A Systematic Analysis of Human Papillomavirus (HPV) E6 PDZ Substrates Identifies MAGI-1 as a Major Target of HPV Type 16 (HPV-16) and HPV-18 Whose Loss Accompanies Disruption of Tight Junctions

High-risk human papillomavirus (HPV) E6 proteins have a C-terminal PDZ binding motif through which they bind, and target for proteasome-mediated degradation, a number of PDZ-containing cellular targets. Recent studies have suggested that the RING-containing ubiquitin-protein ligase PDZRN3 might also be an HPV E6 target. In this analysis, we show that HPV-16 and HPV-18 E6 can target PDZRN3 in a PDZ- and proteasome-dependent manner and provide a connection between the HPV life cycle and differentiation-related STAT signaling.

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Human papillomavirus (HPV) E6/E7 mRNA as a triage test after detection of HPV 16 and HPV 18 DNA

Journal of Medical Virology ◽

10.1002/jmv.23544 ◽

2013 ◽

Vol 85 (6) ◽

pp. 1063-1068 ◽

Cited By ~ 14

Author(s):

Sonia Perez Castro ◽

Amparo Iñarrea Fernández ◽

María José Lamas González ◽

María Teresa Sarán Diez ◽

Ana Cid Lama ◽

...

Keyword(s):

Human Papillomavirus ◽

Hpv 16 ◽

Hpv E6 ◽

Hpv 18 ◽

Triage Test

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PDZ Domain-Containing Protein NHERF-2 Is a Novel Target of Human Papillomavirus 16 (HPV-16) and HPV-18

Journal of Virology ◽

10.1128/jvi.00663-19 ◽

2019 ◽

Vol 94 (1) ◽

Cited By ~ 1

Author(s):

Nathaniel Edward Bennett Saidu ◽

Vedrana Filić ◽

Miranda Thomas ◽

Vanessa Sarabia-Vega ◽

Anamaria Đukić ◽

...

Keyword(s):

Cell Proliferation ◽

Human Papillomavirus ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Cellular Proliferation ◽

Pdz Domain ◽

Hpv 16 ◽

Hpv E6 ◽

Endothelial Proliferation ◽

Hpv 18

ABSTRACT Cancer-causing human papillomavirus (HPV) E6 oncoproteins have a class I PDZ-binding motif (PBM) on their C termini, which play critical roles that are related to the HPV life cycle and HPV-induced malignancies. E6 oncoproteins use these PBMs to interact with, to target for proteasome-mediated degradation, a plethora of cellular substrates that contain PDZ domains and that are involved in the regulation of various cellular pathways. In this study, we show that both HPV-16 and HPV-18 E6 oncoproteins can interact with Na+/H+ exchange regulatory factor 2 (NHERF-2), a PDZ domain-containing protein, which among other cellular functions also behaves as a tumor suppressor regulating endothelial proliferation. The interaction between the E6 oncoproteins and NHERF-2 is PBM dependent and results in proteasome-mediated degradation of NHERF-2. We further confirmed this effect in cells derived from HPV-16- and HPV-18-positive cervical tumors, where we show that NHERF-2 protein turnover is increased in the presence of E6. Finally, our data indicate that E6-mediated NHERF-2 degradation results in p27 downregulation and cyclin D1 upregulation, leading to accelerated cellular proliferation. To our knowledge, this is the first report to demonstrate that E6 oncoproteins can stimulate cell proliferation by indirectly regulating p27 through targeting a PDZ domain-containing protein. IMPORTANCE This study links HPV-16 and HPV-18 E6 oncoproteins to the modulation of cellular proliferation. The PDZ domain-containing protein NHERF-2 is a tumor suppressor that has been shown to regulate endothelial proliferation; here, we demonstrate that NHERF-2 is targeted by HPV E6 for proteasome-mediated degradation. Interestingly, this indirectly affects p27, cyclin D1, and CDK4 protein levels and, consequently, affects cell proliferation. Hence, this study provides information that will improve our understanding of the molecular basis for HPV E6 function, and it also highlights the importance of the PDZ domain-containing protein NHERF-2 and its tumor-suppressive role in regulating cell proliferation.

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Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity

Journal of Virology ◽

10.1128/jvi.01390-17 ◽

2017 ◽

Vol 91 (22) ◽

Cited By ~ 4

Author(s):

Jayashree Thatte ◽

Lawrence Banks

Keyword(s):

Human Papillomavirus ◽

Enzymatic Activity ◽

Ubiquitin Ligase ◽

Subcellular Distribution ◽

Hpv 16 ◽

Human Papillomavirus 16 ◽

Hpv E6 ◽

Ubiquitin Ligase Activity ◽

Hpv 18 ◽

Stimulation Of

ABSTRACT The human papillomavirus (HPV) E6 oncoproteins recruit the cellular ubiquitin ligase E6AP/UBE3A to target cellular substrates for proteasome-mediated degradation, and one consequence of this activity is the E6 stimulation of E6AP autoubiquitination and degradation. Recent studies identified an autism-linked mutation within E6AP at T485, which was identified as a protein kinase A phosphoacceptor site and which could directly regulate E6AP ubiquitin ligase activity. In this study, we have analyzed how T485-mediated regulation of E6AP might affect E6 targeting of some of its known substrates. We show that modulation of T485 has no effect on the ability of E6 to direct either p53 or Dlg for degradation. Furthermore, T485 regulation has no effect on HPV-16 or HPV-31 E6-induced autodegradation of E6AP but does affect HPV-18 E6-induced autodegradation of E6AP. In cells derived from cervical cancers, we find low levels of both phosphorylated and nonphosphorylated E6AP in the nucleus. However, ablation of E6 results in a dramatic accumulation of phospho-E6AP in the cytoplasm, whereas nonphosphorylated E6AP accumulates primarily in the nucleus. Interestingly, E6AP phosphorylation at T485 confers association with 14-3-3 proteins, and this interaction seems to be important, in part, for the ability of E6 to recruit phospho-E6AP into the nucleus. These results demonstrate that HPV E6 overrides the normal phosphoregulation of E6AP, both in terms of its enzymatic activity and its subcellular distribution. IMPORTANCE Recent reports demonstrate the importance of phosphoregulation of E6AP for its normal enzymatic activity. Here, we show that HPV E6 is capable of overriding this regulation and can promote degradation of p53 and Dlg regardless of the phosphorylation status of E6AP. Furthermore, E6 interaction with E6AP also significantly alters how E6AP is subject to autodegradation and suggests that this is not a simple stimulation of an already-existing activity but rather a redirection of E6AP activity toward itself. Furthermore, E6-mediated regulation of the subcellular distribution of phospho-E6AP appears to be dependent, in part, upon the 14-3-3 family of proteins.

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DETEKSI INFEKSI Human papillomavirus (HPV) 16/18 PADA KARSINOMA SEL SKUAMOSA RONGGA MULUT DENGAN NESTED PCR

10.31227/osf.io/y8kg3 ◽

2019 ◽

Author(s):

Siti Hamidatul Aliyah

Keyword(s):

Head And Neck Cancer ◽

Human Papillomavirus ◽

Head And Neck ◽

Neck Cancer ◽

Cancer Incidence ◽

Nested Pcr ◽

Hpv Infection ◽

Hpv 16 ◽

Hpv E6 ◽

Hpv 18

Head and neck cancer ranks fourth nationally cancer incidence in Indonesia. Oral SCC isone of Head and neck cancer incidence. Oral SCCrelated to several factors, includingsmoking, alcohol, viral infection human papillomavirus (HPV 16/18) and genetic On theother hand, HPV E6 oncoprotein binds and inactivates TP53, and result in loss of control ofthe cell cycle.This study aimed to detect HPV 16/18 infection in oral SCC. Detection of HPVserotypes 16 and 18 performed on FFPE DNA isolates oral SCC with the method of nestedPolymerase Chain Reaction (PCR). Nested PCR was performed in two stages, namelyamplification with L1 primer, followed by specific PCR E6 HPV-16 and HPV-18. A total of33% (11/33) FFPE samples showed positive for HPV 18 infection (single-sized DNA bands415bp) and not detected the presence of infection with HPV 16. It can be concluded that thetype of FFPE biosampel can be used for studies related to HPV infection. Furthermore, itshould be tested on different types biosampel by a larger amount so as to represent theprevalence of oncogenic HPV infection in Indonesia.

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Complementation of a p300/CBP defective-binding mutant of adenovirus E1a by human papillomavirus E6 proteins

Journal of General Virology ◽

10.1099/0022-1317-83-4-829 ◽

2002 ◽

Vol 83 (4) ◽

pp. 829-833 ◽

Cited By ~ 10

Author(s):

Agnieszka Bernat ◽

Paola Massimi ◽

Lawrence Banks

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Cell Transformation ◽

Deficient Mutant ◽

Hpv 16 ◽

Adenovirus E1a ◽

Human Papillomavirus Type 16 ◽

Hpv E6 ◽

E6 Protein ◽

Hpv 18

Previous studies have shown that the human papillomavirus type 16 (HPV-16) E6 protein binds to p300/CBP and abrogates its transcriptional co-activator function. However, there is little information on the biological consequences of this interaction and discrepancy as to whether the interaction is high-risk E6 specific or not. We performed a series of studies to compare the interactions of HPV-18 and HPV-11 E6 with p300, and showed that both high- and low- risk E6 proteins bind p300. In addition, using a transformation-deficient mutant of adenovirus E1a, which cannot interact with p300, we demonstrated that HPV-16, HPV-18 and, to a lesser extent, HPV-11 E6, can complement this mutant in cell transformation assays. In contrast, a mutant of HPV-16 E6 which does not bind p300 failed to rescue the E1a mutant. These results suggest that the E6–p300 interaction may be important for the ability of HPV E6 to contribute towards cell transformation.

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PECULIARITIES OF PAPILLOMAVIRUS GENOTYPING IN PATIENTS WITH CERVICAL INTRAEPITHELIAL NEOPLASIA

Ulyanovsk Medico-biological Journal ◽

10.34014/2227-1848-2020-3-104-111 ◽

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.

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Prevalence of precancerous cervical lesions and high-risk human papillomavirus types in Yaounde, Cameroon

The Journal of Infection in Developing Countries ◽

10.3855/jidc.15218 ◽

2021 ◽

Vol 15 (09) ◽

pp. 1339-1345

Author(s):

Richard Tagne Simo ◽

Arsène G Djoko Nono ◽

Hervet Paulin Fogang Dongmo ◽

Paul F Seke Etet ◽

Bertrand Kiafon Fonyuy ◽

...

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Precancerous Lesions ◽

Health Centre ◽

Oral Contraceptive Pill ◽

Cervical Lesions ◽

Hpv 16 ◽

Hpv Types ◽

Cytologic Abnormalities ◽

Hpv 18

Introduction: Various Human papillomavirus (HPV) types cause cervical cancer, and represent the primary cause of cancer death in Africa and the second cause of most common cancers in Cameroon. Herein, we determined the prevalence of high-risk HPV types in women and associated cervical cytologic abnormalities in Yaounde, Cameroon. Methodology: A cross-sectional study targeting HPV-positive women aged 20 and over was conducted between March and June 2020 at the Saint Martin de Porres’ Health Centre in Yaounde. HPV tests were performed by PCR for detection of HPVs 16, 18, 33, and 45. The test was performed on 616 women using exfoliated cell specimens; then, we processed on cytological diagnosis with Pap smears on HPV positive specimens. Results: The HPV types tested were detected in 137 participants, of which 38.7% with multiple HPV infections, and the remaining part with single HPV infections of type HPV 16 (28.5%), HPV 18 (17.5%), HPV 33 (10.2%), and HPV 45 (5.1%). Cervical cytologic abnormalities were found in 69.34% of participants including: LSIL (49.63%), HSIL (15.32%), ASC-US (3.66%) and AGC (0.73%). Co-infections with HPV 16 and HPV 18 were significantly associated with HSIL (p = 0.001) lesions, while HPV 45 was more common in participants with normal cytology (p = 0.001). Cervical lesion occurrence was significantly associated with the number of sexual partners (p = 0.02) and history of oral contraceptive pill use (p = 0.001). Conclusions: Our results suggest that HPV 16 and 18 are predominant in Yaounde, and are associated with more severe precancerous lesions.

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Prognostic implication of human papillomavirus types in cervical cancer patients: a systematic review and meta-analysis

Infectious Agents and Cancer ◽

10.1186/s13027-020-00332-5 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Yuanyuan Xu ◽

Yichao Qiu ◽

Shuang Yuan ◽

Hongjing Wang

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cancer Patients ◽

Meta Analysis ◽

Disease Free Survival ◽

Progression Free Survival ◽

Hpv 16 ◽

Free Survival ◽

American Society ◽

Hpv 18

Abstract Background To estimate the prognostic relevance of human papillomavirus (HPV) 16 and HPV 18 in patients with cervical cancer. Method We searched PubMed, EMBASE, American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO), CNKI, and Wanfang databases to search primary articles illustrating the survival outcomes in cervical cancer patients with or without HPV 16/18 infection. A meta-analysis was conducted to generate a combined hazard ratio (HR) with 95% confidence intervals (CI) for progression-free survival (PFS), disease free survival (DFS) and overall survival (OS). Results A total of 13 studies were included. Our meta-analysis revealed that HPV 16 positive did not have any impact on OS (HR, 0.76; 95% CI = 0.37–1.54; P = 0.44). Cervical cancer patiensts infected with HPV 18 had worse OS (HR, 1.66; 95% CI = 1.28–2.17; P = 0.0001), DFS (HR, 2.10; 95% CI = 1.73–2.54; P < 0.0001) and worse PFS (HR, 2.97; 95% CI = 1.69–5.23; P = 0.00012) compared with those not infected with HPV 18. cervical cancer patiensts infected with HPV 18 had worse PFS compared with those infected with HPV 16 ((HR, 1.34; 95% CI = 1.06–1.70; P = 0.01). Conclusion Cervical cancer patients infected with HPV 18 had worse survival compared with cervical cancer patients with HPV 16 infection.

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Human papillomavirus genotype as a prognostic factor in carcinoma of the uterine cervix

International Journal of Gynecological Cancer ◽

10.1111/j.1525-1438.2007.00933.x ◽

2007 ◽

Vol 17 (6) ◽

pp. 1307-1313 ◽

Cited By ~ 18

Author(s):

S. Y. Tong ◽

Y. S. Lee ◽

J. S. Park ◽

S. E. Namkoong

Keyword(s):

Human Papillomavirus ◽

Prognostic Significance ◽

Rank Test ◽

Lymph Node Status ◽

Clinical Implications ◽

Specific Sequence ◽

Hpv 16 ◽

Hpv Dna ◽

Cervical Carcinomas ◽

Hpv 18

The clinical implications of specific human papillomavirus (HPV) types in invasive cervical carcinomas are only now beginning to be appreciated. The objective of this study was to determine the clinical implications and prognostic value of the HPV genotype in cervical carcinomas. In this study, we employed an HPV DNA chip to detect the type-specific sequence of HPV from cervical swabs taken from women with biopsy-proven neoplastic lesions of the cervix. We divided the patients into four groups: HPV-negative, HPV-16-related, HPV-18-related, and intermediate risk type–related. Associations with clinicopathologic data (stage, histologic type, lymph node status, parametrial invasion, lymphvascular space invasion, tumor size, vaginal involvement) and overall survival were assessed. HPV DNA was detected in 81.4% of the patients, and 19.0% harbored multiple HPV variants. HPV-16-related was the predominant type and was detected in 47.4% (46/97) of the patients. The HPV-16-related types were detected more frequently in patients with squamous cell carcinomas, whereas the HPV-18-related types were more prevalent in cases of adenocarcinomas and adenosquamous carcinomas (P< 0.05). Otherwise, no significant correlations were detected between the HPV genotype and any other clinicopathologic parameters. After a median follow-up of 30 months, the 5-year survival rate was lower in the HPV-18-related patients, but this difference was not found to be statistically significant, according to the results of the log-rank test. We conclude that neither the presence nor type of HPV DNA bears any prognostic significance in cases of cervical carcinoma.

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