Page 31 - GTM-2-4

Global Translational Medicine The research advances in HPV integration

and HPV integration necessitates further investigation. In A study of 25 HNSCC cases exhibiting HPV integration
addition, as detailed below, other influences may affect the identified integration sites within the gene encoding
expression of these two proteins . However, it is essential the DNA repair protein RAD51 homolog 2 (RAD51B),
[38]
to note that breakpoints can occur in any region of the viral resulting in an amplified chimeric segment encoding
genome. Several studies have reported that differences a non-functional RAD51B protein . Li et al. found
[19]
[47]
in E6/E7 transcript levels between samples of different that the genes repeatedly targeted by HPV integration
histopathological grades or between different physical were enriched not only in genes related to DNA repair
states of the viral genome are not statistically significant. pathways but also in genes associated with the pathways
These observations suggest that high levels of E6/E7 may of xenobiotics metabolism by cytochrome P450, chemical
not be imperative for tumorigenesis. Conversely, secondary carcinogenesis, and steroid hormone biosynthesis.
genetic events, such as copy number variation, might be Integration ratios increased with the progression of CC.
required to induce cancer [12,39] . The ERBB2 gene (which enhances the MAPK and PI3CA
pathways) is another reported site of HPV integration . It
[13]
3.2. Imbalance in the expression of tumor-related has been suggested that even though integration can occur
genes and the affected key cellular pathways at multiple separate loci in tumor genomes, there is usually
As mentioned above, the majority of the integration only one transcriptionally active locus . MicroRNAs
[48]
sites cluster in regions of open chromatin and common (miRNAs) close to integration sites may also be influenced.
fragile sites. Identified as “integration hotspots,” locations One study identified 47 integration sites and showed that
such as 3q28, 4q13.3, 8q24.21, 13q22.1, and 17q21 have 32 of these sites were within 3 Mb of a miRNA locus,
been documented [4,26,40,41] . HPV integration disrupts host and 19 of the 75 affected miRNAs were associated with
genes through various mechanisms, including genome tumors, influencing cell proliferation, differentiation, and
rearrangements (amplifications, deletions, inversions, apoptosis .
[26]
translocations, and others), intragenic insertions, and the
introduction of promoters, splice acceptors, splice donors, 3.3. Epigenetic changes
and transcription termination elements . The disruption Epigenetic changes may occur in both the HPV and host
[15]
of host genes by HPV integration can result in gene genomes, providing integrated viruses with a selective
dysfunction through a complete loss of expression of the advantage. Therefore, it is necessary to consider both
affected genes at the RNA or protein level . Integration integration and epigenetic changes . Most studies on
[42]
[4]
within 50 kb of known oncogenes or tumor repressor epigenetic changes to date have focused on methylation.
genes can occur, often resulting in the downregulation of Epigenetic and genetic alterations to E2BSs in the HPV16
tumor suppressor genes and the upregulation of proto- URR (with E2BS3/4 becoming more methylated than
oncogenes . DNA from HPV16 or 18 has been detected E2BS1 in CC) may also block the suppressive function
[41]
downstream, upstream, and within the MYC gene (8q24.21 of E2. A remarkably high degree of heterogeneity has
integration hotspot) at distances ranging from 0 to 513 kb been observed for URR methylation levels in squamous
from this gene. This results in MYC overexpression at cell carcinoma samples displaying HPV genome
both the mRNA and protein levels, suggesting a potential integration [32,49] . The internal copies of the viral genome are
contribution of the MYC activation triggered by the always epigenetically silenced, and Type 2 integration events
insertion of HPV viral DNA to cervical carcinogenesis [28,43] . are associated with greater hypermethylation of the long
In HeLa cells, the integrated HPV fragment is 3300 kb control region . The integration of HPV16 viral DNA into
[50]
away from the 8q24.22 region in the linear distance, but the host genome is associated with hypermethylation in the
the integrated HPV DNA can be brought into the close L1/L2 and E2 regions in vulval intraepithelial neoplasia .
[51]
vicinity of the 8q24.22 region by chromatin folding, which In one study, the methylation status of the integrated HPV
is required for colocalization of the MYC locus and 8q24.22 DNA was found to be correlated with the methylation
region . MYC and PDL1 are also frequently integrated status of the host genome close to the integration site in
[44]
and overexpressed in HNSCC [15,45] . three HNSCC cell lines . Brd4-enriched transcriptional
[52]
The proteins belonging to the apolipoprotein B regulatory hubs have been identified in cells displaying
mRNA-editing catalytic (APOBEC) polypeptide family HPV16 genome integration. These hubs act as a super-
increase the likelihood of DNA breaks. Levels of the enhancer-like element, promoting the transcription of E6
APOBEC3B polypeptides are significantly higher in HPV- and E7 [30,53] . The expression of the E7 gene in HR-HPVs
positive HNSCCs than in HPV-negative HNSCCs , leads to the extensive epigenetic reprogramming of
[46]
and APOBEC3A is overexpressed in biopsy samples from cells. In HPV16-E7 expressing cells and HPV16-positive
oropharyngeal cancer displaying HPV16 integration . cervical intraepithelial neoplasia (CIN) specimens, levels
[20]

Volume 2 Issue 4 (2023) 5 https://doi.org/10.36922/gtm.2034