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Page 10 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60
However, pre-malignant and cSCCs demonstrate increased levels of CSL, leading to the excessive
[75]
proliferation of normal epithelial cells underlying the development of actinic keratoses and cSCCs .
Role of microRNAs
MicroRNAs (miRNAs) play an important role in cell growth of cSCCs. However, the function of the
many miRNAs varies. Within various signaling pathways, some miRNAs are upregulated, while others
are downregulated, causing various responses. However, all these miRNAs increase cell growth of cSCC
malignant lesions. For example, miR-21 works as an oncogene that targets transcription factor GRHL3, an
important element in the PTEN pathway. When miR-21 is upregulated, the PTEN and PI3K/Akt/mTOR
[76]
signaling pathways are overexpressed leading to increased cell growth . This is one of the many miRNAs
that influence cell growth of cSCCs. In fact, some of the upregulated miRNAs determine the aggressiveness
of the cSCC lesion. Because miRNAs influence both the PTEN and mTOR pathways, this information
always shows potential of crosstalk between the BCC and cSCC pathways.
Apoptosis evasion
An important cause of DNA instability is solar UV. Both UVA and UVB radiation induce the most
common types of cSCC. It is well-established that UVB radiation causes direct keratinocyte DNA damage
leading to cSCC, but exposure to UVA radiation has also been shown to foster tumorigenesis through
DNA damage resulting from photosensitizers within the body causing indirect production of ROS. In
[77]
natural sunlight, the ratio of UVA:UVB varies depending on the day, season, and latitude . It is not
well understood how exposure to variable ratios of UVA:UVB radiation affects progression through
these oncogenic pathways. However, use of sunscreen that blocks UVB without blocking UVA, as well as
chronic or acute UV exposure through window glass, can possibly increase the ratio. Foods containing
[78]
furocoumarins (psoralens) also may increase the absorption of UVA and thus alter the UVA:UVB ratio .
Moreover, patients should be precautioned that substances applied to the skin such as retinoids, tanning
oils and products with methyl and benzyl nicotinate may have the opposite effect of sunscreen and enhance
[79]
the cutaneous absorption of UV radiation .
Solar UV radiation can induce DNA mutations within the cyclobutene pyrimidine dimers and 6-4
photoproducts . These mutations can activate the ataxia telangiectasia and Rad3 (ATR) DNA repair
[80]
system that, in turn, activate TP53, a tumor suppressor important for apoptosis. The BCC sections elaborate
on the mechanisms of ATR. Mutation in either or both genes can lead to apoptotic escape and resultant
overactive cell growth.
Mutation of cutaneous TP53 thus evokes an uncontrolled activation of the cell cycle allowing mutated
cells to progress to the synthesis phase (S phase) of the cell cycle prematurely. Wildtype CDKN2A/p16 is
responsible for generating cyclin dependent kinase (cdk) inhibitors INK4A and p14, both of which are
TP53 degradation inhibitors. INK4A binds to cdk4 and cdk6, inhibiting cell cycle progression into the S
phase. When the oncogene CDKN2A/p16 is mutated, INK4A is mutated, resulting in a lack of inhibition
of cdk4 and cdk6 within the cell cycle. This mechanism resembles that of TP53 in that the cell cycle
prematurely progresses into the S phase allowing unregulated DNA replication and advancement into the
mitotic phase of the cell cycle. Recent studies have discovered with flow cytometry targeting ATR-activated
cells can eradicate the number of cells with 6-4 photoproducts. Eliminating these cells can block solar UV
radiation-induced damage from occurring and potentially cSCC tumorigenesis [Figure 6].
Downregulation of certain miRNAs can affect apoptosis; specifically, the downregulation of miR-34a
decreases the function of TP53 leading to avoidance of apoptosis. Select solar UV radiated keratinocytes
appear to have the downregulation of miR-34a, leading to the proapoptotic effect of these tumor cells .
[76]