Dataset Information

Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium.

ABSTRACT: Epidemiological data confirm a much higher incidence of high-risk human papillomavirus 16 (HPV16)-mediated carcinogenesis of the cervical epithelium than for other target sites. In order to elucidate tissue-specific responses to virus infection, we compared gene expression changes induced by productive HPV16 infection of cervical, foreskin, and tonsil organotypic rafts. These rafts closely mimic persistent HPV16 infection, long before carcinogenesis sets in. The total number of gene expression changes varied considerably across the tissue types, with only 32 genes being regulated in common. Among them, we confirmed the Kelch-like family protein KLHL35 and the laminin-5 complex to be upregulated and downregulated, respectively, in all the three tissues. HPV16 infection induces upregulation of genes involved in cell cycle control, cell division, mitosis, DNA replication, and DNA damage repair in all the three tissues, indicative of a hyperproliferative environment. In the cervical and tonsil epithelium, we observe significant downregulation of genes involved in epidermis development, keratinocyte differentiation, and extracellular matrix organization. On the other hand, in HPV16-positive foreskin (HPV16 foreskin) tissue, several genes involved in interferon-mediated innate immunity, cytokine signaling, and cellular defenses were downregulated. Furthermore, pathway analysis and experimental validations identified important cellular pathways like STAT1 and transforming growth factor ? (TGF-?) to be differentially regulated among the three tissue types. The differential modulation of important cellular pathways like TGF-?1 and STAT1 can explain the sensitivity of tissues to HPV cancer progression.IMPORTANCE Although the high-risk human papillomavirus 16 infects anogenital and oropharyngeal sites, the cervical epithelium has a unique vulnerability to progression of cancer. Host responses during persistent infection and preneoplastic stages can shape the outcome of cancer progression in a tissue-dependent manner. Our study for the first time reports differential regulation of critical cellular functions and signaling pathways during productive HPV16 infection of cervical, foreskin, and tonsil tissues. While the virus induces hyperproliferation in infected cells, it downregulates epithelial differentiation, epidermal development, and innate immune responses, according to the tissue type. Modulation of these biological functions can determine virus fitness and pathogenesis and illuminate key cellular mechanisms that the virus employs to establish persistence and finally initiate disease progression.

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC6694821 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium.

Chatterjee Sreejata S Do Kang Sa S Alam Samina S Salzberg Anna C AC Milici Janice J van der Burg Sjoerd H SH Freeman Willard W Meyers Craig C

Journal of virology 20190813 17

Epidemiological data confirm a much higher incidence of high-risk human papillomavirus 16 (HPV16)-mediated carcinogenesis of the cervical epithelium than for other target sites. In order to elucidate tissue-specific responses to virus infection, we compared gene expression changes induced by productive HPV16 infection of cervical, foreskin, and tonsil organotypic rafts. These rafts closely mimic persistent HPV16 infection, long before carcinogenesis sets in. The total number of gene expression c ...[more]

PMID: 31189705

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Project description:Human 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, 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 were 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.IMPORTANCE Persistent 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.

Project description:BACKGROUND: The national Human Papillomavirus (HPV) Immunisation Programme in New Zealand was introduced in 2008, and involves routine vaccination of girls 12-13 years with a catch-up for females aged up to 19 years. The aims of this study were to measure the pre-vaccination prevalence of oncogenic HPV infection in women aged 20-69 years who were participating in the New Zealand National Cervical Screening Programme (NZ-NCSP) and who were: (1) referred with high grade cytology with a subsequent histologically-confirmed high grade cervical intraepithelial neoplasia (CIN2/3) or adenocarcinoma in situ (AIS); or (2) were in the wider group of women who had a cytological prediction of high grade squamous disease or glandular abnormality (ASC-H/ HSIL+/AGC/AIS). METHODS: Women aged 20-69 years appearing on the NZ-NCSP register between August 2009-February 2011 with a cytology record of ASC-H/HSIL+/AGC/AIS were invited to participate in the study. Liquid-based cytology specimens were tested for 37 HPV types using Linear Array genotyping. The prevalence of type-specific HPV infection was reported within women with histologically-confirmed CIN 2/3 and within the wider group with ASC-H/HSIL+/AGC/AIS cytology. Age-specific trends for the relative proportion of HPV 16/18 vs. other oncogenic types in CIN2/3 were assessed. RESULTS: A total of 594 women with ASC-H/HSIL+/AGC/AIS cytology and a valid HPV test were recruited; of these 356 (60%) had confirmed CIN2/3 and 6 (1%) had confirmed AIS or glandular dysplasia. Positivity rates for any oncogenic HPV infection and for HPV16 and/or 18 within confirmed CIN2/3-AIS were 95% (95%CI: 92-97%) and 60% (54-65%) respectively; in all women with ASC-H/HSIL+/AGC/AIS cytology it was 87% (84-89%) and 53% (49-57%), respectively. The most common reported HPV types in women with CIN 2/3 were 16 (51%), 52 (19%), 31 (17%), 33 (13%) and 18 (12%). A trend for higher rates of HPV 16/18 infection compared to other oncogenic types was observed in younger women (p=0.0006). CONCLUSIONS: The prevalence of HPV 16/18 in confirmed high grade disease in New Zealand is comparable to that observed in Australia and European countries. Test positivity rates for type 52 appear higher than in comparable studies in other developed countries. A greater proportion of high grade lesions in younger women appear to be associated with HPV 16/18 infection.

Dataset Information

Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium.

Publications

Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium.

Similar Datasets

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