scholarly journals Cigarette Smoking Promotes Infection of Cervical Cells by High-Risk Human Papillomaviruses, but not Subsequent E7 Oncoprotein Expression

2018 ◽  
Author(s):  
Kimon Chatzistamatiou ◽  
Theodoros Moysiadis ◽  
Dimos Vryzas ◽  
Ekaterini Chatzaki ◽  
Andreas M. Kaufmann ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Sandwich Elisa ◽  
Protein Detection ◽  
Human Papillomaviruses ◽  
Smoking Intensity ◽  
Hpv Dna ◽  
E7 Oncoprotein ◽  
Detection Assay ◽  
Cervical Cells

Persistent cervical infection with high-risk Human papillomaviruses (hrHPVs) is a necessary, but not sufficient, condition for the development of cervical cancer. Therefore, there are other co-factors facilitating the hrHPV carcinogenic process, one of which is smoking. In order to assess the effect of smoking on high-risk (hr) HPV DNA positivity and on the expression of HPV E7 oncoprotein, as a surrogate of persistent hrHPV infection, we used data from women recruited for the PIPAVIR project, which examined the role of E7 protein detection in cervical cancer screening. Women were tested for hrHPV DNA, using Multiplex Genotyping and E7 protein, using a novel sandwich ELISA method, and gave information on their smoking habits. Among 1473 women, hrHPV prevalence was 19.1%. The odds ratio (OR) for hrHPV positivity of smokers compared to non-smokers was 1.785 (95%CI: 1.365-2.332, p<0.001). The ORs for E7 positivity, concerning hrHPV positive women, ranged from 0.720 to 1.360 depending on the E7 detection assay used, but this was not statistically significant. Smoking increases the probability of hrHPV infection, and smoking intensity is positively associated to this increase. Smoking is not related to an increased probability of E7 protein positivity for hrHPV positive women.

scholarly journals The E7 Oncoprotein Is Translated from Spliced E6*I Transcripts in High-Risk Human Papillomavirus Type 16- or Type 18-Positive Cervical Cancer Cell Lines via Translation Reinitiation

2006 ◽  
Vol 80 (9) ◽  
pp. 4249-4263 ◽  
Author(s):  
Shuang Tang ◽  
Mingfang Tao ◽  
J. Philip McCoy ◽  
Zhi-Ming Zheng
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Cell Lines ◽  
Rna Splicing ◽  
Human Papillomaviruses ◽  
Small Interfering Rnas ◽  
Coding Region ◽  
Exon 2 ◽  
E7 Oncoprotein ◽  
Intron 1

ABSTRACT High-risk human papillomaviruses (HPVs) encode two viral oncoproteins, E6 and E7, from a single bicistronic pre-mRNA containing three exons and two introns. Retention of intron 1 in the E6 coding region is essential for production of the full-length E6 oncoprotein. However, splicing of intron 1 is extremely efficient in cervical cancer cells, leading to the production of a spliced transcript, E6*I, of E6. Here, we investigated whether this splicing of intron 1 might benefit E7 production. Using RNA interference as a tool, we targeted the intron 1 region using small interfering RNAs (siRNAs) in HPV-positive cell lines. At an effective low dose, the siRNAs specifically suppressed E6 expression but not E7 expression, as demonstrated by the stabilization of p53. However, at high doses the HPV18 intron 1-specific siRNA substantially and specifically reduced the level of the 18E6*I mRNA lacking the intron region in HeLa cells, implying its nuclear silencing on the pre-mRNA before RNA splicing. Two other siRNAs targeting the exon 2 regions of HPV16 and -18, which encode the E7 oncoprotein, reduced the E6*I mRNAs to a remarkable extent and preferentially suppressed expression of E7, leading to accumulation of hypophosphorylated p105Rb and cell cycle arrest, indicating that the majority of E7 proteins are the translational products of E6*I mRNAs. This was confirmed by transient transfection in 293 cells: E7 could be translated only from the E7 open reading frame (ORF) on E6*I mRNA in a distance-dependent matter of upstream E6*I ORF by translation reinitiation. The data thus provide direct evidence that the E6*I mRNAs of high-risk HPVs are responsible for E7 production.

scholarly journals High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Elizabeth A. White ◽  
Karl Münger ◽  
Peter M. Howley
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Human Papillomaviruses ◽  
E7 Oncoprotein ◽  
Hpv E7 ◽  
Transforming Activity ◽  
E7 Proteins ◽  
High Risk Hpv

ABSTRACTThe major transformation activity of the high-risk human papillomaviruses (HPV) is associated with the E7 oncoprotein. The interaction of HPV E7 with retinoblastoma family proteins is important for several E7 activities; however, this interaction does not fully account for the high-risk E7-specific cellular immortalization and transformation activities. We have determined that the cellular non-receptor protein tyrosine phosphatase PTPN14 interacts with HPV E7 from many genus alpha and beta HPV types. We find that high-risk genus alpha HPV E7, but not low-risk genus alpha or beta HPV E7, is necessary and sufficient to reduce the steady-state level of PTPN14 in cells. High-risk E7 proteins target PTPN14 for proteasome-mediated degradation, which requires the ubiquitin ligase UBR4, and PTPN14 is degraded by the proteasome in HPV-positive cervical cancer cell lines. Residues in the C terminus of E7 interact with the C-terminal phosphatase domain of PTPN14, and interference with the E7-PTPN14 interaction restores PTPN14 levels in cells. Finally, PTPN14 degradation correlates with the retinoblastoma-independent transforming activity of high-risk HPV E7.IMPORTANCEHigh-risk human papillomaviruses (HPV) are the cause of cervical cancer, some other anogenital cancers, and a growing fraction of oropharyngeal carcinomas. The high-risk HPV E6 and E7 oncoproteins enable these viruses to cause cancer, and the mechanistic basis of their carcinogenic activity has been the subject of intense study. The high-risk E7 oncoprotein is especially important in the immortalization and transformation of human cells, which makes it a central component of HPV-associated cancer development. E7 oncoproteins interact with retinoblastoma family proteins, but for several decades, it has been recognized that high-risk HPV E7 oncoproteins have additional cancer-associated activities. We have determined that high-risk E7 proteins target the proteolysis of the cellular protein tyrosine phosphatase PTPN14 and find that this activity is correlated with the retinoblastoma-independent transforming activity of E7.

scholarly journals Cigarette Smoking Promotes Infection of Cervical Cells by High-Risk Human Papillomaviruses, but not Subsequent E7 Oncoprotein Expression

2018 ◽  
Vol 19 (2) ◽  
pp. 422 ◽  
Author(s):  
Kimon Chatzistamatiou ◽  
Theodoros Moysiadis ◽  
Dimos Vryzas ◽  
Ekaterini Chatzaki ◽  
Andreas Kaufmann ◽  
...  
Keyword(s):  
High Risk ◽  
Cigarette Smoking ◽  
Human Papillomaviruses ◽  
E7 Oncoprotein ◽  
Cervical Cells

scholarly journals Human Papillomavirus and Cervical Cancer

2003 ◽  
Vol 16 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Eileen M. Burd
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Precancerous Lesions ◽  
Molecular Techniques ◽  
Hpv Dna ◽  
Molecular Events ◽  
Hpv Types ◽  
Cervical Cells ◽  
High Risk Hpv

SUMMARY Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.

scholarly journals Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer

2019 ◽  
Author(s):  
Anne Van Arsdale ◽  
Nicole E. Patterson ◽  
Elaine C. Maggi ◽  
Lorenzo Agoni ◽  
Koenraad Van Doorslaer ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Human Genome ◽  
Massively Parallel Sequencing ◽  
B Cell Lymphoma ◽  
Human Papillomaviruses ◽  
Cancer Death ◽  
Hpv Dna ◽  
Fusion Transcripts ◽  
Genomic Analyses

AbstractCervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR- E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flankingBCL11BDNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novelBCL11Bvariants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.Statement of SignificanceMultiple HPV types have been defined as high risk for cancer causation. However, genomic analyses applied here detected a non-high risk HPV in a carcinoma that was HPV negative, and elucidated virally-associated tumorigenic genetic events. This stresses the importance of thorough genomic analyses for elucidating genetic processes in HPV-associated tumorigenesis.Author SummaryCervical cancer is the second leading cause of cancer death in women worldwide. Most cervical cancers are caused by one of 15 high risk types of human papilloma viruses (HPVs), although hundreds of types of HPVs exist. We used a series of contemporary genomics analyses to examine a cervical cancer that was clinically determined to be HPV-negative. These detected DNA of HPV70, an HPV type not considered to be high risk, in the tumor. Approximately half of the HPV70 DNA genome was present including the viral E6 and E7 oncogenes. Moreover, the viral DNA was inserted into theBCL11Bgene in the human genome.BCL11Bis known to be mutated in certain human cancers. The HPV70 DNA interacted with the humanBCL11Bgene to produce altered forms of RNA encoding unusual, truncated forms of theBCL11Bprotein. These results strongly implicate HPV70 as being oncogenic, suggest that this tumor was caused by a combination of viral oncogenes plus the virally-activated humanBCL11Bgene, demonstrate novel truncatedBCL11Bvariants with oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate HPV tumorigenesis insights

scholarly journals HPV and Other Microbiota; Who’s Good and Who’s Bad: Effects of the Microbial Environment on the Development of Cervical Cancer—A Non-Systematic Review

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 714
Author(s):  
Matthias Läsche ◽  
Horst Urban ◽  
Julia Gallwas ◽  
Carsten Gründker
Keyword(s):  
Systematic Review ◽  
Cervical Cancer ◽  
High Risk ◽  
Cervical Carcinoma ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Inflammatory Reactions ◽  
Metabolic Signalling ◽  
Microbial Environment ◽  
High Risk Hpv

Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.

Relevance of the Pap Test: A Report of HPV-DNA Test-Negative High-Grade Squamous Intraepithelial Lesions of the Female Lower Genital Tract

2016 ◽  
Vol 60 (5) ◽  
pp. 445-450 ◽  
Author(s):  
Yiang Hui ◽  
Katrine Hansen ◽  
Jayasimha Murthy ◽  
Danielle Chau ◽  
C. James Sung ◽  
...  
Keyword(s):  
High Risk ◽  
Pap Test ◽  
Human Papillomaviruses ◽  
High Grade ◽  
Squamous Intraepithelial Lesions ◽  
Cytologic Examination ◽  
Dna Test ◽  
Hpv Dna ◽  
Intraepithelial Lesions ◽  
Hpv Dna Test

Objective: A vast majority of cervicovaginal intraepithelial lesions are caused by high-risk human papillomaviruses (HPVs). The Pap test has been the sole method used for the screening of cervicovaginal squamous intraepithelial lesions (SIL). Recently, the FDA approved an HPV-DNA assay as a method of primary screening. We report on a series of FDA-approved HPV-DNA test-negative SIL with HPV genotyping, using an alternative method on the corresponding surgical biopsy specimens. Study Design: A retrospective review identified cytology-positive HPV-negative cases over a 15-month period at a tertiary care gynecologic oncology institution. Corresponding biopsies were reviewed and genotyped for high-risk HPVs. Results: Of the 18,200 total cases, 17 patients meeting the study criteria were selected with 27 surgical specimens corresponding to their cytologic diagnoses. Four patients with high-grade lesions were identified, 3 of whom (75%) were positive for HPV. One of these 4 patients (25%) showed high-grade SIL on biopsies from 4 separate sites in the cervix and vagina. Multiviral HPV infections were frequent. Conclusions: We discuss the relevance of cotesting for screening cervical SILs and emphasize that false-negative results are possible with the FDA-approved HPV screening assay, also in patients with high-grade SIL. These cases may be detectable by cytologic examination and this suggests that the Pap test remains an important diagnostic tool.

Early detection of cervical cancer based on high‐risk HPV DNA‐based genosensors: A systematic review

BioFactors ◽  
2018 ◽  
Vol 45 (2) ◽  
pp. 101-117 ◽  
Author(s):  
Pegah Mahmoodi ◽  
Mona Fani ◽  
Majid Rezayi ◽  
Amir Avan ◽  
Zahra Pasdar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cervical Cancer ◽  
High Risk ◽  
Early Detection ◽  
Hpv Dna ◽  
High Risk Hpv

scholarly journals Antibodies against Early Proteins of Human Papillomaviruses as Diagnostic Markers for Invasive Cervical Cancer

1998 ◽  
Vol 36 (2) ◽  
pp. 475-480 ◽  
Author(s):  
Wolfgang Meschede ◽  
Klaus Zumbach ◽  
Joris Braspenning ◽  
Martin Scheffner ◽  
Luis Benitez-Bribiesca ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Invasive Cervical Cancer ◽  
Human Papillomaviruses ◽  
Antibody Detection ◽  
Diagnostic Tools ◽  
Immunological Monitoring ◽  
Hpv Dna ◽  
Native Proteins ◽  
Human Sera ◽  
E6 And E7

Cervical cancer is the most prevalent tumor in developing countries and the second most frequent cancer among females worldwide. Specific human papillomaviruses (HPVs) and, most notably, HPV types 16 and 18 are recognized as being causally associated with this malignancy. Antibodies against early HPV proteins E6 and E7 have been found more often in patients with tumors than in controls. Existing peptide enzyme-linked immunosorbent assays (ELISAs) for the detection of anti-E6 and anti-E7 antibodies in human sera have low levels of sensitivity and specificity and thus are not suitable for use as diagnostic tools. Based on highly purified recombinant native proteins, we developed four sandwich ELISAs for the detection of antibodies against HPV type 16 and 18 E6 and E7 proteins. We demonstrate their sensitivities and high degrees of specificity for cervical cancer. Among a total of 501 serum specimens from unselected patients with invasive cervical cancer, 52.9% reacted positively in at least one of the four assays. In contrast, among 244 serum specimens from control subjects without cervical cancer, only 2 reactive serum specimens (0.8%) were found. For 19 of 19 antibody-positive patients, the HPV type indicated by seroreactivity was identical to the HPV DNA type found in the tumor, which also indicates a high degree of specificity for antibody detection with respect to HPV type. In a direct comparison of 72 serum specimens from patients with cervical cancer, 56% of the specimens reacted in at least one of the four protein ELISAs, whereas 40% reacted in at least one of seven peptide ELISAs covering the four antigens. These assays could be of value for the detection of invasive cervical cancer in settings in which cytology-based early tumor screening is not available, for the clinical management of patients diagnosed with cervical cancer, and for the immunological monitoring of E6 and E7 vaccination trials.

scholarly journals Acceptability and feasibility of human papillomavirus vaccination for adolescents in school environments in Libreville

2020 ◽  
Vol 9 (9) ◽  
pp. 3541
Author(s):  
Nathalie L. Ambounda ◽  
Sylvain H. Woromogo ◽  
Olive M. Kenmogne ◽  
Felicite E. Yagata Moussa ◽  
Vicky N. Simo Tekem ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Precancerous Lesions ◽  
Hpv Vaccination ◽  
Immunization Coverage ◽  
Human Papillomaviruses ◽  
Professional Status ◽  
Human Papillomavirus Vaccination ◽  
Cross Sectional

Background: High-risk oncogenic human papillomaviruses (HPV) are the cause of sexually transmitted viral infection. Its persistence is a risk factor for precancerous lesions of the cervix, which will constitute the base of cervical cancer. In the world, the prevalence of high-risk oncogenic HPV is 66.7%, which is higher among women starting their sexual activity.Methods: An analytical cross-sectional study was conducted in high schools in Gabon regarding parents. The variables selected were the socio-cultural and demographic characteristics of the parents, their knowledge of human papillomavirus vaccination and their acceptability of HPV vaccination and finally the feasibility of HPV vaccination. The statistical test used was Pearson's Chi-square, and a difference was considered significant for p<0.05.Results: The majority of parents, 89%, were informed of the existence of cervical cancer. However, 73.4% of them were unaware of the existence of vaccination against cervical cancer. Only 2.4% of parents had vaccinated their daughters against cervical cancer at the time of the study. These parents only 53.4% expressed an interest in vaccinating their daughters in 53.4% of cases. The ability to vaccinate children is associated with the socio-professional status of parents (p˂0.000).Conclusions: The majority of parents approved school-based vaccination against human papillomavirus infections despite its reported cost and lack of information. The integration of anti-HPV vaccination into the expanded programme on immunization in Gabon will improve immunization coverage.

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