scholarly journals Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer

Immunotherapy ◽  
2015 ◽  
Vol 7 (6) ◽  
pp. 631-640 ◽  
Author(s):  
R Phaëton ◽  
J Gutierrez ◽  
Z Jiang ◽  
RG Karabakhtsian ◽  
J Albanese ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Antitumor Activity ◽  
Hpv 16 ◽  
E6 And E7 ◽  
Radiolabeled Antibodies

scholarly journals Multiple ASF/SF2 Sites in the Human Papillomavirus Type 16 (HPV-16) E4-Coding Region Promote Splicing to the Most Commonly Used 3′-Splice Site on the HPV-16 Genome

2010 ◽  
Vol 84 (16) ◽  
pp. 8219-8230 ◽  
Author(s):  
Monika Somberg ◽  
Stefan Schwartz
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Splice Site ◽  
Binding Sites ◽  
Mrna Levels ◽  
Coding Region ◽  
Cervical Lesions ◽  
Hpv 16 ◽  
Human Papillomavirus Type 16 ◽  
E6 And E7

ABSTRACT Our results presented here demonstrate that the most abundant human papillomavirus type 16 (HPV-16) mRNAs expressing the viral oncogenes E6 and E7 are regulated by cellular ASF/SF2, itself defined as a proto-oncogene and overexpressed in cervical cancer cells. We show that the most frequently used 3′-splice site on the HPV-16 genome, site SA3358, which is used to produce primarily E4, E6, and E7 mRNAs, is regulated by ASF/SF2. Splice site SA3358 is immediately followed by 15 potential binding sites for the splicing factor ASF/SF2. Recombinant ASF/SF2 binds to the cluster of ASF/SF2 sites. Mutational inactivation of all 15 sites abolished splicing to SA3358 and redirected splicing to the downstream-located, late 3′-splice site SA5639. Overexpression of a mutant ASF/SF2 protein that lacks the RS domain, also totally inhibited the usage of SA3358 and redirected splicing to the late 3′-splice site SA5639. The 15 ASF/SF2 binding sites could be replaced by an ASF/SF2-dependent, HIV-1-derived splicing enhancer named GAR. This enhancer was also inhibited by the mutant ASF/SF2 protein that lacks the RS domain. Finally, silencer RNA (siRNA)-mediated knockdown of ASF/SF2 caused a reduction in spliced HPV-16 mRNA levels. Taken together, our results demonstrate that the major HPV-16 3′-splice site SA3358 is dependent on ASF/SF2. SA3358 is used by the most abundantly expressed HPV-16 mRNAs, including those encoding E6 and E7. High levels of ASF/SF2 may therefore be a requirement for progression to cervical cancer. This is supported by our earlier findings that ASF/SF2 is overexpressed in high-grade cervical lesions and cervical cancer.

Wogonin induces apoptosis by suppressing E6 and E7 expressions and activating intrinsic signaling pathways in HPV-16 cervical cancer cells

2013 ◽  
Vol 29 (4) ◽  
pp. 259-272 ◽  
Author(s):  
Man Sub Kim ◽  
Yesol Bak ◽  
Yun Sun Park ◽  
Dong Hun Lee ◽  
Jung Hee Kim ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Hpv 16 ◽  
Cervical Cancer Cells ◽  
E6 And E7

Antibody Response for L1, E6 and E7 HPV 16 and HPV 18 Antigens in Tunisian Women with Cervical Cancer and Controls

2008 ◽  
Vol 29 (3) ◽  
pp. 266-280 ◽  
Author(s):  
M. Achour ◽  
D. Zeghal ◽  
L. Kochbati ◽  
S. Kahla ◽  
F. Zouari ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Antibody Response ◽  
Hpv 16 ◽  
E6 And E7 ◽  
Hpv 18

scholarly journals Human Papillomavirus Type 16 (HPV-16) Virus-Like Particle L1-Specific CD8+ Cytotoxic T Lymphocytes (CTLs) Are Equally Effective as E7-Specific CD8+ CTLs in Killing Autologous HPV-16-Positive Tumor Cells in Cervical Cancer Patients: Implications for L1 Dendritic Cell-Based Therapeutic Vaccines

2009 ◽  
Vol 83 (13) ◽  
pp. 6779-6789 ◽  
Author(s):  
Stefania Bellone ◽  
Karim El-Sahwi ◽  
Emiliano Cocco ◽  
Francesca Casagrande ◽  
Marilisa Cargnelutti ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Lymphocytes ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Copy Number ◽  
Autologous Tumor ◽  
Hpv 16 ◽  
Expression Levels ◽  
E6 And E7

ABSTRACT Papillomavirus-like particles (VLPs) based on L1 capsid protein represent a promising prophylactic vaccine against human papillomavirus (HPV) infections. However, cell-mediated immune responses against this antigen are believed to be of limited therapeutic value in established HPV-infected cervical lesions and, for this reason, have not been intensively investigated in cervical cancer patients. In this study we analyzed and quantified by real-time PCR (RT-PCR) the RNA expression levels of E6, E7, and L1 genes in flash-frozen HPV-16 cervical carcinomas. In addition, the kinetics of expression of E6, E7, and L1 in HPV-16-infected primary cell lines established as long-term cultures in vitro was also evaluated at RNA and protein levels. Finally, in order to evaluate the therapeutic potential of L1-specific CD4+ and CD8+ T lymphocytes responses in cervical cancer patients, L1 VLP-loaded dendritic cells (DCs) were used to stimulate peripheral blood lymphocytes from cervical cancer patients and such responses were compared to those elicited by the E7 oncoprotein. We show that 22 of 22 (100%) flash-frozen cervical biopsy samples collected from HPV-16-positive cervical cancer patients harbor L1, in addition to E6 and E7 RNA, as detected by RT-PCR. E7 RNA copy number (mean, 176.2) was significantly higher in HPV-16-positive cervical cancers compared to the E6 RNA copy number (mean, 47.3) and the L1 copy number (mean, 58.3) (P < 0.0001 and P < 0.001, respectively). However, no significant differences in expression levels between E6 and L1 were found. Kinetic studies of E6, E7, and L1 RNA and protein expression levels in primary tumors showed a sharp reduction in L1 expression after multiple in vitro passages compared to E6 and E7. Autologous DCs pulsed with HPV-16 VLPs or recombinant full-length E7 elicited strong type 1 L1- and E7-specific responses in CD4+ and CD8+ T cells from cervical cancer patients. Importantly, L1 VLP-specific CD8+ T lymphocytes expressed strong cytolytic activity against autologous tumor cells and were as effective as E7-specific cytotoxic T lymphocytes in lysing naturally HPV-16-infected autologous tumor cells. Taken together, these data demonstrate a consistent expression of L1 in primary cervical tumors and the possibility of inducing effective L1/tumor-specific CD4+ and CD8+ T-lymphocyte responses in patients harboring HPV-infected cervical cancer. These results may have important implications for the treatment of patients harboring established HPV-infected lesions with L1 VLPs or combined E7/L1 DC-based vaccinations.

scholarly journals Selection of Indonesian Medicinal Plant Active Compounds as Inhibitor Candidates of Oncoproteins E6 and E7 Human Papillomavirus Type 16 by Molecular Docking

2021 ◽  
Vol 3 (1) ◽  
pp. 9-17
Author(s):  
Riyanti Weni Syafitri ◽  
Azzania Fibriani ◽  
Reza Aditama
Keyword(s):  
Cervical Cancer ◽  
Molecular Docking ◽  
Human Papillomavirus ◽  
Medicinal Plant ◽  
Binding Site ◽  
Active Compounds ◽  
Hpv 16 ◽  
E6 And E7 ◽  
E7 Proteins

Cervical cancer cases caused by infection with Human Papillomavirus (HPV), especially HPV 16 (60.5% of cases) continue to increase every year with a high mortality rate. The current anti-cancer drugs were not only specifically targeting cancer cells, but healthy cells and can cause serious side effects. Therefore, it is necessary to find safer alternative therapies, e.g., using active compounds from natural products. The purpose of this study was to find the active compounds of Indonesian medicinal plants potentially as an inhibitor of oncoprotein E6 and E7 HPV 16, the main protein causing cervical cancer by in silico method. In this study, 711 active compounds from 187 medicinal plant species were selected based on molecular weight, solubility, gastrointestinal absorption index, and drug-likeness. Compounds that meet the criteria were tested for their affinity and interaction profile with E6 and E7 proteins through the molecular docking method. The results of this study showed 164 compounds that met the criteria. The molecular docking analysis showed nine of the most potent compounds as E6 inhibitors on the E6AP binding site and six compounds on the p53 binding site. Besides that, there were eleven most potent compounds as E7 inhibitors.  The results of this study indicate that there are natural compounds that can inhibit E6 and E7 proteins and have further potential to be used as anti-HPV drugs. However, further research is needed to test these compounds in vitro and in vivo.

Phase II trial of MEDI0457 and durvalumab for patients with recurrent/metastatic HPV-associated cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2595-2595
Author(s):  
Van K. Morris ◽  
Amir A. Jazaeri ◽  
Shannon Neville Westin ◽  
Curtis Alvin Pettaway ◽  
Solly George ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Disease Control ◽  
Progression Free Survival ◽  
Complete Response ◽  
Hpv 16 ◽  
Overall Response ◽  
Phase 2 Trial ◽  
Kaplan Meier ◽  
Duration Of Response ◽  
E6 And E7

2595 Background: Infection with human papillomavirus (HPV) types 16 or 18 drives oncogenesis for the majority of patients (pts) with cervical, anal, and some penile cancers via viral oncoproteins E6 and E7. While anti-PD1/PD-L1 antibodies have activity in pts with HPV-associated cancers, the majority do not derive benefit from these agents as monotherapy. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 oncogenes for HPV-16/18 and IL-12 adjuvant, has been shown to be safe and to provoke an immune response against the expressed antigens. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for pts with recurrent or metastatic HPV-associated cancers with the goal of improving anti-tumor activity. Methods: Pts with HPV-16/18 cervical cancer or rare (anal, penile, vaginal, or vulvar) HPV- associated cancers that were recurrent and/or metastatic following standard therapies were eligible. No prior immunotherapy was allowed. Pts received 7 mg of MEDI0457 intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks starting at week 4. The primary endpoint was best overall response according to RECIST 1.1. Adverse events (AE) were assessed using CTCAE v4.03. A Simon two-stage phase 2 trial (Ho: p <.15; Ha: p≥.35) using a one-sided alpha =.05 and beta =.20 was conducted. ≥2 responses were needed in both the “cervical” and non-cervical cohorts during the first stage in order for the trial to proceed. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: 41 pts were screened between 11/2018-10/2020. 21 pts (12 cervical, 7 anal, 2 penile) were treated. All 21 were evaluable for toxicity and 19 for response. Median age was 49 years (range, 29-75), and 18 (86%) were female. There were 17 squamous cell carcinomas (SCC) and 4 cervical adenocarcinomas. Grade ≥3 AEs occurred in 3 (14%) pts and included transaminitis, elevated lipase/amylase, hyponatremia, and neutropenia. No AE required study discontinuation. Overall response rate (ORR) was 21% (95% CI, 6-46%) and disease control rate (DCR) was 42% (95% CI, 20-67%). There was one patient with a complete response, 3 with partial response, and 4 with stable disease. All responses were noted among SCCs (1 cervical, 2 anal, 1 penile). Median duration of response among responders is 16 months (range, 11-27). Median PFS was 3.7 months (95% CI, 2.8-9.2), and median OS was 13.5 months (95% CI, 10.1-NA). 6-month PFS rate was 36% (95% CI, 20-65). Conclusions: The combination of MEDI0457 and durvalumab demonstrated acceptable safety/tolerability in pts with advanced HPV-16/18 cancers. Despite a clinically meaningful DCR, the low ORR among pts with cervical cancer led to study discontinuation for futility. Correlative studies are ongoing to characterize pts with prolonged disease control with study treatment. Clinical trial information: NCT03439085.

Antibodies to HPV-16 E6 and E7 proteins as markers for HPV-16-associated invasive cervical cancer

Virology ◽  
1992 ◽  
Vol 187 (2) ◽  
pp. 508-514 ◽  
Author(s):  
Martin Moller ◽  
Raphael P. Viscidi ◽  
Yeping Sun ◽  
Eloisa Guerrero ◽  
Peter M. Hill ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Invasive Cervical Cancer ◽  
Hpv 16 ◽  
E6 And E7 ◽  
E7 Proteins

PECULIARITIES OF PAPILLOMAVIRUS GENOTYPING IN PATIENTS WITH CERVICAL INTRAEPITHELIAL NEOPLASIA

2020 ◽  
pp. 104-111
Author(s):  
N.A. Shmakova ◽  
G.N. Chistyakova ◽  
I.N. Kononova ◽  
I.I. Remizova
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Viral Load ◽  
Cervical Intraepithelial Neoplasia ◽  
Intraepithelial Neoplasia ◽  
Squamous Intraepithelial Lesions ◽  
Hpv 16 ◽  
The World ◽  
Intraepithelial Lesions ◽  
Hpv 18

Recently, there has been a steady growth of cervical cancer all over the world, especially in Russia. Patients with cervical cancer have become much younger. At the same time, the human papillomavirus is not only the main factor in the neoplastic process, but it is also one of the most common sexually transmitted infections in the world. The aim of the paper is to assess the prevalence and characteristics of human papillomavirus genotypes in patients with cervical intraepithelial neoplasia. Materials and Methods. During the periodic screening we examined 213 women of a reproductive age with HPV infection. All patients underwent liquid-based cytology and human papillomavirus genotyping by polymerase chain reaction. Results. We revealed that the prevalence of cervical intraepithelial neoplasia among women with papillomavirus infection was 80.3 % (n=171). According to human papillomavirus genotyping, HPV 16 (38 %) and HPV 33 (32 %) prevailed. We also observed positive high correlation between high-grade squamous intraepithelial lesions (HSIL) and HPV 18 (r=+0.759, p=0.001), a negative mean correlation between HPV 45 and low-grade squamous intraepithelial lesions (LSIL) (r=-0.643, p=0.002). A cohort of patients with severe intraepithelial cervical lesions demonstrated high viral load rates. Conclusion. According to the results obtained, we established the dominance of HPV 16 and HPV 33 genotypes in cervical intraepithelial neoplasia. There were significant differences between HSIL and LSIL patients with HPV 18 and HPV 45. There was also a correlation between an increase in the viral load with the severity of the pathological process. Keywords: human papillomavirus, intraepithelial cervical neoplasms, cervical cancer. В последние годы в мире, особенно в России, наблюдается неуклонный рост и «омолаживание» рака шейки матки. При этом вирус папилломы человека является не только основным фактором прогрессирования неопластического процесса, но и одной из наиболее распространенных инфекций, предаваемых половым путем, в мире. Цель. Оценить распространенность и характеристику генотипов папилломавирусной инфекции у пациенток с цервикальными интраэпителиальными неоплазиями. Материалы и методы. Проведено обследование 213 пациенток репродуктивного возраста с ВПЧ-инфекцией, пришедших на профилактический осмотр. Всем женщинам было выполнено цитологическое исследование жидкостным методом и генотипирование вируса папилломы человека методом полимеразной цепной реакции. Результаты. Распространенность цервикальных интраэпителиальных неоплазий среди женщин с папилломавирусной инфекцией составила 80,3 % (171 пациентка). Согласно данным генотипирования вируса папилломы человека превалировал 16-й (38 %) и 33-й типы (32 %). Выявлена положительная высокая корреляционная связь между цервикальными неоплазиями высокой степени онкогенного риска (HSIL) и 18-м типом ВПЧ-инфекции (r=+0,759 при р=0,001), отрицательная средняя корреляционная связь 45-го типа ВПЧ с низкой степенью онкогенного риска (LSIL) (r=-0,643 при р=0,002). Продемонстрированы высокие показатели вирусной нагрузки в когорте пациенток с тяжелыми внутриэпителиальными цервикальными поражениями. Выводы. По результатам полученных данных установлено доминирование 16-го и 33-го генотипов ВПЧ при цервикальных интраэпителиальных неоплазиях с наличием значимых различий между пациентами с HSIL и LSIL в отношении 18-го и 45-го типов, а также связь роста уровня вирусной нагрузки с увеличением степени тяжести патологического процесса. Ключевые слова: вирус папилломы человека, интраэпителиальные новообразования шейки матки, рак шейки матки.

E6 and E7 oncoproteins: Potential targets of cervical cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ramarao Malla ◽  
Mohammad Amjad Kamal
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Immune Therapy ◽  
Cervical Lesions ◽  
Diagnostic Strategies ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

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