Transgenic SCLC induced by E6/E7 oncoproteins vs normal controls
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE23962 | GEO | 2014/05/27
SECONDARY ACCESSION(S): PRJNA130389
REPOSITORIES: GEO
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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
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
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.
2014-06-26 | GSE58841 | GEO
Project description:Specific types of human papillomaviruses (HPVs) cause cervical cancer, the second most common tumor in females worldwide. Both cellular transformation and the maintenance of the oncogenic phenotype of HPV-positive tumor cells are linked to the expression of the viral E6 and E7 oncogenes. In order to identify downstream cellular target genes for the viral oncoproteins, we silenced endogenous E6 and E7 expression in HPV-positive HeLa cells by RNA interference (RNAi). Subsequently, we assessed changes of the cellular transcriptome by genome-wide microarray analysis. We identified, 648 genes wich were either downregulated (360 genes) or upregulated (288 genes) upon inhibition of E6/E7 expression. A large fraction of these genes is involved in tumour-relevant processes, such as apoptosis control, cell cycle regulation, or spindle formation. Others may represent novel cellular targets for the HPV oncogenes, such as a large group of C-MYC-associated genes involved in RNA splicing. Keywords: siRNA mediated knockdown
2007-07-01 | GSE6926 | GEO
Project description:The study aimed to explore HPV E7-specific pathways in cervical cancer cells.
2024-08-25 | GSE274812 | GEO
Project description:The W12 cell lineage recapitulates the early events in HPV-driven cervical cancer pathogenesis (which is impossible to investigate using clinical samples) and we are interested in characterising the host transcriptional events that occur at those early stages. Previous work in these cells has identified early biomarkers of cervical cancer (now in widespread commercial use) as well as critical pathways in cervical carcinogenesis. By taking a network-based approach to the whole transcriptome we have identified important master regulators of a tightly and quantitatively regulated expression response to HPV early gene expression. Briefly, transcriptional activity of 16 different clones form the W12 cell line were measured in parallel. Each clone has measured HPV early gene activity at mRNA and protein level, as well as cell growth rates as previously described in Scarpini et al 2014 J Pathol July; 233(3): 281â293 (PubmedID 24752734; DOI: 10.1002/path.4358; http://europepmc.org/articles/PMC4285939#b11).
2016-11-30 | E-MTAB-4409 | biostudies-arrayexpress
Project description:UnlabelledTranscripts of human papillomavirus 16 (HPV16) E6 and E7 oncogenes undergo alternative RNA splicing to produce multiple splice isoforms. However, the importance of these splice isoforms is poorly understood. Here we report a critical role of E6^E7, a novel isoform containing the 41 N-terminal amino acid (aa) residues of E6 and the 38 C-terminal aa residues of E7, in the regulation of E6 and E7 stability. Through mass spectrometric analysis, we identified that HSP90 and GRP78, which are frequently upregulated in cervical cancer tissues, are two E6^E7-interacting proteins responsible for the stability and function of E6^E7, E6, and E7. Although GRP78 and HSP90 do not bind each other, GRP78, but not HSP90, interacts with E6 and E7. E6^E7 protein, in addition to self-binding, interacts with E6 and E7 in the presence of GRP78 and HSP90, leading to the stabilization of E6 and E7 by prolonging the half-life of each protein. Knocking down E6^E7 expression in HPV16-positive CaSki cells by a splice junction-specific small interfering RNA (siRNA) destabilizes E6 and E7 and prevents cell growth. The same is true for the cells with a GRP78 knockdown or in the presence of an HSP90 inhibitor. Moreover, mapping and alignment analyses for splicing elements in 36 alpha-HPVs (α-HPVs) suggest the possible expression of E6^E7 mostly by other oncogenic or possibly oncogenic α-HPVs (HPV18, -30, -31, -39, -42, -45, -56, -59, -70, and -73). HPV18 E6^E7 is detectable in HPV18-positive HeLa cells and HPV18-infected raft tissues. All together, our data indicate that viral E6^E7 and cellular GRP78 or HSP90 might be novel targets for cervical cancer therapy.ImportanceHPV16 is the most prevalent HPV genotype, being responsible for 60% of invasive cervical cancer cases worldwide. What makes HPV16 so potent in the development of cervical cancer remains a mystery. We discovered in this study that, besides producing two well-known oncoproteins, E6 and E7, seen in other high-risk HPVs, HPV16 produces E6^E7, a novel splice isoform of E6 and E7. E6^E7, in addition to self-interacting, binds cellular chaperone proteins, HSP90 and GRP78, and viral E6 and E7 to increase the steady-state levels and half-lives of viral oncoproteins, leading to cell proliferation. The splicing cis elements in the regulation of HPV16 E6^E7 production are highly conserved in 11 oncogenic or possibly oncogenic HPVs, and we confirmed the production of HPV18 E6^E7 in HPV18-infected cells. This study provides new insight into the mechanism of splicing, the interplay between different products of the polycistronic viral message, and the role of the host chaperones as they function.
| S-EPMC4337564 | biostudies-literature
Project description:High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the initiation and progression of high grade serous cancer (HGSC). HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant Transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.
2024-09-01 | GSE268836 | GEO
Project description:Human papillomavirus (HPV) is currently the most identifiable cause of head and neck squamous cell carcinoma (HNSCC) accounting for approximately 25% of these cases. HPV+ cancer incidence is on the rise with metastatic disease accounting for nearly all HPV+ HNSCC related deaths. Thus, developing a relevant in vivo pre-clinical model for these invasive cancers is necessary for testing new disease therapeutics and improving survival. To this end, we characterize a novel metastatic HPV+ murine model of HNSCC. Individual metastatic clonal cell lines were isolated from an animal with late pulmonary metastasis that developed recurrent disease after standard of care cisplatin-radiation therapy. Similar to the parental cells, all metastatic cell lines retain expression of HPV16 E6 and E7 oncogenes and degrade P53. While the in vitro growth rates of these metastatic clones are slower than the parental tumor line their in vivo growth is greatly enhanced. Moreover, resistance to standard therapies (cisplatin and radiation) is dramatically increased in 3 of the 4 clones in vivo. Lymphatic and/or lung metastasis occurs 100% of the time in 2 of the clonal lines while it is nearly undetectable in the parental line. In addition, expression and protein array analyses were completed to investigate the mechanisms driving these phenotypic changes. This model not only provides an economical and rapid screening system in which to develop and test improved therapeutic regimens but may also provide mechanistic insights into tumor metastasis.
2016-04-15 | GSE68935 | GEO
Project description:BackgroundThe oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells.MethodsEnvisioning clinical application of the best characterized anti-HPV16 E6 and -HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed.ResultsWe showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway.ConclusionBased on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.
| S-EPMC7825221 | biostudies-literature