Zhang Ruiyang, Shen Congle, Zhao Lijun, Wang Jianliu, McCrae Malcolm, Chen Xiangmei, Lu Fengmin
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, People's Republic of China.
Int J Cancer. 2016 Mar 1;138(5):1163-74. doi: 10.1002/ijc.29872. Epub 2015 Oct 26.
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.
人乳头瘤病毒（HPV）病毒DNA整合到人类基因组中被认为是宫颈癌发生过程中的一个重要病因学事件。最近的几份报告表明，这种整合靶向细胞基因（ITGs）在宫颈癌发生中可能发挥作用。因此，利用从14篇出版物收集的数据对HPV整合事件进行了全面分析，其中包括人类染色体上的499个整合位点。结果显示，HPV DNA更倾向于整合到人类染色体的基因内区域和基因密集区域。有趣的是，与对照组相比，发现整合位点附近的宿主细胞基因转录活性更高。此外，对人类基因组中整合位点的分析表明，尽管所有染色体都有代表，但存在几个整合热点。利用基因本体论和KEGG分析发现，所鉴定的ITGs在肿瘤相关术语和途径中富集。与此一致的是，在六个测试的ITGs中，有三个在宫颈癌组织中异常表达。其中，首次证明MPPED2可诱导HeLa细胞和SiHa细胞G1/S期阻滞和细胞增殖迟缓。此外，在HeLa细胞系中“敲除”整合的HPV片段会降低位于整合位点下游约500 kb处的MYC的表达，这为整合的HPV片段通过长距离染色质相互作用影响MYC表达这一假说提供了首个实验证据。总体而言，这项全面分析的结果表明，病毒整合导致的ITGs失调可能在宫颈癌发生中具有病因学作用。
