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Moreover F. nucleatum inversely correlates with CD3 -T cell counts, whose aberrant signaling and function
is typical in cervical carcinogenesis.

[15]
Al-Hebshi et al. have reported an abundance of the periodontal pathogen F. nucleatum, selected by the
tumor environment, followed to a lesser extent by Campylobacter, Parvimonas and Prevotella spp. in oral
squamous cell carcinoma, while the Streptococci are frequently associated with a healthy status.

Although the results obtained from clinical studies vary in the oral cancer associated microbiota
composition, partially due to differences in the methodological approaches, the functional data consistently
show an enrichment of a virulent, chronic inflammatory bacteriota that, as a passenger within the tumor
environment, contributes to the worsening of the tumoral disease.

HIGH-RIsK HpVs, mICRObIOTa, epITHeLIaL meseNCHYmaL TRaNsITION aND CaNCeR
pROGessION
As known, EMT associates with cell migration, invasion, resistance to chemotherapy and anoikis. During
this process, several signaling pathways, such as those involving TGF-β, Wnt, Hedgehog, β-catenin, Notch,
Nanog, STAT3 and ERK, are activated in the cell leading to a pro-metastatic behavior [20,21] . In this context,
EMT can be also regulated by HR-HPVs [22,23] .

Despite anogenital and oropharyngeal squamous cell carcinomas (OPSCC) promoted by these viruses
have a more favorable prognosis respect to HPV negative ones, EMT usually associates with an aggressive
tumoral behavior, making HPV role an open issue. In a study on a cohort of 296 OPSCC-patients, EMT
[24]
was confirmed as an adverse marker of evolution of HPV related carcinomas .
In another research, the expression of five EMT markers was assessed in normal and tumoral cervical
tissues, revealing that E-cadherin and β-catenin expression decreases gradually, while that of N-cadherin,
[25]
[26]
vimentin and fibronectin increases during malignant progression . Moreover, Su et al. studied the
role of DNA methylation of the ten-eleven translocation methyl-cytosine dioxygenase 1 (TET1), which
oxidizes 5-methylcytosine to 5-hydroxymethylcytosine within cervical lesions. At a precancerous level,
TET1 inhibits EMT, interacting with chromatin modifiers and downregulating mesenchymal genes such
[26]
as ZEB1 and VIM . In vitro culture of cervical cancer cells revealed that p68, an ATP-dependent RNA
helicase, induces EMT through the transcriptional activation of the TGF-β1 pathway, inducing cancer
[27]
progression .
[28]
Finally, Pang et al. reported that HPV18 E6 regulates YB-1 mRNA expression by promoting EMT and
cervical lesion progression through the enhanced Snail expression.

Moreover, both HPV and EMT upregulate programmed cell death ligand-1 (PD-L1) expression, an
immune checkpoint and therapeutic target in OPSCC, whose efficacy is currently under investigation [29,30] .
Precisely, PD-L1 is overexpressed in about half of OPSCC that seem to have a better response to anti-PD-1
[31]
therapy .

Regarding the involvement of bacterial microbiota in EMT, F. nucleatum has been frequently found
in stools and bioptic specimens of CRC affected patients, and more recently also of OPSCC patients. It
has been suggested that this bacterium triggers EMT to malignant transformation by interacting with
E-cadherin, as suggested by in vitro experiments on NCM460 cells [32,33] . In a cohort of stage III/IV CRC
[34]
affected patients, Yan et al. found a significant correlation between the presence of F. nucleatum and
tumor progression also in relation to chemotherapy efficacy, suggesting its role as a biomarker for a