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Page 16 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

Figure 8. The pathway of human papilloma virus (HPV). This figure describes the effects of HPV on cells involving the E7 and E7
proteins

In keratinocytes, KRT5 and KRT14 normally copolymerize to form intermediate filaments which help
anchor the epidermis [106] . Mutations of helix boundary motifs of KRT5 are thought to lead to the most
severe phenotype of epidermolysis bullosa [107] . These mutations lead to fragile keratinocytes with unstable
cell-to-cell junctions. This instability causes keratinocyte-mediated inflammation, which may contribute to
the pathogenesis of VC [104] .

Oral verrucous carcinoma (OVC) is more commonly seen than the cutaneous subtype. The PI3K/AKT/
mTOR pathway was shown to be upregulated in OVC, suggesting a role for this pathway in the progression
[59]
of OVC . In this pathway, PI3K phosphorylates AKT, which confines AKT to the plasma membrane
[Figure 2]. This is followed by many downstream effects of AKT, one of which is the activation of mTOR.
mTOR is a serine/threonine kinase expressed in human cells, and its action is executed by two complexes,
TORC1 and TORC2. TORC1 leads to the downstream activation of 4EBP1 and P70S6K, which are involved
in the translation of mRNA into proteins for cell growth [108] . This pathway leads to increased proliferation
of tumor cells, as well as resistance to treatment. The PI3K/Akt/mTOR pathway is also upregulated in oral
SCC.

Furthermore, the downregulation of miRNAs contributes to the pathogenesis of OVC. Specifically, miR-195
is found to be significantly downregulated in OVC [109] . miR-195 serves as either an oncogene or a tumor