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.

Abstract

What's new?

Human papillomavirus (HPV) integration into the host genome is associated with increased severity of cervical precancer, suggesting that it is an influential event in cervical carcinogenesis. However, whether the genomic sites affected by HPV integration are relevant to cervical cancer remains unclear. In this study, analysis of 499 loci showed preferred HPV integration into intragenic and gene‐rich chromosomal sites. Frequently, these sites were located near transcriptionally active regions. In addition, multiple HPV integration “hotspots” were identified, the majority of which contained cancer‐related genes, such as MYC and the potentially novel tumor suppressor MPPED2.