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Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 9 of 40

Figure 5. SHH pathway increases intracellular calcium, which can also increase the activation of EGFR. SHH also activates MMPs,
which will activate the EGFR and increase cellular growth [71] . SHH: sonic hedgehog; EGFR: epidermal growth factor receptor; MMP:
metalloproteinases; NF-κB: nuclear factor-kappa B

an imbalance within the SHH pathway leading to atypical signaling and activation of other modulating
[71]
receptors [Figure 5]. Because the crosstalk between the EGFR pathway and SHH pathway occurs early in
the activation of the SHH pathway, the blockade of SHH can lead to shunting of the SHH pathway to the
EGFR pathway causing upregulation in the EGFR pathway and increased proliferation of keratinocytes.
[72]
Eventually, these tumors have the potential to mutate to a different type of skin cancer [Figure 4] .
Moreover, NOTCH gene mutation contributes to cSCC development through its role in chronic
inflammation, trauma, or both. NOTCH genes are responsible for the production of NOTCH proteins
[73]
involved in cell proliferation and regulation of apoptosis . Cytochrome P450 family 1 subfamily B member 1
(CYP1B1), a heme-thiolate monooxygenase, is involved in estrogen metabolism and biosynthesis as well as
a catalyst to hydroxylation of E2 to 4-hydroxyestradiol. Normal keratinocytes have been found to express
this enzyme. In fact, recent studies have found that CYP1B1 antagonizes the signaling of NOTCH1, which,
in turn, blocks keratinocyte proliferation and differentiation. Western blot and immunofluorescence display
that there is increased involucrin, keratin 10, and ki67 (a proliferation marker) after downregulation and
[74]
knock out of CYP1B1, demonstrating augmentation of keratinocyte proliferation and differentiation .
More research is being performed on the effect of CYP1B1 and NOTCH1 within SCC cells. This innovative
[74]
research can lead to a new creation of a pharmacologic agent that can treat lacSCC in the future .
Other NOTCH pathway genes include the recombination signal binding protein for immunoglobulin
J gene (RBPJ). This gene codes for RBP-Jκ also known as “CBF1, Suppressor of Hairless, Lag-1” (CSL)
transcription factor within keratinocytes. Upper epithelial cells downregulate the production of CSL.