Journal articles on the topic 'HPV16 E7'
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1
Alsanea, Madain, Asma Alsaleh, Dalia Obeid, Faten Alhadeq, Basma Alahideb, and Fatimah Alhamlan. "Genetic Variability in the E6, E7, and L1 Genes of Human Papillomavirus Types 16 and 18 among Women in Saudi Arabia." Viruses 15, no. 1 (December 30, 2022): 109. http://dx.doi.org/10.3390/v15010109.
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Cervical cancer is the eighth most frequent cancer in Saudi Arabia, and most cases are associated with human papillomavirus (HPV) types 16 and 18. HPV-induced carcinogenesis may be associated with the intra-type variant, genetic mutation, or the continuous expression of viral oncogenes E6 and E7. Infection efficiency and virus antigenicity may be affected by changes in the L1 gene. Thus, this retrospective cohort study analyzed E6, E7, and L1 gene mutations in cervical specimens collected from Saudi women positive for HPV16 or HPV18 infection. HPV16 and HPV18 lineages in these specimens were predominantly from Europe. The L83V mutation in the E6 gene of HPV16 showed sufficient oncogenic potential for progression to cervical cancer. By contrast, the L28F mutation in the E7 gene of HPV16 was associated with a low risk of cervical cancer. Other specific HPV16 and HPV18 mutations were associated with an increased risk of cancer, cancer progression, viral load, and age. Four novel mutations, K53T, K53N, R365P, and K443N, were identified in the L1 gene of HPV16. These findings for HPV16 and HPV18 lineages and mutations in the E6, E7, and L1 genes among women in Saudi Arabia may inform the design and development of effective molecular diagnostic tests and vaccination strategies for the Saudi population.
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Giarrè, Marianna, Sandra Caldeira, Ilaria Malanchi, Francesca Ciccolini, Maria João Leão, and Massimo Tommasino. "Induction of pRb Degradation by the Human Papillomavirus Type 16 E7 Protein Is Essential To Efficiently Overcome p16INK4a-Imposed G1 Cell Cycle Arrest." Journal of Virology 75, no. 10 (May 15, 2001): 4705–12. http://dx.doi.org/10.1128/jvi.75.10.4705-4712.2001.
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ABSTRACT It has previously been shown that the E7 protein from the cutaneous human papillomavirus type 1 (HPV1), which is associated with benign skin lesions, binds the product of the tumor suppressor gene retinoblastoma (pRb) with an efficiency similar to that of the E7 protein from the oncogenic HPV type 16. Despite this ability, HPV1 E7 does not display any activity in transforming primary cells. In addition, the two viral proteins differ in their mechanisms of targeting pRb. HPV16 E7 promotes pRb destabilization, while cells expressing HPV1 E7 do not show any decrease in pRb levels. In this study, we show that HPV1 E7, in contrast to HPV16 E7, has only a weak activity to neutralize the effect of cyclin-dependent kinase inhibitor p16INK4a. By generation of HPV1/16 E7 chimeric proteins, we have identified a central motif in the two E7 proteins, which determines their different abilities to overcome the p16INK4a-mediated cell cycle arrest. This motif is located downstream of the pRb-binding domain and comprises only three amino acids in HPV16 E7. Swapping this central motif in the two viral proteins causes an exchange of their activities involved in circumventing the inhibitory function of p16INK4a. Most importantly, our data show that the efficiency of the E7 proteins in neutralizing the inhibitory effect of p16INK4a correlates with their ability to promote pRb degradation.
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Ma, Yunyan, LV Xiaoyan, Xiaojiang Jia, Jingzhen Zhou, Zhenbo Ouyang, Zhen Gao, Wenjuan Qiao, Xin Liu, and Ninghu Zhu. "The Role and Mechanism of Human Papillomavirus16 E7 (HPV16 E7) in the Proliferation and Invasion of Cervical Cancer Cells Through Regulating Forkhead Box Protein A1." Journal of Biomaterials and Tissue Engineering 10, no. 8 (August 1, 2020): 1206–12. http://dx.doi.org/10.1166/jbt.2020.2481.
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High-risk HPV16 is an important factor for cervical cancer. HPV16 E7 can promote the malignant transformation of cervical epithelial cells. Forkhead box protein A1 (FOXA1) is abnormally expressed in several tumors. Our study assessed HPV16 E7's effect on cervical cancer cells. Hela cells were divided into control group; HPV16 E7 group; and siFOXA1+ HPV16 E7 group followed by analysis of HPV16 E7 and FOXA1 expression by Real-time PCR and Western blot, cell proliferation by MTT assay, Caspase 3 activity, Bax and Bcl-2 expression by Real-time PCR as well as cell invasion by Transwell assay. In HPV16 E7 group, HPV16 E7 and HOXA1 expression was significantly increased, cell proliferation was promoted, invasive ability was increased, Caspase 3 activity and Bax expression was decreased, and Bcl-2 expression was increased compared to control group (P < 0 05). Conversely, inhibition of FOXA1 expression in Hela cells overexpressing HPV16 E7 can significantly inhibit cell proliferation and invasion, and promote apoptosis (P < 0 05). HPV16 E7 protein can up-regulate FOXA1 in host cells, and promote cervical cancer cell growth, proliferation and invasion, indicating that it is one of the key factors contributing to cervical cancer.
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Wulandari, Dwi, Lisnawati Rachmadi, and Tjahjani M. Sudiro. "Phylogenetic analysis and predicted functional effect of protein mutations of E6 and E7 HPV16 strains isolated in Indonesia." Medical Journal of Indonesia 24, no. 4 (December 31, 2015): 197–205. http://dx.doi.org/10.13181/mji.v24i4.1197.
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Background: E6 and E7 are oncoproteins of HPV16. Natural amino acid variation in HPV16 E6 can alter its carcinogenic potential. The aim of this study was to analyze phylogenetically E6 and E7 genes and proteins of HPV16 from Indonesia and predict the effects of single amino acid substitution on protein function. This analysis could be used to reduce time, effort, and research cost as initial screening in selection of protein or isolates to be tested in vitro or in vivo.Methods: In this study, E6 and E7 gene sequences were obtained from 12 samples of Indonesian isolates, which were compared with HPV16R (prototype) and 6 standard isolates in the category of European (E), Asian (As), Asian-American (AA), African-1 (Af-1), African-2 (Af-2), and North American (NA) branch from Genbank. Bioedit v.7.0.0 was used to analyze the composition and substitution of single amino acids. Phylogenetic analysis of E6 and E7 genes and proteins was performed using Clustal X (1.81) and NJPLOT softwares. Effects of single amino acid substitutions on protein function of E6 and E7 were analysed by SNAP.Results: Java variants and isolate ui66* belonged to European branch, while the others belonged to Asian and African branches. Twelve changes of amino acids were found in E6 and one in E7 proteins. SNAP analysis showed two non neutral mutations, i.e. R10I and C63G in E6 proteins. R10I mutations were found in Af-2 genotype (AF472509) and Indonesian isolates (Af2*), while C63G mutation was found only in Af2*.Conclusion: E6 proteins of HPV16 variants were more variable than E7. SNAP analysis showed that only E6 protein of African-2 branch had functional differences compared to HPV16R.
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Nguyen, Christine L., and Karl Münger. "Human Papillomavirus E7 Protein Deregulates Mitosis via an Association with Nuclear Mitotic Apparatus Protein 1." Journal of Virology 83, no. 4 (December 3, 2008): 1700–1707. http://dx.doi.org/10.1128/jvi.01971-08.
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ABSTRACT We previously observed that high-risk human papillomavirus type 16 (HPV16) E7 expression leads to the delocalization of dynein from mitotic spindles (C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger, Cancer Res. 68:8715-8722, 2008). Here, we show that HPV16 E7 associates with nuclear mitotic apparatus protein 1 (NuMA) and that NuMA binding and the ability to induce dynein delocalization map to similar carboxyl-terminal sequences of E7. Additionally, we show that the delocalization of dynein from mitotic spindles by HPV16 E7 and the interaction between HPV16 E7 and NuMA correlate with the induction of defects in chromosome alignment during prometaphase even in cells with normal centrosome numbers. Furthermore, low-risk HPV6b and HPV11 E7s also associate with NuMA and also induce a similar mitotic defect. It is possible that the disruption of mitotic events by HPV E7, via targeting of the NuMA/dynein complex and potentially other NuMA-containing complexes, contributes to viral maintenance and propagation potentially through abrogating the differentiation program of the infected epithelium. Furthermore, in concert with activities specific to high-risk HPV E6 and E7, such as the inactivation of the p53 and pRB tumor suppressors, respectively, the disruption of the NuMA/dynein network may result in mitotic errors that would make an infected cell more prone to the accumulation of aneuploidy even in the absence of supernumerary centrosomes.
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Santin, Alessandro D., Stefania Bellone, Michela Palmieri, Alessandro Zanolini, Antonella Ravaggi, Eric R. Siegel, Juan J. Roman, Sergio Pecorelli, and Martin J. Cannon. "Human Papillomavirus Type 16 and 18 E7-Pulsed Dendritic Cell Vaccination of Stage IB or IIA Cervical Cancer Patients: a Phase I Escalating-Dose Trial." Journal of Virology 82, no. 4 (December 5, 2007): 1968–79. http://dx.doi.org/10.1128/jvi.02343-07.
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ABSTRACT The safety and immunogenicity of the human papillomavirus type 16 (HPV16) or HPV18 (HPV16/18) E7 antigen-pulsed mature dendritic cell (DC) vaccination were evaluated for patients with stage IB or IIA cervical cancer. Escalating doses of autologous DC (5, 10, and 15 × 106 cells for injection) were pulsed with recombinant HPV16/18 E7 antigens and keyhole limpet hemocyanin (KLH; an immunological tracer molecule) and delivered in five subcutaneous injections at 21-day intervals to 10 cervical cancer patients with no evidence of disease after they underwent radical surgery. Safety, toxicity, delayed-type hypersensitivity (DTH) reaction, and induction of serological and cellular immunity against HPV16/18 E7 and KLH were monitored. DC vaccination was well tolerated, and no significant toxicities were recorded. All patients developed CD4+ T-cell and antibody responses to DC vaccination, as detected by enzyme-linked immunosorbent spot (ELISpot) and enzyme-linked immunosorbent assays (ELISA), respectively, and 8 out of 10 patients demonstrated levels of E7-specific CD8+ T-cell counts, detected by ELISpot during or immediately after immunization, that were increased compared to prevaccination baseline levels. The vaccine dose did not predict the magnitude of the antibody or T-cell response or the time to detection of HPV16/18 E7-specific immunity. DTH responses to intradermal injections of HPV E7 antigen and KLH were detected for all patients after vaccination. We conclude that HPV E7-loaded DC vaccination is safe and immunogenic for stage IB or IIA cervical cancer patients. Phase II E7-pulsed DC-based vaccination trials with cervical cancer patients harboring a limited tumor burden, or who are at significant risk of tumor recurrence, are warranted.
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Nguyen, Christine L., Catherine Eichwald, Max L. Nibert, and Karl Münger. "Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Centrosomal Component γ-Tubulin." Journal of Virology 81, no. 24 (October 3, 2007): 13533–43. http://dx.doi.org/10.1128/jvi.01669-07.
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ABSTRACT Expression of a high-risk human papillomavirus (HPV) E7 oncoprotein is sufficient to induce aberrant centrosome duplication in primary human cells. The resulting centrosome-associated mitotic abnormalities have been linked to the development of aneuploidy. HPV type 16 (HPV16) E7 induces supernumerary centrosomes through a mechanism that is at least in part independent of the inactivation of the retinoblastoma tumor suppressor pRb and is dependent on cyclin-dependent kinase 2 activity. Here, we show that HPV16 E7 can concentrate around mitotic spindle poles and that a small pool of HPV16 E7 is associated with centrosome fractions isolated by sucrose density gradient centrifugation. The targeting of HPV16 E7 to the centrosome, however, was not sufficient for centrosome overduplication. Nonetheless, we found that HPV16 E7 can associate with the centrosomal regulator γ-tubulin and that the recruitment of γ-tubulin to the centrosome is altered in HPV16 E7-expressing cells. Since the association of HPV16 E7 with γ-tubulin is independent of pRb, p107, and p130, our results suggest that the association with γ-tubulin contributes to the pRb/p107/p130-independent ability of HPV16 E7 to subvert centrosome homeostasis.
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Zhou, Fang, JieZhong Chen, and Kong-Nan Zhao. "Human papillomavirus 16-encoded E7 protein inhibits IFN-γ-mediated MHC class I antigen presentation and CTL-induced lysis by blocking IRF-1 expression in mouse keratinocytes." Journal of General Virology 94, no. 11 (November 1, 2013): 2504–14. http://dx.doi.org/10.1099/vir.0.054486-0.
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Human papillomavirus 16 (HPV16) infection causes 50 % or more of cervical cancers in women. The HPV16 E7 oncogene is continuously expressed in infected epithelium with its oncogenicity linked to cervical cancer. The E7 protein is an ideal target in control of HPV infection through T-cell-mediated immunity. Using HPV16 E7-transgenic mouse keratinocytes (KCs–E7) to investigate T-cell-mediated immune responses, we have shown previously that HPV16-encoded E7 protein inhibits IFN-γ-mediated enhancement of MHC class I antigen processing and T-cell-induced target cell lysis. In this study, we found that HPV16 E7 suppresses IFN-γ-induced phosphorylation of STAT1(Tyr701), leading to the blockade of interferon regulatory factor-1 (IRF-1) and transporter associated antigen processing subunit 1 (TAP-1) expression in KCs–E7. The results of a 51Cr release assay demonstrated that IFN-γ-treated KCs–E7 escaped from CTL recognition because HPV16 E7 downregulated MHC class I antigen presentation on KCs. Restoration of IRF-1 expression in KCs–E7 overcame the inhibitory effect of E7 protein on IFN-γ-mediated CTL lysis and MHC class I antigen presentation on KCs. Our results suggest that HPV16 E7 interferes with the IFN-γ-mediated JAK1/JAK2/STAT1/IRF-1 signal transduction pathway and reduces the efficiency of peptide loading and MHC class I antigen presentation on KCs–E7. These results may reveal a new mechanism whereby HPV16 escapes from immune surveillance in vivo.
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Hayashi, Shigenori, Takashi Iwata, Ryotaro Imagawa, Masaki Sugawara, Guanliang Chen, Satoko Tanimoto, Yo Sugawara, et al. "Transcription Factor Homeobox D9 Drives the Malignant Phenotype of HPV18-Positive Cervical Cancer Cells via Binding to the Viral Early Promoter." Cancers 13, no. 18 (September 15, 2021): 4613. http://dx.doi.org/10.3390/cancers13184613.
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Persistent infections with two types of human papillomaviruses (HPV), HPV16 and HPV18, are the most common cause of cervical cancer (CC). Two viral early genes, E6 and E7, are associated with tumor development, and expressions of E6 and E7 are primarily regulated by a single viral promoter: P97 in HPV16 and P105 in HPV18. We previously demonstrated that the homeobox D9 (HOXD9) transcription factor is responsible for the malignancy of HPV16-positive CC cell lines via binding to the P97 promoter. Here, we investigated whether HOXD9 is also involved in the regulation of the P105 promoter using two HPV18-positive CC cell lines, SKG-I and HeLa. Following the HOXD9 knockdown, cell viability was significantly reduced, and E6 expression was suppressed and was accompanied by increased protein levels of P53, while mRNA levels of TP53 did not change. E7 expression was also downregulated and, while mRNA levels of RB1 and E2F were unchanged, mRNA levels of E2F-target genes, MCM2 and PCNA, were decreased, which indicates that the HOXD9 knockdown downregulates E7 expression, thus leading to an inactivation of E2F and the cell-cycle arrest. Chromatin immunoprecipitation and promoter reporter assays confirmed that HOXD9 is directly associated with the P105 promoter. Collectively, our results reveal that HOXD9 drives the HPV18 early promoter activity to promote proliferation and immortalization of the CC cells.
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Huh, KyungWon, Xiaobo Zhou, Hiroyuki Hayakawa, Je-Yoel Cho, Towia A. Libermann, Jianping Jin, J. Wade Harper, and Karl Munger. "Human Papillomavirus Type 16 E7 Oncoprotein Associates with the Cullin 2 Ubiquitin Ligase Complex, Which Contributes to Degradation of the Retinoblastoma Tumor Suppressor." Journal of Virology 81, no. 18 (July 3, 2007): 9737–47. http://dx.doi.org/10.1128/jvi.00881-07.
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ABSTRACT Human papillomavirus type 16 (HPV16) and other high-risk HPVs are etiologically linked to the development of cervical carcinomas and contribute to a number of other tumors of the anogenital tract, as well as oral cancers. The high-risk HPV E6 and E7 oncoproteins are consistently expressed in cervical cancer cells and are necessary for the induction and maintenance of the transformed phenotype. An important aspect of HPV16 E7's oncogenic activities is destabilization of the retinoblastoma tumor suppressor (pRB) through a ubiquitin/proteasome-dependent mechanism, although the exact molecular mechanism is unknown. Here, we report that HPV16 E7 is associated with an enzymatically active cullin 2 ubiquitin ligase complex and that the HPV16 E7/pRB complex contains cullin 2. Depletion of cullin 2 by RNA interference causes increased steady-state levels and stability of pRB in HPV16 E7-expressing cells, and ectopic expression of HPV16 E7 and the cullin 2 complex leads to pRB ubiquitination in vivo. Hence, we propose that the HPV16 E7-associated cullin 2 ubiquitin ligase complex contributes to aberrant degradation of the pRB tumor suppressor in HPV16 E7-expressing cells.
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Deng, Xiao-Mei, Wei Li, Xiao Zhang, Chuan-Xin Wang, Zhao-Gang Dong, Xin Zhang, Gui-Xi Zheng, et al. "RNA Interference of Human Papillomavirus Type 16 E7 Increases HLA Class I Antigen Expression in HaCaT-E7 Cells." International Journal of Gynecologic Cancer 21, no. 1 (2011): 28–34. http://dx.doi.org/10.1097/igc.0b013e3181ffcca1.
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Background:High-risk human papillomaviruses (HPVs) are the major causative agents of cervical cancer. The E7 protein of high-risk HPV disturbs cell cycle control and down-regulates components of the antigen presentation pathway, suggesting an ideal target for development of the immunotherapy in HPV-positive cervical cancers. We previously reported that HPV16 E7 could down-regulate cell-surface HLA class I antigen accompanying decreased expression of transporter associated with antigen processing 1 (TAP-1). The purpose of this study was to determine whether knockdown of HPV16 E7 could up-regulate surface HLA class I antigen expression in HPV16 E7 expressing HaCaT cells (HaCaT-E7).Methods:An E7-specific small interfering RNA (siRNA) was transfected into the HaCaT-E7 cells, and the expression of HPV16 E7 was measured by real-time reverse transcriptase polymerase chain reaction and Western blot. With the use of flow cytometry analysis, the levels of cell surface HLA class I antigen and intracellular TAP-1 expression were detected.Results:It was found that transfection of HPV16 E7-siRNA reduced HPV16 E7 expression as measured on messenger RNA and protein levels. The flow cytometry analysis showed that, compared with mock transfection, a statistically significant increase of approximately 75% in surface HLA class I levels was observed in HaCaT-E7 cells at 72 hours after transfection of E7 siRNA. Moreover, he knockdown of E7 in HaCaT-E7 cells could result in an increase of intracellular TAP-1 expression, which is essential for the expression of HLA class I at cell surface.Conclusions:Our study showed that the knockdown of HPV16 E7 could increase cell surface HLA class I antigen expression in HaCaT-E7 cells. In addition, for HPV-positive human cervical cancer, our observations indicate that theHPV E7gene is a target of choice.
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Saniba, Verli, Wresnindyatsih, Zulkarnain Musa, and Zen Hafy. "Expression of HPV16 Oncoprotein E7 in Precancerous Lesions and Cervical Squamous Cell Carcinoma." Majalah Patologi Indonesia 29, no. 2 (May 1, 2020): 57–64. http://dx.doi.org/10.55816/mpi.v29i2.409.
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BackgroundCervical cancer is the secondmost common malignancy in women worldwide.The vast majority of cervical cancersare associatedwith high risk HPV16 infection. The persistence of HPV16 and integration of viral DNA into cell genome are necessary for thedevelopment of precancerous lesion and squamous cell carcinoma (SCC) of the cervix. The integration of viral DNA in the host cellgenome resulted in the regulation of oncoprotein E7 leading to detection of HPV16 E7 expression in precancerous lesions and SCCof the cervix.The aim of this study was to evaluate differences of HPV16 E7 expression in precancerous lesions and cervical SCC.MethodsAn observational study with cross-sectional design was performedat Department of Anatomical Pathology Faculty of MedicineUniversity of Sriwijaya/dr. Mohammad Hoesin General Hospital Palembang, from 1st July 2014 to 30st Juni 2017. The selectedsamples consisted of 25 precancerous cases lesions (13 cases of LSIL and 12 samples of HSIL) and SCC (25 cases).Immuhistochemical stained was conducted using HPV16 E7 antibody. Fisher exact’s test was used to analyze differences inexpression of HPV16 E7 among precancerous lesions and cervical SCC.ResultsThe pracancerous lesions occurred mostly between the ages of 30-40 years, while SCC were those between the ages of 51-60years. All SCC cases (100%) and 91.6% of HSIL showed weak to strong HPV16 E7 expression, and 84.6% cases of LSIL showedimmunonegative.ConclusionThe positivity of HPV16 E7 increased in HSIL and KSS lesions.
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Hu, Renjian, Zhen Dong, Kui Zhang, Guangzhao Pan, Chongyang Li, and Hongjuan Cui. "Preparation, Characterization and Diagnostic Valuation of Two Novel Anti-HPV16 E7 Oncoprotein Monoclonal Antibodies." Viruses 12, no. 3 (March 19, 2020): 333. http://dx.doi.org/10.3390/v12030333.
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At present, the clinical detection method of human papillomavirus (HPV) is mainly based on the PCR method. However, this method can only be used to detect HPV DNA and HPV types, and cannot be used to accurately predict cervical cancer. HPV16 E7 is an oncoprotein selectively expressed in cervical cancers. In this study, we prepared an HPV16 E7-histidine (HIS) fusion oncoprotein by using a prokaryotic expression and gained several mouse anti-HPV16 E7-HIS fusion oncoprotein monoclonal antibodies (mAbs) by using hybridoma technology. Two mAbs, 69E2 (IgG2a) and 79A11 (IgM), were identified. Immunocytochemistry, immunofluorescence, immunohistochemistry, and Western blot were used to characterize the specificity of these mAbs. The sequences of the nucleotide bases and predicted amino acids of the 69E2 and 79A11 antibodies showed that they were novel antibodies. Indirect enzyme-linked immunosorbent assay (ELISA) with overlapping peptides, indirect competitive ELISA, and 3D structural modeling showed that mAbs 69E2 and 79A11 specifically bound to the three exposed peptides of the HPV16 E7 (HPV16 E749–66, HPV16 E773–85, and HPV16 E791–97). We used these two antibodies (79A11 as a capture antibody and 69E2 as a detection antibody) to establish a double-antibody sandwich ELISA based on a horseradish peroxidase (HRP)-labeled mAb and tetramethylbenzidine (TMB) detection system for quantitative detection of the HPV16 E7-HIS fusion oncoprotein, however, it was not ideal. Then we established a chemiluminescence immunoassay based on a labeled streptavidin-biotin (LSAB)-ELISA method and luminol detection system—this was sufficient for quantitative detection of the HPV16 E7-HIS fusion oncogenic protein in ng levels and was suitable for the detection of HPV16-positive cervical carcinoma tissues. Collectively, we obtained two novel mouse anti-HPV16 E7 oncoprotein mAbs and established an LSAB-lumino-dual-antibody sandwich ELISA method for the detection of the HPV16 E7-HIS fusion oncogenic protein, which might be a promising method for the diagnosis of HPV16-type cervical cancers in the early stage.
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Heideman, Daniëlle A. M., Tim Waterboer, Michael Pawlita, Pien Delis-van Diemen, Ingo Nindl, Joost A. Leijte, Johannes M. G. Bonfrer, Simon Horenblas, Chris J. L. M. Meijer, and Peter J. F. Snijders. "Human Papillomavirus-16 Is the Predominant Type Etiologically Involved in Penile Squamous Cell Carcinoma." Journal of Clinical Oncology 25, no. 29 (October 10, 2007): 4550–56. http://dx.doi.org/10.1200/jco.2007.12.3182.
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PurposeHuman papillomavirus (HPV) infections are suggested to be involved in the development of penile squamous cell carcinoma (SCC), but comprehensive studies to define the association are limited. Therefore, we performed molecular and serologic analyses for a broad spectrum of HPV types on a large series of 83 penile SCCs, and we compared serological findings to those of age-matched male controls (N = 83).MethodsPenile SCCs were subjected to detection and typing assays for mucosal and cutaneous HPVs and to subsequent, type-specific viral load and viral gene expression assays. Sera of patients and of controls were analyzed for type-specific mucosal and cutaneous HPV L1, E6, and/or E7 antibodies using bead-based, multiplex serology.ResultsHPV DNA of mucosal and/or cutaneous types was found in 46 of 83 (55%) penile SCCs. HPV16 was the predominant type, appearing in 24 (52%) of 46 of penile SCCs. The majority of HPV16 DNA–positive SCCs (18 of 24; 75%) demonstrated E6 transcriptional activity and a high viral load. Additionally, HPV16 molecular findings were strongly associated with HPV16 L1-, E6-, and E7-antibody seropositivity. Furthermore, serologic case-control analyses demonstrated that, in addition to the association of HPV16 with penile SCC, seropositivity against any HPV type was significantly more common in patients compared with in controls. HPV18 and HPV6 seropositivity were associated with HPV16-negative SCCs but were not correlated to molecular findings.ConclusionHPV16 is the main HPV type etiologically involved in the development of penile SCC. Although individuals who develop penile SCC show a greater prior exposure to a broad spectrum of HPV types, insufficient evidence was found to claim a role for HPV types other than HPV16 in penile carcinogenesis.
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D. S., Prabakaran, Pankaj Kumar Chaturvedi, Dineshkumar Krishnamoorthy, Young-Seok Seo, Mallikarjuna Thippana, and Woo-Yoon Park. "Fused toes homolog, a potential molecular regulator of human papillomavirus type 16 E6 and E7 oncoproteins in cervical cancer." PLOS ONE 17, no. 4 (April 14, 2022): e0266532. http://dx.doi.org/10.1371/journal.pone.0266532.
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Human papillomavirus type 16 (HPV16) plays a major role in the development of cervical cancer. The oncogenic potential of HPV16 is attributed to E6 and E7 oncoproteins. Here, we investigated the relationship between fused toes homolog (FTS) and HPV16 E6 and E7 in cervical cancer cells. HPV16-positive CaSki and SiHa cell lines were used for in vitro studies. FTS silencing was performed using a small interfering RNA (siRNA)-based approach, and western blotting was performed to determine the protein expression of tumor suppressors and cell survival markers. Immunoprecipitation, immunofluorescence, in silico analysis, and immunohistochemistry were performed to determine the interaction between, and intracellular co-localization of, FTS and both the E6 and E7 proteins. Silencing of FTS reduced the expression of the E6 and E7 proteins in cervical cancer cell lines and conversely increased the expression of the tumor suppressor proteins p53 and retinoblastoma protein. However, the primary transcripts of HPV16 E6 and E7 were unaffected by FTS silencing; furthermore, FTS transcription was unaffected by silencing of either E6 or E7, suggesting their interaction occurs post-translationally. Immunofluorescence and immunohistochemistry analysis demonstrated co-localization of FTS with the HPV16 E6 and E7 proteins, while immunoprecipitation results suggested that FTS interacts with both E6 and E7. Furthermore, in silico structural analysis identified putative residues involved in the binding of FTS with E6 and E7. Taken together, these results show that FTS affects both HPV16 E6 and E7 oncogenes in cervical cancer. We propose FTS as a target for the prevention of cervical cancer development and progression.
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Gouveris, P., T. Rampias, C. Sasaki, and A. Psyrri. "Impact of human papillomavirus (HPV) E6/E7 gene silencing on the expression of biomarkers that distinguish HPV+ versus HPV16- head and neck squamous cell carcinomas (HNSCC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e17024-e17024. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e17024.
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e17024 Background: Three studies (Pyeon et al, Slebos et al, and Schlecht et al) have identified biomarkers that distinguish HPV+ versus HPV- HNSCC using cDNA microarrays. We sought to determine whether the identified biomarker differences are a direct consequence of HPV16 E6 andE7 oncogene expression. Methods: We selected genes that were found to have altered expression in HPV16+ HNSCC compared to HPV16-. Short hairpin RNAs targeting HPV type 16 E6 and E7 genes were delivered by retrovirus infection to HPV16+ oropharyngeal cancer cell lines 147T and 090. cDNA microarray analysis was performed (slides represented approximately 35000 genes) to determine the transcriptional profile before and after E6/E7 silencing. Results: E6/E7 gene silencing affected the expression of the following genes: RFC4, CDKN2A, MCM6, NASP, EP300, E2F2, PCNA, KLK6, ANGPT1, DNAJCI, PRKCG (Table). Conclusions: Expression of several biomarkers that distinguish HPV16+ from HPV16- HNSCC is regulated by E6/E7 gene expression. Targeting E6/E7 will be an effective therapeutic strategy in HPV16+ HNSCC since alteration of key molecules that increase the malignant potential of these tumors is controlled by E6/E7 expression. [Table: see text] No significant financial relationships to disclose.
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Hu, Zheng, Lan Yu, Da Zhu, Wencheng Ding, Xiaoli Wang, Changlin Zhang, Liming Wang, et al. "Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/612823.
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High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.
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Ramberg, Ingvild, Filipe Garrett Vieira, Peter Bjerre Toft, Christian von Buchwald, and Steffen Heegaard. "Viral and Genomic Drivers of Squamous Cell Neoplasms Arising in the Lacrimal Drainage System." Cancers 14, no. 10 (May 23, 2022): 2558. http://dx.doi.org/10.3390/cancers14102558.
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The pathogenesis of squamous cell neoplasms arising in the lacrimal drainage system is poorly understood, and the underlying genomic drivers for disease development remain unexplored. We aimed to investigate the genomic aberrations in carcinomas arising in the LDS and correlate the findings to human papillomavirus (HPV) status. The HPV analysis was performed using HPV DNA PCR, HPV E6/E7 mRNA in-situ hybridization, and p16 immunohistochemistry. The genomic characterization was performed by targeted DNA sequencing of 523 cancer-relevant genes. Patients with LDS papilloma (n = 17) and LDS carcinoma (n = 15) were included. There was a male predominance (68%) and a median age at diagnosis of 46.0 years (range 27.5–65.5 years) in patients with papilloma and 63.8 years (range 34.0–87.2 years) in patients with carcinoma. Transcriptional activity of the HPV E6/E7 oncogenes was detected in the whole tumor thickness in 12/15 (80%) papillomas (HPV6, 11, 16) and 10/15 (67%) squamous cell carcinomas (SCC) (HPV11: 3/15 (20%) and HPV16: 7/15 (47%)). Pathogenic variants in PIK3CA, FGFR3, AKT1, and PIK3R1, wildtype TP53, p16 overexpression, and deregulated high-risk E6/E7 transcription characterized the HPV16-positive SCC. The deregulated pattern of HPV E6/E7 expression, correlating with HPV DNA presence and p16 positivity, supports a causal role of HPV in a subset of LDS papillomas and carcinomas. The viral and molecular profile of LDS SCC resembles that of other HPV-driven SCC.
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Hua, Chunting, Qiaoli Zheng, Jiang Zhu, Siji Chen, Yinjing Song, Stijn van der Veen, and Hao Cheng. "Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5." Oxidative Medicine and Cellular Longevity 2022 (March 10, 2022): 1–19. http://dx.doi.org/10.1155/2022/1863098.
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Consistent high-risk human papillomavirus (HPV) infection leads to various malignant cancers. Autophagy can promote cancer progression by helping cancer cells survive under stress or induce oncogenic effects when mutations or abnormalities occur. Mitogen activated protein kinases (MAPKs) can transduce various external or intrinsic stimuli into cellular responses, including autophagy, and dual-specificity phosphates (DUSPs) contribute to the direct regulation of MAPK activities. Previously, we showed that expression of DUSP5 was repressed in HPV16 E7-expressing normal human epidermal keratinocytes (NHEKs). Here we show that clinical HPV16 E7-positive precancerous and cancerous tissues also demonstrate low DUSP5 levels compared with control tissues, indicating that the inverse correlation between HPV16 E7 and DUSP5 is clinically relevant. We furthermore investigated the autophagy response in both DUSP5-deficient and HPV16 E7-expressing NHEKs. Confocal microscopy and Western analysis showed induction of LC3-II levels, autophagosome formation and autophagy fluxes in DUSP5-deficient NHEKs. Furthermore, Western analysis demonstrated specific induction of phosphorylated ERK in DUSP5-deficient and HPV16 E7-expressing NHEKs, indicating that HPV16 E7-mediated repression of DUSP5 results in induced MAPK/ERK signaling. Finally, phosphorylated mTOR and ULK (S757) were reduced in DUSP5-deficient NHEKs, while phosphorylated ULK (S555) and AMPK were increased, thereby inducing canonical autophagy through the mTOR and AMPK pathways. In conclusion, our results demonstrate that HPV16 E7 expression reduces DUSP5 levels, which in turn results in active MAPK/ERK signaling and induction of canonical autophagy through mTOR and MAPK regulation. Given its demonstrated inverse correlation with clinical cancerous tissues, DUSP5 may serve as a potential therapeutic target for cervical cancer.
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Ressing, M. E., A. Sette, R. M. Brandt, J. Ruppert, P. A. Wentworth, M. Hartman, C. Oseroff, H. M. Grey, C. J. Melief, and W. M. Kast. "Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides." Journal of Immunology 154, no. 11 (June 1, 1995): 5934–43. http://dx.doi.org/10.4049/jimmunol.154.11.5934.
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Abstract Human papillomavirus type 16 (HPV16) is strongly associated with cervical carcinogenesis. The HPV16 E6 and E7 oncoproteins are constitutively expressed in the majority of cervical tumor cells and are, therefore, attractive targets for CTL-mediated immunotherapy. In mice, the outgrowth of a lethal dose of HPV16-induced tumor cells has been prevented by vaccination with a CTL epitope encoded by HPV16 E7, indicating the feasibility of peptide immunization to obtain antitumor CTL responses. In the present study, the immunogenicity of 9 HLA-A*0201-binding peptides encoded by HPV16 E6 and E7 was analyzed in vivo in HLA-A*0201Kb transgenic mice and in vitro in CTL cultures induced from PBMC of HLA-A*0201+ healthy donors. Four peptides with a good binding affinity were immunogenic in HLA-A*0201Kb transgenic mice, and three of them were also highly immunogenic in CTL induction experiments with PBMC of HLA-A*0201+ healthy donors. Human CTL clones specific for these three peptides were capable of lysing the HPV16 E7-containing HLA-A*0201+ cervical carcinoma cell line CaSki. These E7-derived peptides (11-20, YMLDLQPETT; 82-90, LLMGTLGIV; 86-93, TLGIVCPI), therefore, are likely to represent naturally processed human CTL epitopes of HPV16. Additionally, these three HPV16-encoded peptides have the highest affinity of binding to the HLA-A*0201 molecule. In this study, peptides with a lower binding affinity were less immunogenic. Therefore, our data illustrate that the HLA-binding affinity of a peptide has a major impact on its immunogenicity. In conclusion, we have identified immunogenic peptides encoded by HPV16 E6 and E7 that could be used in vaccines for the prevention and treatment of cervical carcinoma.
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Grinstein, Edgar, Peter Wernet, Peter J. F. Snijders, Frank Rösl, Inge Weinert, Wentao Jia, Regine Kraft, et al. "Nucleolin as Activator of Human Papillomavirus Type 18 Oncogene Transcription in Cervical Cancer." Journal of Experimental Medicine 196, no. 8 (October 21, 2002): 1067–78. http://dx.doi.org/10.1084/jem.20011053.
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High risk human papillomaviruses (HPVs) are central to the development of cervical cancer and the deregulated expression of high risk HPV oncogenes is a critical event in this process. Here, we find that the cell protein nucleolin binds in a sequence-specific manner to the HPV18 enhancer. The DNA binding activity of nucleolin is primarily S phase specific, much like the transcription of the E6 and E7 oncoproteins of HPV18 in cervical cancer cells. Antisense inactivation of nucleolin blocks E6 and E7 oncogene transcription and selectively decreases HPV18+ cervical cancer cell growth. Furthermore, nucleolin controls the chromatin structure of the HPV18 enhancer. In contrast, HPV16 oncogene transcription and proliferation rates of HPV16+ SiHa cervical cancer cells are independent of nucleolin activity. Moreover, nucleolin expression is altered in HPV18+ precancerous and cancerous tissue from the cervix uteri. Whereas nucleolin was homogeneously distributed in the nuclei of normal epithelial cells, it showed a speckled nuclear phenotype in HPV18+ carcinomas. Thus, the host cell protein nucleolin is directly linked to HPV18-induced cervical carcinogenesis.
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Wang, J. F., C. X. Wang, L. S. Wang, J. Zhang, X. J. Yang, M. Liu, and G. X. Zheng. "Association of Human Papillomavirus Type 16 E7 and HLA Class I Antigen Expression in Cervical Premalignant and Malignant Lesions." International Journal of Biological Markers 22, no. 2 (April 2007): 124–31. http://dx.doi.org/10.1177/172460080702200206.
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In the present experiment we studied the correlation between HPV16 infection and expression of HLA-I antigen in cervical premalignant and malignant lesions (cervicitis, CIN, cervical squamous carcinomas and adenocarcinoma samples). The HPV16 E7 DNA load and the expression of HLA-I antigen in the samples were measured by real-time fluorescence quantitative polymerase chain reaction (RFQ-PCR) and immunohistochemical S-P staining, respectively. Our data indicate that HPV16 E7 load was highly and positively associated with the development of cervical lesions (Spearman's correlation coefficient r=0.848, p<0.001), the negative rate of HLA-I antigen was significantly distinguished among groups (p<0.001), and HPV16 E7 infection and downregulation of HLA-I antigen were highly correlated in cervical lesions (Pearson's correlation coefficient r=-0.487, p<0.001). HPV16 E7 may play an important role in the downregulation of HLA-I antigen in cervical lesions, which results in the immune escape of the virus and the occurrence, development, invasion and metastasis of cancer. Furthermore, quantitative PCR for HPV16 E7 may play an important role in the early detection of cervical diseases and in guiding future therapy toward prevention.
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Cui, Penghua, Lijing Li, Yujuan Zhang, and Zhiyan Li. "Effect of radiofrequency therapy on HPV16-E7 lentivirus infection in the reproductive tract of mice and its effect on immune function of splenic lymphocytes." Allergologia et Immunopathologia 50, no. 1 (January 1, 2022): 60–67. http://dx.doi.org/10.15586/aei.v50i1.498.
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Objective: To investigate the effect of radiofrequency therapy (RFT) on HPV16-E7 lentivirus infection in the reproductive tract of mice and reveal its effect on immune function of splenic lymphocytes. Materials and Methods: The mouse reproductive tract model was established by infection with HPV16-E7 lentivirus. Fluorescence microscope was used to evaluate successful injection. The expression of HPV16-E7 protein was detected by Western blotting test. The levels of CD4+ and CD8+ were determined by flow cytometry, and the ratio was calculated. The proliferation of splenic lymphocytes was detected by MTT assay. Expression of Interleukin (IL)-2 and interferon-γ (IFN-γ) messenger RNA (mRNA) in lymphocyte was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: Fluorescence microscope determined the successful injection of HPV16-E7 lentivirus. Compared with model group, RFT treatment decreased HPV16-E7 protein, and increased CD4+/CD8+ ratio and the proliferation activity of splenic lymphocytes. Besides, RFT treatment increased the mRNA expression levels of IL-2 and IFN-γ compared to the model group. In particular, the proliferation activity of spleen lymphocytes and the expression levels of IL-2 mRNA and IFN-γ mRNA in RFT were higher at 12 days than at 6 days after treatment. Conclusion: RFT could eliminate HPV16-E7 lentivirus infection in the reproductive tract of mice, and the mechanism was related to the immune system.
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Oton-Gonzalez, Lucia, John Charles Rotondo, Carmen Lanzillotti, Elisa Mazzoni, Ilaria Bononi, Maria Rosa Iaquinta, Luca Cerritelli, et al. "Serum HPV16 E7 Oncoprotein Is a Recurrence Marker of Oropharyngeal Squamous Cell Carcinomas." Cancers 13, no. 13 (July 5, 2021): 3370. http://dx.doi.org/10.3390/cancers13133370.
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Despite improved prognosis for many HPV-positive head and neck squamous cell carcinomas (HNSCCs), some cases are still marked by recurrence and metastasis. Our study aimed to identify novel biomarkers for patient stratification. Classical HPV markers: HPV-DNA, p16 and HPV mRNA expression were studied in HNSCC (n = 67) and controls (n = 58) by qPCR. Subsequently, ELISA tests were used for HPV16 L1 antibody and HPV16 E7 oncoprotein detection in serum at diagnosis and follow-up. All markers were correlated to relapse-free survival (RFS) and overall survival (OS). HPV-DNA was found in HNSCCs (29.85%), HPV16-DNA in 95% of cases, HPV16 E7 mRNA was revealed in 93.75%. p16 was overexpressed in 75% of HPV-positive HNSCC compared to negative samples and controls (p < 0.001). Classical markers correlated with improved OS (p < 0.05). Serological studies showed similar proportions of HPV16 L1 antibodies in all HNSCCs (p > 0.05). Serum E7 oncoprotein was present in 30% HPV-positive patients at diagnosis (p > 0.05) and correlated to HNSCC HPV16 E7 mRNA (p < 0.01), whereas it was associated to worse RFS and OS, especially for oropharyngeal squamous cell carcinoma (OPSCC) (p < 0.01). Detection of circulating HPV16 E7 oncoprotein at diagnosis may be useful for stratifying and monitoring HPV-positive HNSCC patients for worse prognosis, providing clinicians a tool for selecting patients for treatment de-escalation.
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Mao, Yifan, Liya Zhang, and Yuan Li. "Role and Mechanism of Exosome CircRNA Eukaryotic Translation Initiation Factor 4γ2 (EIF4G2) in Cervical Cancer." Journal of Biomaterials and Tissue Engineering 11, no. 11 (November 1, 2021): 2183–91. http://dx.doi.org/10.1166/jbt.2021.2812.
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Our work was to evaluate Exosome CircRNA EIF4G2 in cervical cancer development. Methods: Using Hela and Siha in our present study. Transfection vector, exosome cirEIF4G2, exosome si-NC or exosome si-circEIF4G2 in cells. Using RT-qPCR to measure circEIF4G2 gene expression in difference cell groups. Evaluating cell proliferation, apoptosis, invasion and wound healing rate by MTT, flow cytometry, transwell and wound healing assay. The relative proteins, HPV16 E6 and HPV16 E7, were evaluated by WB assay. With Exosome CircRNA EIF4G2 transfection, Hela and Siha cells proliferation, invasion cells number and wound healing rates were significantly increased and cells apoptosis were significantly depressed (P < 0.001, respectively) with HPV16 E6 and HPV16 E7 proteins expression were significantly up-regulation (P < 0.001, respectively). However, with Exosome si-CircRNA EIF4G2 transfection, Hela and Siha cells proliferation, invasion cells number and wound healing rates were significantly depressed and cells apoptosis were significantly increased (P < 0.001, respectively) with HPV16 E6 and HPV16 E7 proteins expression were significantly down-regulation (P < 0.001, respectively). Exosome CircRNA EIF4G2 as an oncology role in cervical cancer via regulation HPV16 E6/E7 up-regulation in vitro study.
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Collins, Asha S., Tomomi Nakahara, Anh Do, and Paul F. Lambert. "Interactions with Pocket Proteins Contribute to the Role of Human Papillomavirus Type 16 E7 in the Papillomavirus Life Cycle." Journal of Virology 79, no. 23 (December 15, 2005): 14769–80. http://dx.doi.org/10.1128/jvi.79.23.14769-14780.2005.
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ABSTRACT Human papillomaviruses (HPVs), most commonly the HPV16 genotype, are the principle etiological determinant for cervical cancer, a common cancer worldwide resulting in over 200,000 deaths annually. The oncogenic properties of HPVs are attributable in part to the virally encoded protein E7, best known for its ability to bind to and induce the degradation of the retinoblastoma tumor suppressor, pRb, and related “pocket proteins” p107 and p130. Previously, we defined a role for E7 in the productive stage of the HPV16 life cycle, which takes place in stratified squamous epithelia. HPV perturbs the normal processes of cell growth and differentiation of stratified squamous epithelia. HPVs reprogram cells to support continued DNA synthesis and inhibit their differentiation in the suprabasal compartment of the epithelia, where cells normally have withdrawn from the cell cycle and initiated a well-defined pattern of terminal differentiation. These virus-induced perturbations, which contribute to the production of progeny HPVs, are dependent on E7. In this study, we define the mechanism of action by which E7 contributes to the productive stage of the HPV16 life cycle. We found that the ability of HPV16 to reprogram suprabasal cells to support DNA synthesis correlates with E7's ability to bind pocket proteins but not its ability to induce their degradation. In contrast, the ability of HPV16 to perturb differentiation correlated with both E7's binding to and degradation of pocket proteins. These data indicate that different hallmarks of the productive stage of the HPV16 life cycle rely upon different sets of requirements for E7.
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Lou, Hong, Joseph F. Boland, Hongchuan Li, Robert Burk, Meredith Yeager, Stephen K. Anderson, Nicolas Wentzensen, Mark Schiffman, Lisa Mirabello, and Michael Dean. "HPV16 E7 Nucleotide Variants Found in Cancer-Free Subjects Affect E7 Protein Expression and Transformation." Cancers 14, no. 19 (October 6, 2022): 4895. http://dx.doi.org/10.3390/cancers14194895.
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The human papillomavirus (HPV) type 16 E7 oncogene is critical to carcinogenesis and highly conserved. Previous studies identified a preponderance of non-synonymous E7 variants amongst HPV16-positive cancer-free controls compared to those with cervical cancer. To investigate the function of E7 variants, we constructed full-length HPV16 E7 genes and tested variants at positions H9R, D21N, N29S, E33K, T56I, D62N, S63F, S63P, T64M, E80K, D81N, P92L, and P92S (found only in controls); D14E, N29H cervical intraepithelial neoplasia (CIN2), and P6L, H51N, R77S (CIN3). We determined the steady-state level of cytoplasmic and nuclear HPV16 E7 protein. All variants from controls showed a reduced level of E7 protein, with 7/13 variants having lower protein levels. In contrast, 2/3 variants from the CIN3 precancer group had near-wild type E7 levels. We assayed the activity of representative variants in stably transfected NIH3T3 cells. The H9R, E33K, P92L, and P92S variants found in control subjects had lower transforming activity than D14E and N29H variants (CIN2), and the R77S (CIN3) had activity only slightly reduced from wild-type E7. In addition, R77S and WT E7 caused increased migration of NIH3T3 cells in a wound-healing assay compared with H9R, E33K, P92L, and P92S (controls) and D14E (CIN2). These data provide evidence that the E7 variants found in HPV16-positive cancer-free women are partially defective for transformation and cell migration, further demonstrating the importance of fully active E7 in cancer development
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Piontek, Till, Christoph Harmel, Michael Pawlita, Katrin Carow, Juliane Schröter, Ingo B. Runnebaum, Matthias Dürst, Frederik Graw, and Tim Waterboer. "Post-treatment human papillomavirus antibody kinetics in cervical cancer patients." Philosophical Transactions of the Royal Society B: Biological Sciences 374, no. 1773 (April 8, 2019): 20180295. http://dx.doi.org/10.1098/rstb.2018.0295.
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Antibodies to the E6 and E7 oncoproteins of high-risk human papillomavirus (HPV) types are strongly associated with HPV-driven cancer, while antibodies against the capsid protein L1 are considered cumulative exposure markers. To test the hypothesis that L1 antibody levels are stable over time, whereas E6 and E7 levels undergo decay after cervical cancer (CxCa) treatment, we performed multiplex serology for HPV16 and 18 antigens E6, E7 and L1 in a post-treatment study of 184 patients with invasive CxCa that were characterized with a median follow-up time of 725 days, and 2–12 sera per patient. Antibody titers significantly decreased within the first six months for HPV16 E6 and E7 but not L1, and stabilized for the following 12 months on a high level, with few patients showing seroreversion. Of 67 patients seropositive for HPV16 E6 at diagnosis, 28 (41.8%) showed a decrease in antibody titers of at least 50% within the first 18 months. Similarly, of 50 HPV16 E7 seropositives, 33 (66.0%) showed decreasing antibody levels, whereas antibody decay was less frequent for HPV16 L1 (12 of 47, 25.5%). Using a power-law mathematical model to characterize antibody decay kinetics, the mean (±s.e.) durations to a 50% reduction in antibody titers within individual patients were estimated to be 56.9 (±26.1) and 56.3 (±19.0) days for HPV16 E6 and E7, respectively. In summary, HPV16 E6 and E7 antibodies undergo a slow but significant decrease in antibody titers within the first 6–18 months following CxCa treatment. However, larger studies are needed to confirm the utility of serology for prediction of disease progression and time to relapse based on antibody decay kinetics. This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
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Nilges, Katja, Hanni Höhn, Henryk Pilch, Claudia Neukirch, Kirsten Freitag, P. J. Talbot, and Markus J. Maeurer. "Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein." Journal of Virology 77, no. 9 (May 1, 2003): 5464–74. http://dx.doi.org/10.1128/jvi.77.9.5464-5474.2003.
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ABSTRACT Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed ≥0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.
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Martí, Cristina, Lorena Marimón, Ariel Glickman, Carla Henere, Adela Saco, Natalia Rakislova, Aureli Torné, Jaume Ordi, and Marta del Pino. "Usefulness of E7 mRNA in HPV16-Positive Women to Predict the Risk of Progression to HSIL/CIN2+." Diagnostics 11, no. 9 (September 7, 2021): 1634. http://dx.doi.org/10.3390/diagnostics11091634.
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Objective: To evaluate whether E7 mRNA can predict the risk of progression in women with HPV16 infection. Design: A prospective observational study. Setting: A tertiary university hospital. Population: A cohort of 139 women referred to colposcopy for an abnormal screening result fulfilling the following inclusion criteria: (1) a positive test result confirming HPV16 infection; (2) a biopsy sample with a histological diagnosis of an absence of lesion or low-grade SIL/CIN grade1 (LSIL/CIN1); (3) no previous HPV vaccination; (4) no pregnancy; and (5) no previous cervical treatments; and (6) no immunosuppression. Methods: At the first visit, all women underwent a cervical sample for liquid-based cytology, HPV testing and genotyping, and HPV16 E7 mRNA analysis and a colposcopy with at least one colposcopy-guided biopsy. Follow-up visits were scheduled every six months. In each control, a liquid-based Pap smear, HPV testing, as well as a colposcopy examination with biopsy if necessary were performed. Main outcome measures: Histological diagnosis of HSIL/CIN2+ at any time during follow-up. Results: E7 mRNA expression was positive in 55/127 (43.3%) women included in the study and seven (12.7%) progressed to HSIL/CIN2+. In contrast, only 1/72 (1.4%) women with no HPV16 E7 mRNA expression progressed (p = 0.027). HPV16 E7 mRNA expression was associated with a 10-fold increased risk of progression (HR 10.0; 95% CI 1.2–81.4). Conclusions: HPV16 E7 mRNA could be useful for risk stratification of women with HPV16 infection in whom a HSIL/CIN2+ has been ruled out. Funding: Instituto de Salud Carlos III (ICSIII)-Fondo de Investigación Sanitaria and ERDF ‘One Way to Europe’ (PI17/00772).
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Park, Soyeong, Andrew Auyeung, Denis L. Lee, Paul F. Lambert, Evie H. Carchman, and Nathan M. Sherer. "HIV-1 Protease Inhibitors Slow HPV16-Driven Cell Proliferation through Targeted Depletion of Viral E6 and E7 Oncoproteins." Cancers 13, no. 5 (February 24, 2021): 949. http://dx.doi.org/10.3390/cancers13050949.
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High-risk human papillomavirus strain 16 (HPV16) causes oral and anogenital cancers through the activities of two viral oncoproteins, E6 and E7, that dysregulate the host p53 and pRb tumor suppressor pathways, respectively. The maintenance of HPV16-positive cancers requires constitutive expression of E6 and E7. Therefore, inactivating these proteins could provide the basis for an anticancer therapy. Herein we demonstrate that a subset of aspartyl protease inhibitor drugs currently used to treat HIV/AIDS cause marked reductions in HPV16 E6 and E7 protein levels using two independent cell culture models: HPV16-transformed CaSki cervical cancer cells and NIKS16 organotypic raft cultures (a 3-D HPV16-positive model of epithelial pre-cancer). Treatment of CaSki cells with some (lopinavir, ritonavir, nelfinavir, and saquinavir) but not other (indinavir and atazanavir) protease inhibitors reduced E6 and E7 protein levels, correlating with increased p53 protein levels and decreased cell viability. Long-term (>7 day) treatment of HPV16-positive NIKS16 raft cultures with saquinavir caused epithelial atrophy with no discernible effects on HPV-negative rafts, demonstrating selectivity. Saquinavir also reduced HPV16′s effects on markers of the cellular autophagy pathway in NIKS16 rafts, a hallmark of HPV-driven pre-cancers. Taken together, these data suggest HIV-1 protease inhibitors be studied further in the context of treating or preventing HPV16-positive cancers.
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Tsakogiannis, D., A. Papadopoulou, G. Kontostathi, I. G. A. Ruether, Z. Kyriakopoulou, T. G. Dimitriou, G. Orfanoudakis, and P. Markoulatos. "Molecular and evolutionary analysis of HPV16 E6 and E7 genes in Greek women." Journal of Medical Microbiology 62, no. 11 (November 1, 2013): 1688–96. http://dx.doi.org/10.1099/jmm.0.055491-0.
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Human papillomavirus type 16 (HPV16) non-European variants have been associated with persistent infection and cervical cancer development, while the L83V variant of the E6 gene has been correlated with the progression of cervical malignancy. The present study investigated the presence of the HPV16 L83V variant in Greek women. Molecular evolutionary analysis of the HPV16 E6 and E7 oncogenes was conducted in order to estimate the evolution of the HPV16 genome in the Greek population. The E6 L83V variant was found in 78.2 % of high- and 64.28 % of low-grade specimens. Moreover, the prototype and E6 L83V variants were both prevalent in high- and low-grade malignancies in Greek women. Selective pressure analysis of the individual amino acid residues of HPV16 sequences from the Greek population indicates that codon 83 of the E6 protein, as well as codon 85 of the E7 protein, are undergoing positive selection. Novel sequence variations were recorded within the E6 and E7 genes in cervical samples, characterized as (T350G) European variants. However, no signal of intratypic recombination event was identified within the E6–E7 region. Molecular and evolutionary analyses of HPV16 genomes from distinct geographical locations might provide valuable information about viral evolution and oncogenecity.
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Lifsics, Andrejs, Valerija Groma, Maksims Cistjakovs, Sandra Skuja, Renars Deksnis, and Modra Murovska. "Identification of High-Risk Human Papillomavirus DNA, p16, and E6/E7 Oncoproteins in Laryngeal and Hypopharyngeal Squamous Cell Carcinomas." Viruses 13, no. 6 (May 27, 2021): 1008. http://dx.doi.org/10.3390/v13061008.
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Human papillomavirus (HPV) was proven to play a significant role in cancer development in the oropharynx. However, its role in the development of laryngeal (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) remains to be clarified. High-risk HPV (HR-HPV) viral proteins E6 and E7 are considered to be pertinent to HPV-related carcinogenesis. Hence, our aim was to estimate LSCC and HPSCC for HR-HPV DNA, p16, and E6/E7 oncoprotein status by using molecular virology and immunohistochemistry methods. The prevalence of HPV16 infection was 22/41 (53.7%) and 20/31 (64.5%) for LSCC and HPSCC, accordingly. The majority of HPV16+ tumor samples were stage III or IV. In most samples, the presence of either HPV16 E6 or HPV16 E7 viral protein in dysplastic or tumor cells was confirmed using immunohistochemistry. Our results suggest a high prevalence of HPV16 as a primary HR-HPV type in LSCC and HPSCC. The lack of HPV E6/E7 oncoproteins in some tumor samples may suggest either the absence of viral integration or the presence of other mechanisms of tumorigenesis. The utilization of p16 IHC as a surrogate marker of HR-HPV infection is impractical in LSCC and HPSCC.
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Smola-Hess, Sigrun, Jenny Pahne, Cornelia Mauch, Paola Zigrino, Hans Smola, and Herbert J. Pfister. "Expression of membrane type 1 matrix metalloproteinase in papillomavirus-positive cells: role of the human papillomavirus (HPV) 16 and HPV8 E7 gene products." Journal of General Virology 86, no. 5 (May 1, 2005): 1291–96. http://dx.doi.org/10.1099/vir.0.80551-0.
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Matrix metalloproteinases (MMPs) degrade extracellular matrix. They are involved in cellular proliferation, migration, angiogenesis, invasion and metastasis. MT-1 MMP, a membrane-bound MMP, is expressed in carcinomas of the uterine cervix in vivo. This type of cancer is associated with human papillomavirus (HPV) infection. Here it was shown that keratinocytes transformed with HPV16 or HPV18 in vitro, and HPV-positive cervical carcinoma cell lines, constitutively expressed MT-1 MMP. Expression of the E7 protein from the mucosal and cutaneous high-risk types HPV16 and HPV8, but not from the cutaneous low-risk type HPV1, was sufficient to induce MT-1 MMP expression in primary human keratinocytes and HaCaT cells. As a consequence, MMP-2 was activated. MT-1 MMP expression might play a role in the HPV life cycle by promoting proliferation of host cells and might contribute to their invasive phenotype during malignant progression.
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Nor Rashid, Nurshamimi, Rohana Yusof, and Roger J. Watson. "Disruption of repressive p130–DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells." Journal of General Virology 92, no. 11 (November 1, 2011): 2620–27. http://dx.doi.org/10.1099/vir.0.035352-0.
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Human papillomaviruses (HPVs) with tropism for mucosal epithelia are the major aetiological factors in cervical cancer. Most cancers are associated with so-called high-risk HPV types, in particular HPV16, and constitutive expression of the HPV16 E6 and E7 oncoproteins is critical for malignant transformation in infected keratinocytes. E6 and E7 bind to and inactivate the cellular tumour suppressors p53 and Rb, respectively, thus delaying differentiation and inducing proliferation in suprabasal keratinocytes to enable HPV replication. One member of the Rb family, p130, appears to be a particularly important target for E7 in promoting S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large protein complex termed DREAM. The composition of DREAM is cell cycle-regulated, associating with E2F4 and p130 in G0/G1 and with the B-myb transcription factor in S/G2. In this study, we addressed whether p130–DREAM is disrupted in HPV16-transformed cervical cancer cells and whether this is a critical function for E6/E7. We found that p130–DREAM was greatly diminished in HPV16-transformed cervical carcinoma cells (CaSki and SiHa) compared with control cell lines; however, when E6/E7 expression was targeted by specific small hairpin RNAs, p130–DREAM was reformed and the cell cycle was arrested. We further demonstrated that the profound G1 arrest in E7-depleted CaSki cells was dependent on p130–DREAM reformation by also targeting the expression of the DREAM component Lin-54 and p130. The results show that continued HPV16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130–DREAM complex.
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Bello-Rios, Ciresthel, Sarita Montaño, Olga Lilia Garibay-Cerdenares, Lilian Esmeralda Araujo-Arcos, Marco Antonio Leyva-Vázquez, and Berenice Illades-Aguiar. "Modeling and Molecular Dynamics of the 3D Structure of the HPV16 E7 Protein and Its Variants." International Journal of Molecular Sciences 22, no. 3 (January 30, 2021): 1400. http://dx.doi.org/10.3390/ijms22031400.
Full textAbstract:
The oncogenic potential of high-risk human papillomavirus (HPV) is predicated on the production of the E6 and E7 oncoproteins, which are responsible for disrupting the control of the cell cycle. Epidemiological studies have proposed that the presence of the N29S and H51N variants of the HPV16 E7 protein is significantly associated with cervical cancer. It has been suggested that changes in the amino acid sequence of E7 variants may affect the oncoprotein 3D structure; however, this remains uncertain. An analysis of the structural differences of the HPV16 E7 protein and its variants (N29S and H51N) was performed through homology modeling and structural refinement by molecular dynamics simulation. We propose, for the first time, a 3D structure of the E7 reference protein and two of Its variants (N29S and H51N), and conclude that the mutations induced by the variants in N29S and H51N have a significant influence on the 3D structure of the E7 protein of HPV16, which could be related to the oncogenic capacity of this protein.
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Díaz-Tejeda, Yakelin, Miriam C. Guido-Jiménez, Helga López-Carbajal, Alfredo Amador-Molina, Rocío Méndez-Martínez, Patricio Gariglio-Vidal, Marcela Lizano, and Alejandro García-Carrancá. "Nanog, in Cooperation with AP1, Increases the Expression of E6/E7 Oncogenes from HPV Types 16/18." Viruses 13, no. 8 (July 28, 2021): 1482. http://dx.doi.org/10.3390/v13081482.
Full textAbstract:
Persistent infections with some types of human papillomavirus (HPV) constitute the major etiological factor for cervical cancer development. Nanog, a stem cell transcription factor has been shown to increase during cancer progression. We wanted to determine whether Nanog could modulate transcription of E6 and E7 oncogenes. We used luciferase reporters under the regulation of the long control region (LCR) of HPV types 16 and 18 (HPV16/18) and performed RT-qPCR. We found that Nanog increases activity of both viral regulatory regions and elevates endogenous E6/E7 mRNA levels in cervical cancer-derived cells. We demonstrated by in vitro mutagenesis that changes at Nanog-binding sites found in the HPV18 LCR significantly inhibit transcriptional activation. Chromatin immunoprecipitation (ChIP) assays showed that Nanog binds in vivo to the HPV18 LCR, and its overexpression increases its binding as well as that of c-Jun. Surprisingly, we observed that mutation of AP1-binding sites also affect Nanog’s ability to activate transcription, suggesting cooperation between the two factors. We searched for putative Nanog-binding sites in the LCR of several HPVs and surprisingly found them only in those types associated with cancer development. Our study shows, for the first time, a role for Nanog in the regulation of E6/E7 transcription of HPV16/18.
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Liao, John B., Jean Publicover, John K. Rose, and Daniel DiMaio. "Single-Dose, Therapeutic Vaccination of Mice with Vesicular Stomatitis Virus Expressing Human Papillomavirus Type 16 E7 Protein." Clinical and Vaccine Immunology 15, no. 5 (March 12, 2008): 817–24. http://dx.doi.org/10.1128/cvi.00343-07.
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ABSTRACT We are developing recombinant attenuated vesicular stomatitis virus (VSV) as a vaccine vector to generate humoral and cell-mediated immune responses. Here, we explore the use of VSV vaccines for cancer immunotherapy. Immunotherapy targeting high-risk human papillomavirus (HPV) lesions has the potential to benefit HPV-infected individuals and cervical cancer patients by generating cytotoxic T cells that kill tumor cells that express viral antigens. A single dose of VSV expressing the HPV type 16 (HPV16) E7 oncogene was used for therapeutic vaccination of mice bearing TC-1 syngeneic tumors, which express HPV16 E7. HPV16 E7-specific T cells were generated and displayed cytotoxic activity against the tumor cells. By 14 days postvaccination, average tumor volumes were 10-fold less in the vaccinated group than in mice that received the empty-vector VSV, and regression of preexisting tumors occurred in some cases. This antitumor effect was CD8 T-cell dependent. Our results demonstrate antitumor responses to HPV16 E7 and suggest that recombinant-VSV-based vaccination should be explored as a therapeutic strategy for cervical carcinoma and other HPV-associated cancers.
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Rampias, T., C. Sasaki, and A. Psyrri. "Effect of human papillomavirus (HPV) 16 E6 and E7 gene silencing on epidermal growth factor receptor (EGFR) phosphorylation status in HPV16+oropharyngeal cancer cell lines." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e17006-e17006. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e17006.
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e17006 Background: Aberrant activation of EGFR intrinsic tyrosine phosphotransferase activity correlates with poor prognosis in several cancers. In this study, we sought to determine the effect of HPV16 E6 and E7 gene silencing on the status of EGFR phosphorylation in HPV16+ oropharyngeal cancer cell lines. Methods: Short hairpin RNAs targeting HPV type 16 E6 and E7 genes were delivered by retrovirus infection to HPV16+ oropharyngeal cancer cell lines 147T and 090. E6/E7 repression was assessed by quantitative reverse transcription polymerase chain reaction and western blotting for p53 and Rb protein levels 48 hours after retrovirus infection. Phospho-EGFR (Tyr1068), (Tyr845), (Tyr992), (Tyr1045) and total EGFR protein levels before and after silencing were then analyzed by western blotting in 147T and 090 oropharyngeal cancer cell lines. Results: Quantitative RT-PCR analysis showed reduction in E6/E7 mRNA levels up to 85% the level in uninfected or control shRNA infected cell lines. Protein expression revealed substantial downregulation of phospho-EGFR (Tyr992) protein levels, 48 h after the retrovirus infection of 090 and 147T cell lines. A slight reduction of phospho-EGFR (Tyr845) was also observed in both HPV16+ cell lines after silencing. No phosphorylation was detected at sites Y1068 and Y1045 of EGFR. Conclusions: We provide evidence that E6 and E7 are involved in tyrosine phosphorylation of epidermal growth factor receptor at sites Y992 and Y845. Phospho-tyrosine 992 is a direct binding site for the PLCγ SH2 domain and phosphorylation in this site is associated with activation of PLCγ-mediated downstream signaling. Phosphorylation of Tyr845 in the kinase domain is implicated in stabilizing the activation loop maintaining the enzyme in an active state. Since enhanced EGFR activation appears to be a direct consequence of E6/E7 expression, targeting E6/E7 may be effective EGFR blockade in HPV16+oropharyngeal cancers. No significant financial relationships to disclose.
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Hasan, Uzma A., Claudia Zannetti, Peggy Parroche, Nadège Goutagny, Marine Malfroy, Guillaume Roblot, Christine Carreira, et al. "The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter." Journal of Experimental Medicine 210, no. 7 (June 10, 2013): 1369–87. http://dx.doi.org/10.1084/jem.20122394.
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Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-κBp50–p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-κB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor.
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Tugizov, Sharof, Jennifer Berline, Rossana Herrera, Maria Elena Penaranda, Mayumi Nakagawa, and Joel Palefsky. "Inhibition of Human Papillomavirus Type 16 E7 Phosphorylation by the S100 MRP-8/14 Protein Complex." Journal of Virology 79, no. 2 (January 15, 2005): 1099–112. http://dx.doi.org/10.1128/jvi.79.2.1099-1112.2005.
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ABSTRACT The human papillomavirus type 16 (HPV16) E7 is a major viral oncoprotein that is phosphorylated by casein kinase II (CKII). Two S100 family calcium-binding proteins, macrophage inhibitory-related factor protein 8 (MRP-8) and MRP-14, form a protein complex, MRP-8/14, that inactivates CKII. The MRP-8/14 protein complex may inhibit CKII-mediated E7 phosphorylation and therefore may alter its interaction with cellular ligands and reduce E7 oncogenic activity. We examined the inhibitory effect of the MRP-8/14 complex on CKII activity and HPV16 E7 phosphorylation. We have shown that CKII activity and HPV16 E7 phosphorylation were inhibited by uptake of exogenous MRP-8/14 and activation of endogenous MRP-8/14. MRP-8/14-mediated inhibition of E7 phosphorylation occurred at the G1 phase of the cell cycle. Analysis of MRP expression in primary keratinocytes and in HPV16- and 18-transformed cervical and foreskin epithelial cell lines showed that expression of MRP-8, MRP-14, and the MRP-8/14 complex was detected only in primary untransformed keratinocytes and not in the HPV-infected immortalized epithelial cells. CKII activity in HPV-immortalized keratinocytes was approximately fourfold higher than in HPV-negative primary keratinocytes. Treatment of HPV-positive immortalized epithelial cells with exogenous MRP-8/14 resulted in E7 hypophosphorylation and complete inhibition of cell growth within 2 weeks, compared with HPV-negative primary and immortalized HPV-negative cervical epithelial cells, which showed 25 and 40% growth inhibition, respectively. Together these results suggests that the MRP-8/14 protein complex in HPV-infected epithelial cells may play an important role in regulation of CKII-mediated E7 phosphorylation and inhibition of its oncogenic activity.
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Baldwin, Amy, Kyung-Won Huh, and Karl Münger. "Human Papillomavirus E7 Oncoprotein Dysregulates Steroid Receptor Coactivator 1 Localization and Function." Journal of Virology 80, no. 13 (July 1, 2006): 6669–77. http://dx.doi.org/10.1128/jvi.02497-05.
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ABSTRACT High-risk human papillomaviruses (HPVs) are present in virtually all cervical carcinomas. However, the majority of women infected with high-risk HPVs do not develop cervical cancer. Therefore, cofactors must contribute to the development and progression of cervical cancer. Although numerous studies have implicated steroid hormones as cofactors in the initiation and progression of cervical neoplasia, the molecular mechanisms by which they contribute to cervical carcinogenesis are currently unknown. These observations led us to investigate a newly discovered association of the high-risk HPV type 16 (HPV16) E7 oncoprotein with steroid receptor coactivator 1 (SRC-1), an essential component of steroid hormone signaling. HPV16 E7 has been previously reported to interact with p300 and p300/CBP-associated factor (PCAF), members of some SRC-1 transcriptional complexes. We demonstrate here that HPV16 E7 associates in vivo and in vitro with SRC-1 independently of p300 and PCAF. Luciferase reporter constructs under the control of either the interleukin-8 promoter or a promoter containing multimerized synthetic estrogen response elements were used to determine the effect of high- and low-risk HPV E7 expression on SRC-1-mediated transcription. In addition, histone acetyltransferase (HAT) assays were performed to determine the effect of HPV E7 on SRC-1-associated HAT activity. These experiments reveal that HPV16 E7 expression down-regulates SRC-1-mediated transcription and SRC-1-associated HAT activity. SRC-1 localization experiments show that SRC-1 is relocalized to the cytoplasm in the presence of high- and low-risk HPV E7 proteins. Our data suggest that HPV E7 proteins dysregulate hormone-dependent gene expression by association with and relocalization of SRC-1. Dysregulation of SRC-1 localization and function by HPV E7 may provide insight into the molecular mechanisms by which steroid hormones act as cofactors in the induction and progression of cervical neoplasia.
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Lee, Seoung-Ae, Charles Ho, Madison Troxler, Chin-Yo Lin, and Sang-Hyuk Chung. "Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein." Viruses 13, no. 3 (March 8, 2021): 433. http://dx.doi.org/10.3390/v13030433.
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Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV+ than HPV− cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV+ SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation.
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Cui, Xiaoxu, Chengyu Hao, Lijing Gong, Naoko Kajitani, and Stefan Schwartz. "HnRNP D activates production of HPV16 E1 and E6 mRNAs by promoting intron retention." Nucleic Acids Research 50, no. 5 (March 2, 2022): 2782–806. http://dx.doi.org/10.1093/nar/gkac132.
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Abstract Human papillomavirus type 16 (HPV16) E1 and E6 proteins are produced from mRNAs with retained introns, but it has been unclear how these mRNAs are generated. Here, we report that hnRNP D act as a splicing inhibitor of HPV16 E1/E2- and E6/E7-mRNAs thereby generating intron-containing E1- and E6-mRNAs, respectively. N- and C-termini of hnRNP D contributed to HPV16 mRNA splicing control differently. HnRNP D interacted with the components of splicing machinery and with HPV16 RNA to exert its inhibitory function. As a result, the cytoplasmic levels of intron-retained HPV16 mRNAs were increased in the presence of hnRNP D. Association of hnRNP D with HPV16 mRNAs in the cytoplasm was observed, and this may correlate with unexpected inhibition of HPV16 E1- and E6-mRNA translation. Notably, hnRNP D40 interacted with HPV16 mRNAs in an HPV16-driven tonsillar cancer cell line and in HPV16-immortalized human keratinocytes. Furthermore, knockdown of hnRNP D in HPV16-driven cervical cancer cells enhanced production of the HPV16 E7 oncoprotein. Our results suggest that hnRNP D plays significant roles in the regulation of HPV gene expression and HPV-associated cancer development.
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Kanduc, Darja. "Translational Regulation of Human Papillomavirus Type 16 E7 mRNA by the Peptide SEQIKA, Shared by Rabbit α1-Globin and Human Cytokeratin 7." Journal of Virology 76, no. 14 (July 15, 2002): 7040–48. http://dx.doi.org/10.1128/jvi.76.14.7040-7048.2002.
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ABSTRACT The possible biochemical factors able to affect the in vitro expression of the high-risk human papillomavirus type 16 (HPV16) E7 oncoprotein have been analyzed. Evidence is provided that E7 mRNA stability is increased and, conversely, transcript translation is inhibited by binding to a 32-kDa protein from rabbit reticulocyte lysate; sequence analysis identified the 32-kDa binding protein as rabbit α1-globin protein; and interaction between rabbit α1-globin and E7 mRNA occurs through the 6-mer peptide SEQIKA present in human cytokeratin 7 protein. The in vitro data were confirmed by the occurrence of HPV16 E7 mRNA-cytokeratin 7 binding in squamous cervical cancer SiHa cells.
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Salazar-León, Jonathan, Fabiola Reyes-Román, Angélica Meneses-Acosta, Horacio Merchant, Alfredo Lagunas-Martínez, Elizabeth Meda-Monzón, María Luisa Pita-López, et al. "Silencing of hpv16 e6 and e7 oncogenic activities by small interference rna induces autophagy and apoptosis in human cervical cancer cells." Journal of Nucleic Acids Investigation 2, no. 1 (August 30, 2011): 10. http://dx.doi.org/10.4081/jnai.2011.2583.
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Cervical cancer is the second most common form of death by cancer in women worldwide and has special attention for the development of new treatment strategies. Human Papilloma Virus (HPV) persistent infection is the main etiological agent of this neoplasia, and the main cellular transformation mechanism is by disruption of p53 and pRb function by interaction with HPV E6 and E7 oncoproteins. This generates alterations in cellular differentiation and cellular death inhibition. Thus, HPV E6 and E7 oncogenes represent suitable targets for the development of gene therapy strategies against cervical cancer. An attractive technology platform is developing for post-transcriptional selective silencing of gene expression, using small interference RNA. Therefore, in the present study, we used SiHa cells (HPV16+) transiently transfected with specific siRNA expression plasmids for HPV16 E6 and E7 oncogenes. In this model we detected repression of E6 and E7 oncogene and oncoprotein expression, an increase in p53 and hypophosphorylated pRb isoform protein expression, and autophagy and apoptosis morphology features. These findings suggest that selective silencing of HPV16 E6 and E7 oncogenes by siRNAs, has significant biological effects on the survival of human cancer cells and is a potential gene therapy strategy against cervical cancer.
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He, Wanxia, Doug Staples, Clark Smith, and Chris Fisher. "Direct Activation of Cyclin-Dependent Kinase 2 by Human Papillomavirus E7." Journal of Virology 77, no. 19 (October 1, 2003): 10566–74. http://dx.doi.org/10.1128/jvi.77.19.10566-10574.2003.
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ABSTRACT Addition of human papillomavirus (HPV) E7 CDK2/cyclin A or CDK2/cyclin E, purified from either insect cells or bacteria, dramatically upregulates histone H1 kinase activity. Activation is substrate specific, with a smaller effect noted for retinoblastoma protein (Rb). The CDK2 stimulatory activity is equivalent in high-risk (HPV type 16 [HPV16] and HPV31) and low-risk (HPV6b) E7. Mutational analyses of HPV16 E7 indicate that the major activity resides in amino acids 9 to 38, spanning CR1 and CR2, and does not require casein kinase II or Rb-binding domain functions. Synthetic peptides spanning HPV16 amino acid residues 9 to 38 also activate CDK2. Peptides containing this sequence that carry biotin on the carboxy terminus, as well as a photoactivated cross-linking group (benzophenone), also activate the complex and covalently associate with the CDK2/cyclin A complex in a specific manner requiring UV. Cross-linking studies that use protein monomers detect association of the E7 peptides with cyclin A but not CDK2. Together, our results indicate a novel mechanism whereby E7 promotes HPV replication by directly altering CDK2 activity and substrate specificity.
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Xu, Minzhen, Xueqing Lu, Margaret Sposato, John W. Zinckgraf, Shuzhen Wu, and Eric von Hofe. "Ii-Key/HPV16 E7 hybrid peptide immunotherapy for HPV16+ cancers." Vaccine 27, no. 34 (July 2009): 4641–47. http://dx.doi.org/10.1016/j.vaccine.2009.05.054.
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Camus, Claire, Sébastien Vitale, Céline Loubatier, Guillaume Pénaranda, Hacène Khiri, Anne Plauzolles, Xavier Carcopino, Philippe Halfon, and Valérie Giordanengo. "Quantification of HPV16 E6/E7 mRNA Spliced Isoforms Viral Load as a Novel Diagnostic Tool for Improving Cervical Cancer Screening." Journal of Clinical Medicine 7, no. 12 (December 8, 2018): 530. http://dx.doi.org/10.3390/jcm7120530.
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High-risk human papillomaviruses (HPVs) have been identified as the main contributors to cervical cancer. Despite various diagnostic tools available, including the predominant Papanicolaou test (Pap test), technical limitations affect the efficiency of cervical cancer screening. The aim of this study was to evaluate the diagnostic performance of spliced HPV16 E6/E7 mRNA viral loads (VL) for grade 2 or higher cervical intraepithelial neoplasia diagnosis. A new dedicated (quantitative reverse transcription polymerase chain reaction) qRT-PCR assay was developed, allowing selective quantification of several HPV16 E6/E7 mRNA: Full length (FL) with or without all or selected spliced forms (total E6/E7 mRNA corresponding to SP + E6^E7 mRNA (T), + spliced E6/E7 mRNA containing intact E7 ORF (SP), and E6/E7 mRNA containing disrupted E6 and E7 ORFs calculated by the following subtraction T-SP (E6^E7)). Twenty HPV16 DNA and mRNA positive uterine cervical smears representative of all cytological and histological stages of severity were tested. We have shown that all E6/E7 mRNA isoforms expression levels were significantly increased in high grade cervical lesions. Statistical analysis demonstrated that the SP-E6/E7 VL assay exhibited: (i) The best diagnostic performance for identification of both cervical intraepithelial neoplasia (CIN)2+ (90% (56–100) sensitivity and specificity) and CIN3+ (100% (72–100) sensitivity and 79% (49–95) specificity) lesions; (ii) a greater sensitivity compared to the Pap test for CIN2+ lesions detection (80% (44–97)); (iii) a predictive value of the histological grade of cervical lesions in 67% of atypical squamous cells of unknown significance (ASC-US) and 100% of low-grade (LSIL) patients. Overall, these results highlight the value of SP-E6/E7 mRNA VL as an innovative tool for improving cervical cancer screening.
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Carrillo-Beltrán, Diego, Juan P. Muñoz, Nahir Guerrero-Vásquez, Rancés Blanco, Oscar León, Vanesca de Souza Lino, Julio C. Tapia, et al. "Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells." Cancers 12, no. 7 (July 15, 2020): 1904. http://dx.doi.org/10.3390/cancers12071904.
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A subset of oral carcinomas is etiologically related to high-risk human papillomavirus (HR-HPV) infection, with HPV16 being the most frequent HR-HPV type found in these carcinomas. The oncogenic role of HR-HPV is strongly dependent on the overexpression of E6 and E7 oncoproteins, which, in turn, induce p53 and pRb degradation, respectively. Additionally, it has been suggested that HR-HPV oncoproteins are involved in the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducing cancer progression and metastasis. Previously, we reported that HPV16 E7 oncoprotein promotes Pirin upregulation resulting in increased epithelial–mesenchymal transition (EMT) and cell migration, with Pirin being an oxidative stress sensor and activator of NF-κB. In this study, we demonstrate the mechanism by which HPV16 E7-mediated Pirin overexpression occurs by promoting EGFR/PI3K/AKT1/NRF2 signaling, thus causing PIR/NF-κB activation in oral tumor cells. Our results demonstrate a new mechanism by which E7 contributes to oral cancer progression, proposing PIR as a potential new therapeutic target.