Title | Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV-related cervical carcinogenesis |
Authors | Zhang, Ruiyang Shen, Congle Zhao, Lijun Wang, Jianliu McCrae, Malcolm Chen, Xiangmei Lu, Fengmin |
Affiliation | Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Microbiol, 38 Xueyuan Rd, Beijing 100191, Peoples R China. Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Infect Dis, 38 Xueyuan Rd, Beijing 100871, Peoples R China. Peking Univ, Peoples Hosp, Dept Obstet & Gynecol, Beijing 100871, Peoples R China. Pirbright Inst, Pirbright, Surrey, England. Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Microbiol, 38 Xueyuan Rd, Beijing 100191, Peoples R China. Chen, XM Lu, FM (reprint author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Ctr Infect Dis, 38 Xueyuan Rd, Beijing 100871, Peoples R China. |
Keywords | HPV integration cervical cancer functional annotation analysis MYC MPPED2 HEPATOCELLULAR-CARCINOMA CANCER PROLIFERATION INFECTION GENOME SITES CELLS LINE DNA |
Issue Date | 2016 |
Publisher | INTERNATIONAL JOURNAL OF CANCER |
Citation | INTERNATIONAL JOURNAL OF CANCER.2016,138,(5),1163-1174. |
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 similar to 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. |
URI | http://hdl.handle.net/20.500.11897/417824 |
ISSN | 0020-7136 |
DOI | 10.1002/ijc.29872 |
Indexed | SCI(E) PubMed |
Appears in Collections: | 基础医学院 人民医院 |