The Asian-American variant of human papillomavirus type 16 exhibits higher activation of MAPK and PI3K/AKT signaling pathways, transformation, migration and invasion of primary human keratinocytes

Hochmann, Jimena; Villa, Luisa L.; Sichero, Laura

doi:10.1016/j.virol.2016.02.015

Cited by 26 publications

(25 citation statements)

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“…This result suggests that non-European HPV16 variants are more oncogenic than European variants, and is in agreement with the findings of previous studies [5,44,59,60] demonstrating that HPV16 non-European viral variants were significantly more likely than European variants to cause persistence and a CIN3+ evolution [8,14,16,61] inducing proliferation phenotype in an organotypic epithelial model [45 ,46], probably due to 1) modification of the immunogenic properties of the virus [46,62,63], 2) stimulation of cell migration and cell invasion [64] and 3) viral DNA integration into the host genome [45,46].…”

Section: Discussionsupporting

confidence: 91%

Relationship between E6-E7 lineage sequences, viral loads, and integration of HPV16 in women with atypical squamous cells of undetermined significance (ASCUS) pap smears

Loubatier¹,

Monte²,

Cannavo³

et al. 2018

Obstet Gynecol Rep

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HPV16 DNA associated with histologic high-grade precancer lesions (cervical intraepithelial neoplasia grade 2 or 3 [CIN2 or CIN3]) is sometimes found in women with atypical squamous cells of undetermined significance (ASCUS) Pap smears, the mildest form of cellular abnormality in a cervical smear. This study evaluated, in a population of patients with ASCUS Pap smears, the prevalence of different HPV16 lineages (or isolates) and the physical status, total viral load, and integrated viral load of HPV16 DNA in a population, stratified by HPV16 isolates (primarily either EUR-350T or EUR-350G) that was found. We demonstrated, in smears of women diagnosed with ASCUS and infected with EUR-350G HPV16 isolates (sublineage A1) that both the physical status of HPV16 and the distribution of integrated HPV16 DNA viral loads were different when compared to a population infected with EUR-350T HPV16 isolates. We showed that the mean and median percentages of HPV16 DNA were higher, and a distribution of log 10 integrated HPV16 viral load was more homogeneous in a population infected with EUR-350G HPV16 isolates than in a population infected with EUR-350T HPV16 isolates. No difference was found in terms of total HPV16 viral load between these two isolates. Here, we investigate E6-E7 sequencing as an easy technique to detect women with a greater proportion of integrated HPV genome, and we suggest an adaptation of the current protocol for monitoring women with ASCUS Pap smears.

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Section: Discussionsupporting

confidence: 91%

Relationship between E6-E7 lineage sequences, viral loads, and integration of HPV16 in women with atypical squamous cells of undetermined significance (ASCUS) pap smears

Loubatier¹,

Monte²,

Cannavo³

et al. 2018

Obstet Gynecol Rep

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“…Our previous study demonstrated enhanced tumourigenesis by the full HPV16 genome with AAE6 [31], while another study presented altered gene expression by the AA variant [89]. Work by other groups have studied the downstream pathways in the AA variant [90, 91], and have utilized high-throughput techniques to investigate genetic variation within HPV16 [39, 40, 92], but this is the first study investigating the downstream pathways affected by the HPV16 variants in an organotypic epithelial model using next-generation sequencing. We hypothesized two scenarios that can be associated with these findings and analyzed in our present study: i) the global gene expression profile within AAE6-infected epithelium would differ significantly from that of EPE6 and ii) significant gene expression differences in the host due not only to the actions of the viral oncogenes E6 and E7, but also as a result of integration [56].…”

Section: Resultsmentioning

confidence: 99%

Functional variants of human papillomavirus type 16 demonstrate host genome integration and transcriptional alterations corresponding to their unique cancer epidemiology

et al. 2016

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BackgroundHuman papillomaviruses (HPVs) are a worldwide burden as they are a widespread group of tumour viruses in humans. Having a tropism for mucosal tissues, high-risk HPVs are detected in nearly all cervical cancers. HPV16 is the most common high-risk type but not all women infected with high-risk HPV develop a malignant tumour. Likely relevant, HPV genomes are polymorphic and some HPV16 single nucleotide polymorphisms (SNPs) are under evolutionary constraint instigating variable oncogenicity and immunogenicity in the infected host.ResultsTo investigate the tumourigenicity of two common HPV16 variants, we used our recently developed, three-dimensional organotypic model reminiscent of the natural HPV infectious cycle and conducted various “omics” and bioinformatics approaches. Based on epidemiological studies we chose to examine the HPV16 Asian-American (AA) and HPV16 European Prototype (EP) variants. They differ by three non-synonymous SNPs in the transforming and virus-encoded E6 oncogene where AAE6 is classified as a high- and EPE6 as a low-risk variant. Remarkably, the high-risk AAE6 variant genome integrated into the host DNA, while the low-risk EPE6 variant genome remained episomal as evidenced by highly sensitive Capt-HPV sequencing. RNA-seq experiments showed that the truncated form of AAE6, integrated in chromosome 5q32, produced a local gene over-expression and a large variety of viral-human fusion transcripts, including long distance spliced transcripts. In addition, differential enrichment of host cell pathways was observed between both HPV16 E6 variant-containing epithelia. Finally, in the high-risk variant, we detected a molecular signature of host chromosomal instability, a common property of cancer cells.ConclusionsWe show how naturally occurring SNPs in the HPV16 E6 oncogene cause significant changes in the outcome of HPV infections and subsequent viral and host transcriptome alterations prone to drive carcinogenesis. Host genome instability is closely linked to viral integration into the host genome of HPV-infected cells, which is a key phenomenon for malignant cellular transformation and the reason for uncontrolled E6 oncogene expression. In particular, the finding of variant-specific integration potential represents a new paradigm in HPV variant biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3203-3) contains supplementary material, which is available to authorized users.

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“…(7,8,9,10,11) Several studies have demonstrated the transformation potential of these oncoproteins in cell lines of diverse origins, (8,12,13) and this transformation is primarily associated with the disruption of a variety of signal transduction pathways that are crucial for cell homeostasis. (14,15,16,17) Of particular interest is the MAPK/ERK pathway that governs the signal transduction of mitogenic growth factor receptors such as epithelial growth factor receptor (EGFR). It has been reported that HR-HPV E5 oncoproteins enhance ligand-dependent activation of EGFR that elicits signals that are transduced via the MAPK/ERK pathway and to ultimately lead to the expression of genes related to cell proliferation.…”

mentioning

confidence: 99%

Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state

Hochmann

Parietti

Martínez

et al. 2020

Mem. Inst. Oswaldo Cruz

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BACKGROUND High-risk human papillomaviruses (HR-HPVs) are the etiological agents of cervical cancer. Among them, types 16 and 18 are the most prevalent worldwide. The HPV genome encodes three oncoproteins (E5, E6, and E7) that possess a high transformation potential in culture cells when transduced simultaneously. In the present study, we analysed how these oncoproteins cooperate to boost key cancer cell features such as uncontrolled cell proliferation, invasion potential, and cellular redox state imbalance. Oxidative stress is known to contribute to the carcinogenic process, as reactive oxygen species (ROS) constitute a potentially harmful by-product of many cellular reactions, and an efficient clearance mechanism is therefore required. Cells infected with HR-HPVs can adapt to oxidative stress conditions by upregulating the formation of endogenous antioxidants such as catalase, glutathione (GSH), and peroxiredoxin (PRX). OBJECTIVES The primary aim of this work was to study how these oncoproteins cooperate to promote the development of certain cancer cell features such as uncontrolled cell proliferation, invasion potential, and oxidative stress that are known to aid in the carcinogenic process. METHODS To perform this study, we generated three different HaCaT cell lines using retroviral transduction that stably expressed combinations of HPV-18 oncogenes that included HaCaT E5-18, HaCaT E6/E7-18, and HaCaT E5/E6/E7-18. FINDINGS Our results revealed a statistically significant increment in cell viability as measured by MTT assay, cell proliferation, and invasion assays in the cell line containing the three viral oncogenes. Additionally, we observed that cells expressing HPV-18 E5/E6/E7 exhibited a decrease in catalase activity and a significant augmentation of GSH and PRX1 levels relative to those of E5, E6/E7, and HaCaT cells. MAIN CONCLUSIONS This study demonstrates for the first time that HPV-18 E5, E6, and E7 oncoproteins can cooperate to enhance malignant transformation.

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The Asian-American variant of human papillomavirus type 16 exhibits higher activation of MAPK and PI3K/AKT signaling pathways, transformation, migration and invasion of primary human keratinocytes

Cited by 26 publications

References 46 publications

Relationship between E6-E7 lineage sequences, viral loads, and integration of HPV16 in women with atypical squamous cells of undetermined significance (ASCUS) pap smears

Relationship between E6-E7 lineage sequences, viral loads, and integration of HPV16 in women with atypical squamous cells of undetermined significance (ASCUS) pap smears

Functional variants of human papillomavirus type 16 demonstrate host genome integration and transcriptional alterations corresponding to their unique cancer epidemiology

Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state

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