Individual and Complementary Effects of Human Papillomavirus Oncogenes on Epithelial Cell Proliferation and Differentiation

2015 ◽  
Vol 201 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Sven Bergner ◽  
Gordana Halec ◽  
Markus Schmitt ◽  
François Aubin ◽  
Angel Alonso ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Human Papillomavirus ◽  
Three Dimensional ◽  
Morphological Characteristics ◽  
Intraepithelial Neoplasia ◽  
Vector System ◽  
Proliferation Markers ◽  
Raft Culture ◽  
E6 And E7 ◽  
Differentiation And Proliferation

Previous studies on human papillomavirus (HPV) type 16 protein functions have established the oncogenic nature of three viral proteins: E5, E6 and E7. Here we have studied the functions of these proteins by functional deletion of the individual E5, E6 or E7, or both E6 and E7 oncogenes in the context of the whole viral genome. These mutants, or the intact wild-type genome, were expressed from the natural viral promoters along with differentiation of epithelial HaCaT cells in three-dimensional collagen raft cultures. High episomal viral copy numbers were obtained using a transfection-based loxp-HPV16-eGFP-N1 vector system. All epithelial equivalents carrying the different HPV type 16 genomes showed pronounced hyperplastic and dysplastic morphology. Particularly the E7 oncogene, with contribution of E6, was shown to enhance cell proliferation. Specifically, the crucial role of E7 in HPV-associated hyperproliferation was clearly manifested. Based on morphological characteristics, immunohistochemical staining for differentiation and proliferation markers, and low expression of E1^E4, we propose that our raft culture models produce cervical intraepithelial neoplasia (CIN)1 and CIN2-like tissue. Our experimental setting provides an alternative tool to study concerted functions of HPV proteins in the development of epithelial dysplasia.

scholarly journals RNA Interference of Human Papillomavirus Type 18 E6 and E7 Induces Senescence in HeLa Cells

2003 ◽  
Vol 77 (10) ◽  
pp. 6066-6069 ◽  
Author(s):  
Allison H. S. Hall ◽  
Kenneth A. Alexander
Keyword(s):  
Cell Proliferation ◽  
Human Papillomavirus ◽  
Rna Interference ◽  
Hela Cells ◽  
Tumor Suppressors ◽  
Small Interfering Rna ◽  
Promote Cell Proliferation ◽  
E6 And E7 ◽  
Cellular Dna ◽  
Interfering Rna

ABSTRACT The human papillomavirus oncoproteins E6 and E7 promote cell proliferation and contribute to carcinogenesis by interfering with the activities of cellular tumor suppressors. We used a small interfering RNA molecule targeting the E7 region of the bicistronic E6 and E7 mRNA to induce RNA interference, thereby reducing expression of E6 and E7 in HeLa cells. RNA interference of E6 and E7 also inhibited cellular DNA synthesis and induced morphological and biochemical changes characteristic of cellular senescence. These results demonstrate that reducing E6 and E7 expression is sufficient to cause HeLa cells to become senescent.

scholarly journals T-Cell Response to Human Papillomavirus Type 58 L1, E6, and E7 Peptides in Women with Cleared Infection, Cervical Intraepithelial Neoplasia, or Invasive Cancer

2010 ◽  
Vol 17 (9) ◽  
pp. 1315-1321 ◽  
Author(s):  
Paul K. S. Chan ◽  
Shih-Jen Liu ◽  
T. H. Cheung ◽  
Winnie Yeo ◽  
S. M. Ngai ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Amino Acid ◽  
T Cell ◽  
Cell Response ◽  
Positive Response ◽  
Intraepithelial Neoplasia ◽  
Amino Acid Position ◽  
T Cell Response ◽  
Ifn Γ ◽  
E6 And E7

ABSTRACT Human papillomavirus type 58 (HPV-58) exists in a relatively high prevalence in certain parts of the world, including East Asia. This study examined the T-cell response to HPV-58 L1, E6, and E7 peptides among women with cleared infection, cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3, or invasive cervical cancer (ICC). Peptides found to be reactive in the in vitro peptide binding assay or mouse-stimulating study were tested with a gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay to detect peptide-specific responses from the peripheral blood mononuclear cells (PBMC) collected from 91 HPV-58-infected women (32 with cleared infection, 16 CIN2, 15 CIN3, and 28 ICC). Four HLA-A11-restricted HPV-58 L1 peptides, located at amino acid positions 296 to 304, 327 to 335, 101 to 109, and 469 to 477, showed positive IFN-γ ELISPOT results and were mainly from women with cleared infection. Two HLA-A11-restricted E6 peptides (amino acid positions 64 to 72 and 94 to 102) and three HLA-A11-restricted E7 peptides (amino acid positions 78 to 86, 74 to 82, and 88 to 96) showed a positive response. A response to E6 and E7 peptides was mainly observed from subjects with CIN2 or above. One HLA-A2-restricted E6 peptide, located at amino acid position 99 to 107, elicited a positive response in two CIN2 subjects. One HLA-A24-restricted L1 peptide, located at amino acid position 468 to 476, also elicited a positive response in two CIN2 subjects. In summary, this study has identified a few immunogenic epitopes for HPV-58 E6 and E7 proteins. It is worthwhile to further investigate whether responses to these epitopes have a role in clearing an established cervical lesion.

Clinical and immunological rationale for comprehensive approach to prevention and treatment of cervical intraepithelial neoplasia associated with human papillomavirus

2021 ◽  
Vol 20 (3) ◽  
pp. 161-168
Author(s):  
A.I. Davydov ◽  
◽  
D.V. Isakov ◽  
R.А. Chilova ◽  
V.A. Lebedev ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
Cervical Intraepithelial Neoplasia ◽  
Antiviral Agent ◽  
Intraepithelial Neoplasia ◽  
Inosine Pranobex ◽  
Trained Immunity ◽  
Adaptive Immune Cells ◽  
Infected Cells ◽  
E6 And E7

A clinical and immunological analysis of the use of antiviral agent Inosine Pranobex (IP) as postoperative drug therapy in patients with cervical intraepithelial neoplasia (CIN) associated with human papillomavirus (HPV) is performed. It is known that IP has a high anti-relapse activity adapted to the mechanisms of HPV elimination (through the sequence of oncoproteins E5, E6 and E7, a decrease in the synthesis of interferons (IFNs) occurs and resistance of HPV-infected cells to IFN is formed). In this work, a number of statements justifying the priority of IP in the treatment of patients with CIN associated with HPV is covered, namely that IP induces trained immunity, differentiation of the Th1 subset of CD4+ T cells and proliferation of CD8+ T cells. Conclusion. Inosine Pranobex should be considered as the medication of choice for postoperative monotherapy in patients with HPV-associated CIN. Inosine Pranobex is characterized by mechanisms of action in both virus-infected cells and through the activation of innate and adaptive immune cells. Key words: CIN, human papillomavirus, inosine pranobex, clinical and immunological aspects, trained immunity

scholarly journals The Major Constituent of Green Tea, Epigallocatechin-3-Gallate (EGCG), Inhibits the Growth of HPV18-Infected Keratinocytes by Stimulating Proteasomal Turnover of the E6 and E7 Oncoproteins

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 459
Author(s):  
Jason K. W. Yap ◽  
Sean T. Kehoe ◽  
Ciaran B. J. Woodman ◽  
Christopher W. Dawson
Keyword(s):  
Cell Proliferation ◽  
Green Tea ◽  
Keratinocyte Differentiation ◽  
Major Constituent ◽  
Tumour Suppressor Genes ◽  
Raft Culture ◽  
Egcg Treatment ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
E7 Proteins

Epigallocatechin-3-gallate (EGCG), the primary bioactive polyphenol in green tea, has been shown to inhibit the growth of human papilloma virus (HPV)-transformed keratinocytes. Here, we set out to examine the consequences of EGCG treatment on the growth of HPV18-immortalised foreskin keratinocytes (HFK-HPV18) and an authentic HPV18-positive vulvar intraepithelial neoplasia (VIN) clone, focusing on its ability to influence cell proliferation and differentiation and to impact on viral oncogene expression and virus replication. EGCG treatment was associated with degradation of the E6 and E7 oncoproteins and an upregulation of their associated tumour suppressor genes; consequently, keratinocyte proliferation was inhibited in both monolayer and organotypic raft culture. While EGCG exerted a profound effect on cell proliferation, it had little impact on keratinocyte differentiation. Expression of the late viral protein E4 was suppressed in the presence of EGCG, suggesting that EGCG was able to block productive viral replication in differentiating keratinocytes. Although EGCG did not alter the levels of E6 and E7 mRNA, it enhanced the turnover of the E6 and E7 proteins. The addition of MG132, a proteasome inhibitor, to EGCG-treated keratinocytes led to the accumulation of the E6/E7 proteins, showing that EGCG acts as an anti-viral, targeting the E6 and E7 proteins for proteasome-mediated degradation.

scholarly journals Feasibility study of a human papillomavirus E6 and E7 oncoprotein test for the diagnosis of cervical precancer and cancer

2018 ◽  
Vol 46 (3) ◽  
pp. 1033-1042 ◽  
Author(s):  
Jin-Jun Zhang ◽  
Xin-Chun Cao ◽  
Xiang-Yu Zheng ◽  
Hai-Ying Wang ◽  
Yong-Wei Li
Keyword(s):  
Human Papillomavirus ◽  
Intraepithelial Neoplasia ◽  
Clinical Value ◽  
Early Screening ◽  
Protein Assay ◽  
Dna Test ◽  
Hpv Dna ◽  
E7 Oncoprotein ◽  
Hpv E6 ◽  
E6 And E7

Objective To evaluate the clinical value of human papillomavirus (HPV) E6 and E7 oncoprotein (HPV E6/E7) detection in the early screening of cervical cancer. Methods This prospective study evaluated all patients with suspected cervical intraepithelial neoplasia (CIN) as identified by the presence of at least one positive indicator from a ThinPrep cytologic test (TCT) and/or a Hybrid Capture 2 (HC2) HPV DNA test. The levels of E6/E7 oncoproteins were determined using Western blot analysis. The diagnostic value of the HPV E6/E7 protein assay was compared with the clinical diagnosis from TCT, HC2 and the gold standard of cervical biopsy histology. Results A total of 450 patients were enrolled in the study and based on histological findings, 102 patients were diagnosed with CIN1 (22.7%), 241 with CIN2 (53.6%), 96 with CIN3 (21.3%) and 11 with squamous cell carcinoma (2.4%). For a diagnosis of CIN2+, although the sensitivity of the HPV E6/E7 assay was lower than HC2 (65.5% versus 96.6%, respectively), the specificity was higher (38.2% versus 5.9%, respectively). The sensitivity of the HPV E6/E7 assay was higher than TCT (65.5% versus 36.2%, respectively). Conclusion Measuring HPV E6/E7 oncoprotein levels is a potential new biomarker for HPV type 16.

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