers, as well as in head and neck squamous cell cancer. Numerous pieces of evidence suggest that E7 may drive CCNA1 methylation. First, the CCNA1 promoter is methylated in HPV-positive epithelial lesions after transformation. Second, the CCNA1 promoter is methylated at a high level when HPV is integrated into the human genome. Finally, E7 has been shown to interact with DNA methyltransferase 1 (Dnmt1). Here, we sought to determine the mechanism by which E7 increases methylation in cervical cancer by using CCNA1 as a gene model. We investigated whether E7 induces CCNA1 promoter methylation, resulting in the loss of expression. Using both E7 knockdown and overexpression approaches in SiHa and C33a cells, our data showed that CCNA1 promoter methylation decreases with a corresponding increase in expression in E7 siRNA-transfected cells. By contrast, CCNA1 promoter methylation was augmented with a corresponding reduction in expression in E7-overexpressing cells. To confirm whether the binding of the E7-Dnmt1 complex to the CCNA1 promoter induced methylation and loss of expression, ChIP assays were carried out in E7-, del CR3-E7 and vector control-overexpressing C33a cells. The data showed that E7 induced CCNA1 methylation by forming a complex with Dnmt1 at the CCNA1 promoter, resulting in the subsequent reduction of expression in cancers. It is interesting to further explore the genome-wide mechanism of E7 oncoprotein-mediated DNA methylation.

| S-EPMC4638020 | biostudies-literature

Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600.

Project description:The human papillomavirus type 16 (HPV-16) E7 gene encodes a multifunctional oncoprotein that can subvert multiple cellular regulatory pathways. The best-known cellular targets of the HPV-16 E7 oncoprotein are the retinoblastoma tumor suppressor protein pRB and the related pocket proteins p107 and p130. However, there is ample evidence that E7 has additional cellular targets that contribute to its transforming potential. We isolated HPV-16 E7 associated cellular protein complexes by tandem affinity purification and mass spectrometry and identified the 600-kDa retinoblastoma protein associated factor, p600, as a cellular target of E7. Association of E7 with p600 is independent of the pocket proteins and is mediated through the N terminal E7 domain, which is related to conserved region 1 of the adenovirus E1A protein and importantly contributes to cellular transformation independent of pRB binding. Depletion of p600 protein levels by RNA interference substantially decreased anchorage-independent growth in HPV-positive and -negative human cancer cells. Therefore, p600 is a cellular target of E7 that regulates cellular pathways that contribute to anchorage-independent growth and cellular transformation.

| S-EPMC1182135 | biostudies-literature

Characterization of the methylation patterns in human papillomavirus type 16 viral DNA in head and neck cancers.

Project description:Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16-associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers.

| S-EPMC3079312 | biostudies-literature

Digital RNA Sequencing of Human Epidermal Keratinocytes Carrying Human Papillomavirus Type 16 E7.

Project description:High-risk human papillomavirus (HPV) infections are the predominant cause of cervical cancer and its early gene E7 plays an important role in cellular proliferation and cell-cycle progression. While tremendous progress has been made in exploring the molecular mechanisms in late tumorigenesis, many pathways showing how HPV deregulates host gene expression in early inapparent infections and early tumorigenesis still remain undefined. Digital RNA sequencing was performed and a total of 195 differentially expressed genes were identified between the HPV16 E7-transfected NHEKs and control cells (p < 0.05, fold-change > 2). GO enrichment showed that HPV16 E7 primarily affected processes involved in anti-viral and immune responses, while KEGG pathway analysis showed enrichment of gene clusters of associated with HPV infection and MAPK signaling. Of the differentially expressed genes, IFI6, SLC39A9 and ZNF185 showed a strong correlation with tumor progression and patient survival in the OncoLnc database while roles for AKAP12 and DUSP5 in carcinogenesis and poor prognosis have previously been established for other cancer types. Our study identified several novel HPV16 E7-regulated candidate genes with putative functions in tumorigenesis, thus providing new insights into HPV persistence in keratinocytes and early onset of tumorigenesis.

| S-EPMC7419603 | biostudies-literature

Rational genomic optimization of DNA detection for human papillomavirus type 16 in head and neck squamous cell carcinoma.

Project description:BackgroundWe aimed to use genomic data for optimizing polymerase chain reaction (PCR) primer/probe sets for detection of human papillomavirus (HPV)-16 in body fluids of patients with HPV-related head and neck squamous cell carcinoma (HPV-HNSCC).MethodsWe used genomic HPV-HNSCC sequencing data from a single institutional and a TCGA cohort. Optimized primer/probe sets were designed and tested for analytical performance in CaSki HPV-16 genome and confirmed in salivary rinse samples from patients with HPV-HNSCC.ResultsThe highest read density was observed between E5 and L2 regions. The E1 region contained a region that was universally present. Among candidate PCR primer/probe sets created, six reliably detected 30 HPV-16 copy number. In a CLIA certified laboratory setting, the combination of two novel primer/probe with E7 sets improved performance in salivary rinse samples with a sensitivity of 96% and specificity of 100%.ConclusionsPCR-based detection of HPV-16 DNA in HPV-HNSCC can be improved using rational genomic design.

| S-EPMC7699136 | biostudies-literature

Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage.

Project description:Background and purposePatients with human papillomavirus related (HPV+) head and neck cancers (HNCs) demonstrate improved clinical outcomes compared to traditional HPV negative (HPV-) HNC patients. We have recently shown that HPV+ HNC cells are more sensitive to radiation than HPV- HNC cells. However, roles of HPV oncogenes in regulating the response of DNA damage repair remain unknown.Material and methodsUsing immortalized normal oral epithelial cell lines, HPV+ HNC derived cell lines, and HPV16 E7-transgenic mice we assessed the repair of DNA damage using γ-H2AX foci, single and split dose clonogenic survival assays, and immunoblot. The ability of E7 to modulate expression of proteins associated with DNA repair pathways was assessed by immunoblot.ResultsHPV16 E7 increased retention of γ-H2AX nuclear foci and significantly decreased sublethal DNA damage repair. While phospho-ATM, phospho-ATR, Ku70, and Ku80 expressions were not altered by E7, Rad51 was induced by E7. Correspondingly, HPV+ HNC cell lines showed retention of Rad51 after γ-radiation.ConclusionsOur findings provide further understanding as to how HPV16 E7 manipulates cellular DNA damage responses that may underlie its oncogenic potential and influence the altered sensitivity to radiation seen in HPV+ HNC as compared to HPV- HNC.

| S-EPMC4268372 | biostudies-literature

Diagnostic accuracy of serum antibodies to human papillomavirus type 16 early antigens in the detection of human papillomavirus-related oropharyngeal cancer.

Project description:BACKGROUND:Because of the current epidemic of human papillomavirus (HPV)-related oropharyngeal cancer (OPC), a screening strategy is urgently needed. The presence of serum antibodies to HPV-16 early (E) antigens is associated with an increased risk for OPC. The purpose of this study was to evaluate the diagnostic accuracy of antibodies to a panel of HPV-16 E antigens in screening for OPC. METHODS:This case-control study included 378 patients with OPC, 153 patients with nonoropharyngeal head and neck cancer (non-OPC), and 782 healthy control subjects. The tumor HPV status was determined with p16 immunohistochemistry and HPV in situ hybridization. HPV-16 E antibody levels in serum were identified with an enzyme-linked immunosorbent assay. A trained binary logistic regression model based on the combination of all E antigens was predefined and applied to the data set. The sensitivity and specificity of the assay for distinguishing HPV-related OPC from controls were calculated. Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for the association of head and neck cancer with the antibody status. RESULTS:Of the 378 patients with OPC, 348 had p16-positive OPC. HPV-16 E antibody levels were significantly higher among patients with p16-positive OPC but not among patients with non-OPC or among controls. Serology showed high sensitivity and specificity for HPV-related OPC (binary classifier: 83% sensitivity and 99% specificity for p16-positive OPC). CONCLUSIONS:A trained binary classification algorithm that incorporates information about multiple E antibodies has high sensitivity and specificity and may be advantageous for risk stratification in future screening trials. Cancer 2017;123:4886-94. © 2017 American Cancer Society.

| S-EPMC5716885 | biostudies-literature

Prognostic implications of human papillomavirus type 16 status in non-oropharyngeal head and neck cancer: a propensity score matching analysis.

Project description:BackgroundThe purpose of this study was to investigate the association between HPV 16 status and survival outcomes in patients with non-oropharyngeal squamous carcinoma (non-OPSCC).MethodsPatients with non-OPSCC diagnosed between 2006 and 2016 were included in this study. The presence of HPV 16 DNA was confirmed by quantitative real-time polymerase chain reaction. Survival analysis was performed using Kaplan-Meier estimates, the Cox proportional hazards model, and propensity score matching (PSM).ResultsOverall, 1,539 patients with adequate specimens were identified, of whom 131 (8.51%) were positive for HPV 16. Compared to HPV 16-negative patients, the adjusted hazard ratios (aHR) for HPV 16-positive non-OPSCC patients were 0.77 and 0.81 for disease-specific survival (DSS) and overall survival (OS), respectively. Additionally, the larynx was the only subsite in which DSS was significantly improved. After PSM, cohorts consisted of 129 patients in the HPV 16-positive group and 129 in the HPV 16-negative group. HPV 16-positive non-OPSCC patients had favorable survival outcomes, however, these outcomes were not significantly different compared to HPV 16-negative patients. Stratified analysis performed according to primary site showed that only in the larynx was HPV 16-positive status a significant factor for predicting favorable DSS.ConclusionsOur findings indicate that HPV 16-positive non-OPSCC patients did not have significantly better survival outcomes compared to HPV 16-negative patients.

| S-EPMC6989993 | biostudies-literature

A longitudinal study of human papillomavirus 16 L1, e6, and e7 seropositivity and oral human papillomavirus 16 infection.

Project description:Individuals with human papillomavirus (HPV) infections can develop IgG antibodies to HPV proteins including the L1 capsid and E6 and E7 oncoproteins. Evidence on whether L1 antibodies reduce the risk of cervical HPV infection is mixed, but this has not been explored for oral HPV infections. Antibodies to HPV16's E6 oncoprotein have been detected in some oropharyngeal cancer cases years before cancer diagnosis, but it is unknown if these antibodies are associated with oral HPV16 DNA.Enzyme-linked immunosorbent assays tested for serum antibodies to HPV16's L1 capsid in 463 HIV-infected and 293 HIV-uninfected adults, and for antibodies to recombinantly expressed E6 and E7 oncoproteins to HPV16 in 195 HIV-infected and 69 HIV-uninfected cancer-free participants at baseline. Oral rinse samples were collected semiannually for up to 3 years and tested for HPV DNA using PGMY 09/11 primers. Adjusted Poisson, logistic, and Wei-Lin-Weissfeld regression models were used.Human papillomavirus 16 L1 seroreactivity did not reduce the subsequent risk of incident oral HPV16 infection in unadjusted (hazard ratio, 1.4; 95% confidence interval, 0.59-3.3) or adjusted (adjusted hazard ratio = 1.1; 95% confidence interval, 0.41-3.0) analysis. Antibodies to HPV16 E6 and E7 oncoproteins were detected in 7.6% and 3.4% of participants, respectively, but they were not associated with baseline oral HPV16 DNA prevalence or oral HPV16 persistence (each P > 0.40).Naturally acquired HPV16 L1 antibodies did not reduce the risk of subsequent oral HPV16 infection. Human papillomavirus 16 E6 and E7 seropositivity was not a marker for oral HPV16 infection in this population without HPV-related cancer.

| S-EPMC4295625 | biostudies-literature

Extracellular overproduction of E7 oncoprotein of Iranian human papillomavirus type 16 by genetically engineered Lactococcus lactis.

Project description:BACKGROUND:We aimed at constructing Lactococcus lactis strains expressing HPV-16 recombinant E7 (rE7) oncoprotein and examining its overproduction ability followed by optimizing batch and fed-batch fermentations. Thereafter, in order to assess the immunogenicity of recombinant L. lactis cells, C57BL/6 mice were immunized by oral gavage. RESULTS:The results suggested that recombinant strains harboring optiE7 and E7 genes produced a maximum of 4.84 and 1.91??g/mL of rE7 in static flask experiments, while the corresponding strains gave a maximum yield of 35.49 and 14.24??g/mL in batch experiments, respectively. Fed-batch study indicated that the concentration of rE7 protein significantly increased after feeding yeast extract plus GM17 medium. The rE7 production of the best performing strains was 2.09- and 1.48-fold higher than that of the strains during the batch fermentation. Furthermore, biomass levels were 1.98- and 1.92-fold higher than those in batch cultivation. Oral immunization of C57BL/6 mice with recombinant L. lactis produced significant specific IgG and IgA antibody responses in serum and vaginal fluids, respectively. Our outcomes suggest that vaccination with L. lactis expressing rE7 can generate significant protective effects against E7-expressing cell line. Also, our study provides evidence that the presence of large amounts of E7-specific CD4+ T helper and CD8+ T cell precursors was stimulated. Significantly higher frequencies of HPV-16 E7 specific IL-2- and IFN-?-secreting T cells were detected in antigen-stimulated splenocytes and intestinal mucosal lymphocytes, when compared to the control groups. CONCLUSIONS:We conclude that optimization of culture conditions along with recombinant protein expression can highly stimulate both specific humoral and cell-mediated immune responses in mice after oral immunization. These promising results represent a step towards fast-tracking a vaccine against HPV-16-associated cervical cancer.

| S-EPMC6346575 | biostudies-literature

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