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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 3 of 40

through the skin and damages keratinocytes of the basal epidermal layer. UV is emitted from the sun
as well as from some man-made light. UVA (315-400 nm) compared to UVB (280-315 nm) accounts
[3,4]
for 95% of sunlight. UVA is the primary source of light in tanning beds and it is less mutagenic . UVA
penetrates deeper into the epithelium affecting dermal stroma, while UVB is absorbed into the stratum
[5]
corneum layer . Primarily, UV causes DNA damage by generating cyclobutene pyrimidine dimers and
[6]
6-4 photoproducts . Under stress, Sestrin2, an antioxidant, is activated by tumor suppressor p53 and
[7,8]
inhibits positive cell growth regulator mammalian target of rapamycin (mTOR) . The activity and skin
penetration of UV depends on its wavelength with UVA penetrating between 700 nm - 1 mm and UVB
[9]
penetrating between 280-320 nm .

Damage to chromosome 9 hedgehog pathway
BCC is the most common NMSC and accounts for 80% of NMSC diagnoses . BCC-specific risk
[10]
factors include intermittent/recreational sun exposure, other sources of UV light, ionizing radiation, and
[11]
skin phototype . The most critical pathway in BCC tumorigenesis appears to be the Hedgehog [sonic
hedgehog (SHH)] pathway composed of three genes: SHH, DHH, and IHH as well as two patched genes:
PTCH1 and PTCH2. The SHH pathway is important for the patterning, growth, and development of
vertebrates. The patched genes encode SHH pathway receptors responsible for suppressing Smoothened
(SMO), a transmembrane protein/proto-oncogene capable of activating Glioma-associated oncogene (Gli)
[12]
transcription factors . In the SHH pathway, a SHH ligand binds to its receptor, PTCH (a transmembrane
[13]
protein) to disinhibit SMO . The activation of SMO, which occurs in the primary cilium, causes the
accumulation of intracellular calcium ions resulting in a disruption in calcium homeostasis [14,15] . The
[16]
transcription of Gli proteins has been shown to be sufficient to induce BCC development . After the
SHH pathway, TP53 gene point mutations are the second most common genetic mutation in BCCs [11,17] .
Traditional advanced BCC therapy consists of surgical resection, but the advent of small-molecule
inhibitors of the SHH pathway allowed for new therapeutic options for patients with locally advanced or
metastatic BCC [13,18] .

Activation of the SHH pathway at the level of PTCH involves SHH interaction with PTCH through two
distinct interfaces, the interface between PTCH and the calcium and zinc binding surfaces of SHH and
the interface between PTCH and the N-terminal palmitoyl and C-terminal cholesteroyl moiety of SHH.
Mutations at these interfaces that increase SHH binding to PTCH may subsequently increase the signaling
strength of the SHH pathway and may drive tumorigenesis in BCC. Activation of the SHH pathway at
the level of SMO involves side-chain oxysterols (endogenous cholesterol metabolites) that induce SMO
accumulation in primary cilia even in the absence of SHH ligands. Excess side-chain oxysterols may lead to
overactivation of the SHH pathway while pharmaceutical and genetic approaches aimed at reducing cellular
cholesterol levels have been shown to attenuate SHH signaling in target cells, highlighting a potential role
[19]
of excess side-chain oxysterols in the pathogenesis of BCC [Figure 1].

DNA damage repair
Damaged keratinocytes must depend on DNA repair mechanisms such as ataxia-telangiectasia-
mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins, members of the PIKK family
of proteins. After the cell experiences a UV-induced double-stranded DNA break, ATM undergoes
autophosphorylation which empowers ATM to phosphorylate checkpoint kinase (CHK) 2 [20,21] . CHK2
[22]
inhibits CD25 phosphatases which then prohibit the cell from undergoing mitosis . ATM also can
[23]
phosphorylate p53, arresting the cell in G1 . If the UV induces a single-stranded DNA break, ATR will be
activated. ATR will autophosphorylate and then CHK1 which goes on to phosphorylate CDC25 [24,25] . This,
once again, prevents the cell from completing mitosis. In addition, ATR is involved in the p21 pathway
which can modulate various cyclins/CDKs to inhibit the cell cycle . ATR phosphorylates murine double
[26]
minute 2 (MDM2) to then inactivate p53. The inactivation of p53 results in the uncontrolled proliferation