scholarly journals Effect of Productive Human Papillomavirus 16 Infection on Global Gene Expression in Cervical Epithelium

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Sa Do Kang ◽  
Sreejata Chatterjee ◽  
Samina Alam ◽  
Anna C. Salzberg ◽  
Janice Milici ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Immune Response ◽  
Human Papillomavirus ◽  
Early Stage ◽  
Global Gene Expression ◽  
Hpv Infection ◽  
Cervical Tissue ◽  
First Time ◽  
Hpv16 Infection

ABSTRACTHuman papillomavirus (HPV) infection is the world's most common sexually transmitted infection and is responsible for most cases of cervical cancer. Previous studies of global gene expression changes induced by HPV infection have focused on the cancerous stages of infection, and therefore, not much is known about global gene expression changes at early preneoplastic stages of infection. We show for the first time the global gene expression changes during early-stage HPV16 infection in cervical tissue using 3-dimensional organotypic raft cultures, which produce high levels of progeny virions. cDNA microarray analysis showed that a total of 594 genes were upregulated and 651 genes were downregulated at least 1.5-fold with HPV16 infection. Gene ontology analysis showed that biological processes including cell cycle progression and DNA metabolism were upregulated, while skin development, immune response, and cell death were downregulated with HPV16 infection in cervical keratinocytes. Individual genes were selected for validation at the transcriptional and translational levels, includingUBC, which was central to the protein association network of immune response genes, and top downregulated genesRPTN,SERPINB4,KRT23, andKLK8. In particular,KLK8andSERPINB4were shown to be upregulated in cancer, which contrasts with the gene regulation during the productive replication stage. Organotypic raft cultures, which allow full progression of the HPV life cycle, allowed us to identify novel gene modulations and potential therapeutic targets of early-stage HPV infection in cervical tissue. Additionally, our results suggest that early-stage productive infection and cancerous stages of infection are distinct disease states expressing different host transcriptomes.IMPORTANCEPersistent HPV infection is responsible for most cases of cervical cancer. The transition from precancerous to cancerous stages of HPV infection is marked by a significant reduction in virus production. Most global gene expression studies of HPV infection have focused on the cancerous stages. Therefore, little is known about global gene expression changes at precancerous stages. For the first time, we measured global gene expression changes at the precancerous stages of HPV16 infection in human cervical tissue producing high levels of virus. We identified a group of genes that are typically overexpressed in cancerous stages to be significantly downregulated at the precancerous stage. Moreover, we identified significantly modulated genes that have not yet been studied in the context of HPV infection. Studying the role of these genes in HPV infection will help us understand what drives the transition from precancerous to cancerous stages and may lead to the development of new therapeutic targets.

scholarly journals The Effect of Productive HPV16 Infection on Global Gene Expression of Cervical Epithelium

2018 ◽  
Author(s):  
Sa Do Kang ◽  
Sreejata Chatterjee ◽  
Samina Alam ◽  
Anna C. Salzberg ◽  
Janice Milici ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Immune Response ◽  
Early Stage ◽  
Therapeutic Targets ◽  
Global Gene Expression ◽  
Hpv Infection ◽  
Cervical Tissue ◽  
First Time ◽  
Hpv16 Infection

AbstractHuman papillomavirus (HPV) infection is the world’s most common sexually transmitted infection, and is responsible for most cases of cervical cancer. Previous studies of global gene expression changes induced by HPV infection have focused on the cancerous stages of infection, and therefore, not much is known about global gene expression changes at early pre-neoplastic stages of infection. We show for the first time, global gene expression changes of early stage HPV16 infection in cervical tissue using 3-dimensional organotypic raft cultures that produce high levels of progeny virions.cDNA microarray analysis showed that a total of 594 genes were upregulated and 651 genes were downregulated at least 1.5-fold with HPV16 infection. Gene ontology analysis showed that biological processes including cell cycle progression and DNA metabolism were upregulated, while skin development, immune response, and cell death were downregulated with HPV16 infection in cervical keratinocytes. Individual genes were selected for validation at the transcriptional and translational levels including UBC, which was central to the protein association network of immune response genes, and top downregulated genes RPTN, SERPINB4, KRT23, and KLK8. In particular, KLK8 and SERPINB4 have shown to be upregulated in cancer, which contrasts our results.Organotypic raft cultures that allow full progression of the HPV life-cycle have allowed us to identify novel gene modulations and potential therapeutic targets of early stage HPV infection in cervical tissue. Additionally, our results suggest that early stage productive infection and cancerous stages of infection are distinct disease states expressing different transcriptomes.ImportancePersistent HPV infection is responsible for most cases of cervical cancer. Transition from precancerous to cancerous stages of HPV infection is marked by a significant reduction in virus production. Most global gene expression studies of HPV infection have focused on the cancerous stages. Therefore, little is known about global gene expression changes at precancerous stages. For the first time, we measured global gene expression changes at precancerous stages of HPV16 infection in human cervical tissue producing high levels of virus. We identified a group of genes that are typically overexpressed in cancerous stages to be significantly downregulated at the precancerous stage. Moreover, we identified significantly modulated genes that have not yet been studied in the context of HPV infection. Studying the role of these genes in HPV infection will help us understand what drives the transition from precancerous to cancerous stages, and may lead to development of new therapeutic targets.

scholarly journals RNA-Seq Analysis of Differentiated Keratinocytes Reveals a Massive Response to Late Events during Human Papillomavirus 16 Infection, Including Loss of Epithelial Barrier Function

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
T. Klymenko ◽  
Q. Gu ◽  
I. Herbert ◽  
A. Stevenson ◽  
V. Iliev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Papillomavirus ◽  
Life Cycle ◽  
Cell Differentiation ◽  
Barrier Function ◽  
Hpv Infection ◽  
Epithelial Barrier ◽  
Rna Seq ◽  
Epithelial Barrier Function ◽  
Hpv16 Infection

ABSTRACT The human papillomavirus (HPV) replication cycle is tightly linked to epithelial cell differentiation. To examine HPV-associated changes in the keratinocyte transcriptome, RNAs isolated from undifferentiated and differentiated cell populations of normal, spontaneously immortalized keratinocytes (NIKS) and NIKS stably transfected with HPV16 episomal genomes (NIKS16) were compared using next-generation sequencing (RNA-Seq). HPV16 infection altered expression of 2,862 cellular genes. Next, to elucidate the role of keratinocyte gene expression in late events during the viral life cycle, RNA-Seq was carried out on triplicate differentiated populations of NIKS (uninfected) and NIKS16 (infected). Of the top 966 genes altered (>log2 = 1.8, 3.5-fold change), 670 genes were downregulated and 296 genes were upregulated. HPV downregulated many genes involved in epithelial barrier function, which involves structural resistance to the environment and immunity to infectious agents. For example, HPV infection repressed expression of the differentiated keratinocyte-specific pattern recognition receptor TLR7, the Langerhans cell chemoattractant CCL20, and proinflammatory cytokines interleukin 1α (IL-1α) and IL-1β. However, the type I interferon regulator IRF1, kappa interferon (IFN-κ), and viral restriction factors (IFIT1, -2, -3, and -5, OASL, CD74, and RTP4) were upregulated. HPV infection abrogated gene expression associated with the physical epithelial barrier, including keratinocyte cytoskeleton, intercellular junctions, and cell adhesion. Quantitative PCR (qRT-PCR) and Western blotting confirmed changes in expression of seven of the most significantly altered mRNAs. Expression of three genes showed statistically significant changes during cervical disease progression in clinical samples. Taken together, the data indicate that HPV infection manipulates the differentiating keratinocyte transcriptome to create an environment conducive to productive viral replication and egress. IMPORTANCE HPV genome amplification and capsid formation take place in differentiated keratinocytes. The viral life cycle is intimately associated with host cell differentiation. Deep sequencing (RNA-Seq) of RNA from undifferentiated and differentiated uninfected and HPV16-positive keratinocytes showed that almost 3,000 genes were differentially expressed in keratinocytes due to HPV16 infection. Strikingly, the epithelial barrier function of differentiated keratinocytes, comprising keratinocyte immune function and cellular structure, was found to be disrupted. These data provide new insights into the virus-host interaction that is crucial for the production of infectious virus and reveal that HPV infection remodels keratinocytes for completion of the virus replication cycle.

Correlation Between IL-10 Gene Expression and HPV Infection in Cervical Cancer: A Mechanism for Immune Response Escape

2008 ◽  
Vol 26 (10) ◽  
pp. 1037-1043 ◽  
Author(s):  
Victor H. Bermúdez-Morales ◽  
Lourdes X. Gutiérrez ◽  
Juan M. Alcocer-González ◽  
Ana Burguete ◽  
Vicente Madrid-Marina
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Immune Response ◽  
Hpv Infection

scholarly journals Human Papillomavirus Type 16 Infection of Human Keratinocytes Requires Clathrin and Caveolin-1 and Is Brefeldin A Sensitive

2009 ◽  
Vol 83 (16) ◽  
pp. 8221-8232 ◽  
Author(s):  
Valerie Laniosz ◽  
Sarah A. Dabydeen ◽  
Mallory A. Havens ◽  
Patricio I. Meneses
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Brefeldin A ◽  
Human Keratinocytes ◽  
Clear Understanding ◽  
Bovine Papillomavirus ◽  
Caveolin 1 ◽  
Human Papillomavirus Type 16 ◽  
First Time ◽  
Hpv16 Infection

ABSTRACT Human papillomavirus type 16 (HPV16) has been identified as being the most common etiological agent leading to cervical cancer. Despite having a clear understanding of the role of HPV16 in oncogenesis, details of how HPV16 traffics during infection are poorly understood. HPV16 has been determined to enter via clathrin-mediated endocytosis, but the subsequent steps of HPV16 infection remain unclear. There is emerging evidence that several viruses take advantage of cross talk between routes of endocytosis. Specifically, JCV and bovine papillomavirus type 1 have been shown to enter cells by clathrin-dependent endocytosis and then require caveolin-1-mediated trafficking for infection. In this paper, we show that HPV16 is dependent on caveolin-1 after clathrin-mediated endocytosis. We provide evidence for the first time that HPV16 infection is dependent on trafficking to the endoplasmic reticulum (ER). This novel trafficking may explain the requirement for the caveolar pathway in HPV16 infection because clathrin-mediated endocytosis typically does not lead to the ER. Our data indicate that the infectious route for HPV16 following clathrin-mediated entry is caveolin-1 and COPI dependent. An understanding of the steps involved in HPV16 sorting and trafficking opens up the possibility of developing novel approaches to interfere with HPV16 infection and reduce the burden of papillomavirus diseases including cervical cancer.

scholarly journals Low proteolytic processing of histone H3 in cervical tissue positive to hrHPV

2021 ◽  
Author(s):  
Sofia L. Alcaraz-Estrada ◽  
Nicolás Serafín-Higuera ◽  
Roberto Ramos-Mondragón ◽  
Octavio D. Reyes-Hernández ◽  
Gabriela Figueroa-González ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Histone H3 ◽  
Hpv Infection ◽  
Proteolytic Processing ◽  
Epigenetic Mechanism ◽  
Cervical Carcinogenesis ◽  
Epigenetic Alterations ◽  
Cervical Tissue ◽  
Primary Risk Factor

Abstract During the different stages of cervical carcinogenesis there is an accumulation of epigenetic alterations leading to changes in gene expression. High-risk human papillomavirus (hrHPV) is a primary risk factor for cervical cancer (CC). Impaired proteolytic processing of histone H3 constitutes a potential epigenetic mechanism in CC. However, whether this event occurs in early stages of the HPV infection is unknown. Using human cervical samples with normal pathology but positive and negative to hrHPV, we identified that the H3 cleavage was low in the hrHPV positive cervix compared to the hrHPV negative cervix. These results suggest that low H3 processing previously observed in CC may be a primary effect of hrHPV infection.

scholarly journals Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Cervical Intraepithelial Neoplasia in Chinese Women Living With HIV

2021 ◽  
Vol 11 ◽  
Author(s):  
Min Feng ◽  
Rufei Duan ◽  
Yang Gao ◽  
Han Zhang ◽  
Youlin Qiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cervical Intraepithelial Neoplasia ◽  
Epstein Barr Virus ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Barr Virus ◽  
Epstein Barr

Given that only a small percentage of human papillomavirus (HPV)-positive women develop cancer, HPV is necessary but insufficient for carcinogenesis. Mucosally transmitted viral cofactors appear to contribute to HPV-related cervical cancer, such as Epstein-Barr virus (EBV), but previous studies have shown inconsistent outcomes. The exact role of EBV in cervical cancer remains unclear, and more studies are needed to determine its involvement. In this study, we describe the prevalence of EBV and HPV coinfection in HIV-positive women and explore how abnormal host immune status induced by viral coinfections modulates epithelial gene expression. We found a significant correlation between EBV-HPV coinfection and the incidence of high-grade cervical intraepithelial neoplasia (CIN2+). RNA sequencing indicated that CIN tissues coinfected with EBV and HPV led to significant changes in the gene expression of epithelial differentiation and development compared to normal tissues with HPV infection alone. In particular, several differentially expressed genes (DEGs) are closely associated with cancer, such as CACNG4, which was confirmed to be upregulated at both the mRNA and protein levels. Therefore, these findings provide some evidence that EBV may act as a cofactor or mediator in HPV-related cervical cancer. Specific genes or proteins, such as CACNG4, may serve as biomarkers that can risk stratify patients based on pathological changes in the cervix.

A combined ultrastructural and gene molecular research for the relationship between human uterine cervical carcinoma and human papillomavirus

1990 ◽  
Vol 48 (3) ◽  
pp. 204-205
Author(s):  
Kun Lee ◽  
Jingyi Si ◽  
Ricai Han ◽  
Wei Zhang ◽  
Bingbing Tan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Dot Blot ◽  
Homologous Sequences ◽  
Normal Cervical Epithelium ◽  
The Relationship ◽  
Chronic Cervicitis

There are more supports for the view that human papillomavirus (HPV) infection might be an etiological factor in the development of cervical cancer when the association of persistent condylomata is considered. Biopsies from 318 cases with squamous cell carcinoma of uterine cervix, 48 with cervical and vulvar condylomata, 14 with cervical intraepithelial neoplasia (CIN), 34 with chronic cervicitis and 24 normal cervical epithelium were collected from 5 geographic regions of China with different cervical cancer mortalities. All specimens were prepared for Dot blot, Southern blot and in situ DNA-DNA hybridizations by using HPV-11, 16, 18 DNA labelled with 32P and 3H as probes to detect viral homologous sequences in samples. Among them, 32 cases with cervical cancer, 27 with condyloma and 10 normal cervical epitheliums were randomly chosen for comparative EM observation. The results showed that: 1), 192 out of 318 (60.4%) cases of cervical cancer were positive for HPV-16 DNA probe (Table I)

Human Papillomavirus Selected Properties and Related Cervical Cancer Prevention Issues

2020 ◽  
Vol 26 (18) ◽  
pp. 2073-2086
Author(s):  
Saule Balmagambetova ◽  
Andrea Tinelli ◽  
Ospan A. Mynbaev ◽  
Arip Koyshybaev ◽  
Olzhas Urazayev ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Prevention ◽  
Screening Program ◽  
Hpv Infection ◽  
Cervical Cancer Prevention ◽  
Point Of View ◽  
Prevention Strategies ◽  
Middle Income ◽  
Screening Programs

High-risk human papillomavirus strains are widely known to be the causative agents responsible for cervical cancer development. Aggregated damage caused by papillomaviruses solely is estimated in at least 5% of all malignancies of the human body and 16% in cancers that affect the female genital area. Enhanced understanding of the complex issue on how the high extent of carcinogenicity is eventually formed due to the infection by the Papoviridae family would contribute to enhancing current prevention strategies not only towards cervical cancer, but also other HPV associated cancers. This review article is aimed at presenting the key points in two directions: the current cervical cancer prevention and related aspects of HPV behavior. Virtually all applied technologies related to HPV diagnostics and screening programs, such as HPV tests, colposcopy-based tests (VIA/VILI), conventional and liquid-based cytology, currently available are presented. Issues of availability, advantages, and drawbacks of the screening programs, as well as vaccination strategies, are also reviewed in the article based on the analyzed sources. The current point of view regarding HPV is discussed with emphasis on the most problematic aspect of the HPV family concerning the observed increasing number of highly carcinogenic types. Present trends in HPV infection diagnostics throughout the human fluids and tissues are also reported, including the latest novelties in this field, such as HPV assay/self-sample device combinations. Besides, a brief outline of the related prevention issues in Kazakhstan, the leading country of Central Asia, is presented. Kazakhstan, as one of the post-soviet middle-income countries, may serve as an example of the current situation in those terrains, concerning the implementation of globally accepted cervical cancer prevention strategies. Along with positive achievements, such as the development of a nationwide screening program, a range of drawbacks is also analyzed and discussed.

scholarly journals Molecular characterization of high-risk human papillomavirus (HR-HPV) in women in Lomé, Togo

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Akouélé P. Kuassi-Kpede ◽  
Essolakina Dolou ◽  
Théodora M. Zohoncon ◽  
Ina Marie Angèle Traore ◽  
Gnatoulma Katawa ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
West Africa ◽  
Public Health Problem ◽  
Hpv Infection ◽  
Cervical Lesions ◽  
Hpv Genotypes ◽  
Precancerous Cervical Lesions ◽  
High Risk Hpv ◽  
First Time

Abstract Background The causative agent of cervical cancer referred to as Human papillomavirus (HPV) remains a real public health problem. Many countries in West Africa, such as Togo have no data on the high-risk HPV (HR-HPV) infection and genotypes distribution. In order to fill the knowledge gap in the field in Togo, the main objective of this study was to determine the prevalence of pre-cancerous lesions of the cervix and HR-HPV genotypes among Togolese women. Methods Samples were collected from 240 women by introducing a swab in the cervix. Then, the screening of precancerous cervical lesions using the visual inspection with acetic acid and lugol (VIA / VIL) was conducted. The HR-HPV genotypes were characterised by real-time multiplex PCR. Results Out of 240 women recruited, 128 (53.3%) were infected by HR-HPV. The most common genotypes were HPV 56 (22.7%), followed by HPV 51 (20.3%), HPV 31 (19.5%), HPV 52 (18.8%) and HPV 35 (17.2%). The least common genotypes were HPV 33 (2.3%) and HPV 16 (2.3%). Among the women, 1.3% (3/240) were positive to VIA/VIL. Conclusion This study allowed HR-HPV genotypes to be characterised for the first time in Lomé, Togo. This will help in mapping the HR-HPV genotypes in West Africa.

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