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.

Genomic characterization of viral integration sites in HPV‐related cancers

“…For reasons that are not well understood, cancers infected with HPV18 tend to have a higher prevalence of integration (TCGA data). Our analysis stratifying by HPV type revealed that integration events in HPV18 samples were more likely to be in 8q24.21 where the MYC oncogene is located than HPV16 infected samples . MYC codes for a protein with roles in cell cycle progression, apoptosis and cellular transformation.…”

Genomic Integration of High-Risk HPV Alters Gene Expression in Oropharyngeal Squamous Cell Carcinoma

“…These results suggest that such integrations are not always entirely random and that viral integration is more likely to occur in gene-poor regions of the cellular genome that are already unstable or into regions with sequence or structural characteristics that favor integration. Zhang et al (42) analyzed 14 publications and concluded that in cervical cancers HPV integration showed a preference for intragenic areas and transcriptionally active regions of the human chromosomes.…”

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV‐negative cervical cancer

“…At least part of the viral genome is inserted into human DNA in most HPV‐induced ICCs, and the integration process is thought to be mediated by host DNA repair mechanisms. Integration causes stable association of the virally encoded oncogenes with a host cell, triggers human genome rearrangements, and drives expression of the human oncogenes that flank the sites of integration . In most ICCs, the HPV genome is inserted near one allele of a human, dominant‐acting oncogene, and many human oncogenes have been identified as recurring HPV insertion sites in tumors .…”