title: Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV-related cervical carcinogenesis.
abstract: Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration-targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, "knocking out" the integrated HPV fragment in HeLa cell line decreased expression of MYC located ∼500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis.
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Ruiyang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Congle
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, People's Republic of China.
authors.forename: Jianliu
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Pirbright Institute, Pirbright, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: McCrae
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Lu
mesh_terms: D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D015894:Genome, Human; D006801:Humans; D027383:Papillomaviridae / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000821:virology; D016662:Virus Integration
chemical_list: C561977:MPPED2 protein, human; D010727:Phosphoric Diester Hydrolases
keywords: HPV; MPPED2; MYC; cervical cancer; functional annotation analysis; integration