title: Identification of host transcriptional networks showing concentration-dependent regulation by HPV16 E6 and E7 proteins in basal cervical squamous epithelial cells.
abstract: Development of cervical squamous cell carcinoma requires increased expression of the major high-risk human-papillomavirus (HPV) oncogenes E6 and E7 in basal cervical epithelial cells. We used a systems biology approach to identify host transcriptional networks in such cells and study the concentration-dependent changes produced by HPV16-E6 and -E7 oncoproteins. We investigated sample sets derived from the W12 model of cervical neoplastic progression, for which high quality phenotype/genotype data were available. We defined a gene co-expression matrix containing a small number of highly-connected hub nodes that controlled large numbers of downstream genes (regulons), indicating the scale-free nature of host gene co-expression in W12. We identified a small number of 'master regulators' for which downstream effector genes were significantly associated with protein levels of HPV16 E6 (n = 7) or HPV16 E7 (n = 5). We validated our data by depleting E6/E7 in relevant cells and by functional analysis of selected genes in vitro. We conclude that the network of transcriptional interactions in HPV16-infected basal-type cervical epithelium is regulated in a concentration-dependent manner by E6/E7, via a limited number of central master-regulators. These effects are likely to be significant in cervical carcinogenesis, where there is competitive selection of cells with elevated expression of virus oncoproteins.
authors.affiliation: Cambridge University Hospitals, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Cambridge, CB2 1QP, UK.
authors.forename: Cinzia G
authors.initials: CG
authors.lastname: Scarpini
authors.affiliation: Department of Pathology, University of Cambridge, CB2 1QP, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Groves
authors.affiliation: Department of Pathology, University of Cambridge, CB2 1QP, UK.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Odle
authors.affiliation: Cambridge University Hospitals, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.|Department of Pathology, University of Cambridge, CB2 1QP, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Coleman
mesh_terms: D002584:Cervix Uteri / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D053263:Gene Regulatory Networks; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16