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Effect of HPV 16 E6, E7 oncoproteins on the expression level of cellular genes

ABSTRACT: The life cycle of human papillomaviruses (HPV) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes, however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to down-regulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to down-regulate the expression of several genes involved in keratinocyte differentiation, at least partially by down-regulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus induced carcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58841 | GEO | 2014/06/26

SECONDARY ACCESSION(S): PRJNA253679

REPOSITORIES: GEO

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Effect of HPV 16 E6, E7 oncoproteins on the expression level of cellular genes

Project description:The life cycle of human papillomaviruses (HPV) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes, however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to down-regulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to down-regulate the expression of several genes involved in keratinocyte differentiation, at least partially by down-regulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus induced carcinogenesis. Primary human foreskin keratinocytes were transduced by retrovirus vectors containing HPV 16 E6, E7, E6/E7 or the control vector LXSN. The global gene expression patterns of transduced keratinocytes were analyzed on Affymetrix microarrays

2014-06-26 | E-GEOD-58841 | biostudies-arrayexpress

Systematic analysis of IL-1 cytokine signaling by high-risk HPV oncoproteins

Project description:Human papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1beta. Models of early-stage HPV infection (human keratinocytes expressing HPV16 E6 and E7) and models of established HPV-positive head and neck cancers (patient-derived xenografts, head and neck cancer cell lines) exhibited similar dysregulation of IL-1 pathway genes and suppressed responses to IL-1beta treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1beta-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells.

2022-10-31 | GSE211730 | GEO

RNA expression profile comparison of HFKs expressing E6/E7 from beta-3 HPVs (49, 75, 76, 115) and from HR alpha HPV16 and beta-2 HPV38

Project description:Comparative analysis of RNA expression profiles of keratinocytes expressing E6/E7 from the different beta-3, with the RNA profiles of HPV16 and HPV38 E6/E7 HFKs reveals that HPV115 is the more divergent from the HR-mucosal type. Moreover beta-3 HPV 49, 75 and 76 E6/E7 HFKs show altered expression of genes involved in cell cycle regulation and DNA damage response which are also deregulated by expression of E6/E7 of HPV16.

2020-07-04 | GSE100681 | GEO

Transgenic SCLC induced by E6/E7 oncoproteins vs normal controls

Project description:The human papillomavirus virus (HPV) is a proven cause of most human cervical cancers, and might have a role in other malignancies including vulva, skin, oesophagus, head and neck cancer. HPV has also been speculated to have a role in the pathogenesis of lung cancer. To validate the hypothesis of HPV involvement in small cell lung cancer pathogenesis we performed gene expression profile of transgenic mouse model of SCLC induced by HPV-16 E6/E7 oncoproteins. Gene expression profile of SCLC has been performed using Agilent whole mouse genome (4x44k) representing ~ 41000 genes and mouse transcripts. Samples were obtained from two HPV16-E6/E7 transgenic mouse model and from littermateM-bM-^@M-^Ys normal lung.

2014-05-27 | E-GEOD-23962 | biostudies-arrayexpress

MicroRNA expression profile in human foreskin keratinocytes (HFKs) transduced with retroviral vectors carrying E6 and E7 genes of either HPV6 or HPV16 and with the LXSN empty vector

Project description:Cervical cancer is a leading cause of cancer-related death in women worldwide. Nearly all cases of cervical cancer are attributed to infection with human papillomavirus (HPV), mainly high-risk type HPV16 and HPV18. Two viral genes, E6 and E7, play an important role in viral life cycle, since they delay keratinocyte differentiation and stimulate cell cycle progression, allowing the virus to exploit host DNA replication machinery to replicate its genome. Some of the oncogenic properties of E6 and E7 are mediated by host microRNAs (miRNAs) involved in the control of cell proliferation, senescence, and apoptosis. In order to identify genome-wide changes in miRNA expression profile, miRNA microarray analysis was performed on HFKs transduced with retroviral vectors carrying E6 and E7 genes of either HPV6 or HPV16 and with the LXSN empty vector. This dataset was used to identify and to further investigate the role of miR-146a-5p in cervical cancer.

2018-01-16 | E-MTAB-6360 | biostudies-arrayexpress

Human Papillomavirus (HPV) genomic integration, expression and E6/E7 splicing patterns in cervical cancer associated with HPV16 or HPV18 infection

Project description:Human papillomavirus (HPV) genome integration into the host genome, blocking E2 expression and leading to overexpression of E6 and E7 viral oncogenes, is considered a major step in cervical cancer development. In high-risk HPVs, E6 and E7 oncogenes are expressed as a bicistronic pre-mRNA, with alternative splicing producing the ultimate mRNAs required for E6 and E7 translation. Given the number of alternative donor and acceptor splicing sites, ten E6/E7 different alternative transcripts might be formed for HPV16 and three for HPV18, although only six isoforms have been previously reported for HPV16. In the present work, we employ high-throughput sequencing of invasive cervical cancer transcriptome (RNA-Seq) to characterize the expression of the HPV genome in 24 invasive cervical cancers associated with HPV16 and HPV18 single infections. Based on high-resolution transcriptional maps, we herein report three viral gene expression patterns which might be associated with the presence of the viral genome in episomal and/or integrated stages. Alternative mRNAs splicing isoforms coding for E6 and E7 oncoproteins were characterized and quantified, and two novel isoforms were identified. Three major isoforms (E6*I, E6*II, and E6+E7) were detected for HPV16 and two for HPV18 (E6*I and E6+E7). Minor transcript isoforms, including the novel ones, were very rare in some tumor samples or were not detected. Our data suggested that minor transcript isoforms of E6/E7 do not play a relevant role in cervical cancer.

2019-08-06 | GSE91065 | GEO

Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

Project description:The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR) levels and to determine the potential consequences on cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary, undifferentiated cultures of human foreskin keratinocytes (HFKs) with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets we identified 51 differentially expressed cellular miRs associated with modulation of 1,456 potential target mRNAs in HPV16 E6/E7 expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation.

2017-01-17 | GSE92496 | GEO

Transcriptome of human keratinocytes with or without HPV16 oncogene expression

Project description:We used freshly established immortalized human keratinocytes with a well-defined HPV16 E6 E7 expression cassette to get a more complete and less biased overview about global changes induced by HPV16 using RNA-seq. We identified novel factors regulated by HPV oncogenes that could serve an essential role in cancer development.

2019-03-03 | GSE124357 | GEO

Ecdysoneless protein regulates viral and cellular mRNA splicing to promote cervical oncogenesis

Project description:The high-risk subgroup of Human papilloma viruses (HPVs), exemplified by HPV16/18, are causally linked to human cancers of the anogenital tract, skin, and upper aerodigestive tract. The high-risk HPV oncoproteins E6 and E7 are expressed from a polycistronic transcript that can potentially give rise to alternatively spliced E6 mRNAs, a process important for E6 and E7 expression and oncogenic transformation. Previously, we identified ECD, the human homologue of the Drosophila ecdysoneless gene, as a novel HPV16 E6-interacting protein using Yeast two-hybrid system. Here, we show that the C-terminal region of ECD selectively binds to high-risk but not to low-risk HPV E6 proteins. We demonstrate that ECD is overexpressed in HPV+ as well as HPV- cervical and head and neck patient tumor samples. Using the TCGA dataset, we show that ECD mRNA overexpression predicts shorter survival in these cancer patients. Recent work from our laboratory showed that ECD associates with several components of RNA biogenesis/splicing machinery and are involved in mRNA export. Here, we show that ECD is an RNA binding protein and regulates mRNA splicing. RNAseq analyses of SiHa cells upon ECD knockdown (KD) revealed alterations of many cellular pathways with prominent downregulation of components of the mRNA splicing machinery. Further investigation revealed that ECD KD resulted in dysregulation of E6 RNA splicing, resulting in decreased E7 and increased RB protein. Furthermore, ECD KD dysregulated several cellular mRNAs known to be critical for HPV oncogenesis. Finally, we demonstrate that while ECD KD in cervical cancer cell lines led to a reduction in oncogenic traits, ECD overexpression together with E7 led to the immortalization of keratinocytes. Taken together, our results support a novel role of ECD in transcription and in viral and cellular mRNA splicing to support HPV-driven oncogenesis.

2022-06-01 | GSE174317 | GEO

Expression signatures and cytogenetic aberrations in HPV16 E6, E7 and E6/E7-positive immortalized human epithelial cells

Project description:Identification of genetic/cytogenetic alterations and differentially expressed cellular genes in HPV16 E6, E7 and E6/E7 positive human foreskin keratinocytes Keywords: ordered

2013-11-27 | GSE14051 | GEO

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