**2. Photocarcinogenesis**

Solar UVR is composed of UVA (320-400 nm), UVB (290-320 nm), and UVC (200-290 nm). The atmospheric ozone layer inhibits all UVC and some UVB from reaching the surface of the Earth. The composition of UVR that reaches humans is approximately 95% UVA and 5% UVB, depending on factors such as cloud coverage, weather, thickness of the ozone layer, and latitude. UVA can penetrate deep into the dermis, while most UVB is absorbed by the stratum corneum in the epidermis but some passes into the upper dermis [7]. Human skin has evolved protective mechanisms against solar UVR. Melanocytes produce melanin that absorbs and scatters light in the lower epidermis [8]. The stratum corneum scatters UV light, and stratum corneum, spinosum, and basale can absorb UV light. Endogenously produced antioxidants and DNA repair enzymes protect skin cells from the damaging effects of UVR [9, 10].

Irradiation of the skin with UV damages the tissue and cellular components, and contrib‐ utes to skin aging and carcinogenesis. The characteristic adverse effects of UVB include sunburn, inflammation, immunosuppression, erythema, and DNA damage. UVA expo‐ sure is primarily associated with the generation of reactive oxygen species (ROS), some oxidative DNA damage, cell membrane oxidation, and can result in immunosuppression. UVA indirectly causes oxidative DNA damage through the generation of ROS. The oxidation of guanine bases to 8-hydroxy-2'deoxyguanine (8-OH-dG) is primarily associat‐ ed with UVA irradiation. UVB can induce oxidative stress indirectly through the activa‐ tion of the inflammatory cells. Signature mutagenic DNA lesions caused by UVB consistently found in skin cancers are cyclobutane pryimidine dimers (CPD), pyrimidine- (6-4)-pyrimidine photoproducts, and C → T transitions [6, 7, 11-16]. Signature UVB mutations, CPDs and G:C → A:T transitions, have been found to localize in the superfi‐ cial epithelial layers of human SCC samples, while signature UVA mutations, 8-OH-dG and A:T → C:G transversions, localized in the basal layers [15]. This distribution of DNA lesions is consistent with knowledge that UVA penetration into the skin is deeper than UVB penetration. Signature gene mutations found in skin cancers are those of tumor protein 53 (p53) tumor suppressor gene and proto-oncogene B-raf. Mutations to p53 are particularly detrimental because p53 plays a central role in pausing the cell cycle to allow time for DNA repair [2, 13]. UVR exposure can induce signal transduction pathways, such as mitogenactivated protein kinase (MAPK) and activation of transcription factor AP-1 that regulate cell growth, differentiation, apoptosis, and production of pro-inflammatory cytokines [17].

Inappropriate cell proliferation and survival contributes to carcinogenesis. Severely damaged DNA that cannot be repaired triggers skin cells to undergo apoptosis. Cells that survive the damage could carry mutations if the repair was not carried out perfectly [18]. There is a greater tendency for damaged keratinocytes to undergo apoptosis than damaged melanocytes, possibly to preserve melanin-producing cells for photoprotection [19]. In addition to genotoxic effects, UVB exposure increases cell proliferation as is observed in animal models where hyperproliferation of the epidermis and inflammation are the result of prostaglandin and epidermal growth factor receptor activation by UVB [9].

discouraged. There is scientific evidence that indicates oral and topical supplementation with antioxidants, vitamins, and phytochemicals is beneficial for chemoprevention. Secondary prevention for skin cancer is performing periodic examinations of the skin for suspicious growths, and having dangerous-looking growths excised by a dermatologist. Practicing a combination of these skin cancer prevention strategies will reduce the risk of skin cancer.

Solar UVR is composed of UVA (320-400 nm), UVB (290-320 nm), and UVC (200-290 nm). The atmospheric ozone layer inhibits all UVC and some UVB from reaching the surface of the Earth. The composition of UVR that reaches humans is approximately 95% UVA and 5% UVB, depending on factors such as cloud coverage, weather, thickness of the ozone layer, and latitude. UVA can penetrate deep into the dermis, while most UVB is absorbed by the stratum corneum in the epidermis but some passes into the upper dermis [7]. Human skin has evolved protective mechanisms against solar UVR. Melanocytes produce melanin that absorbs and scatters light in the lower epidermis [8]. The stratum corneum scatters UV light, and stratum corneum, spinosum, and basale can absorb UV light. Endogenously produced antioxidants

and DNA repair enzymes protect skin cells from the damaging effects of UVR [9, 10].

Irradiation of the skin with UV damages the tissue and cellular components, and contrib‐ utes to skin aging and carcinogenesis. The characteristic adverse effects of UVB include sunburn, inflammation, immunosuppression, erythema, and DNA damage. UVA expo‐ sure is primarily associated with the generation of reactive oxygen species (ROS), some oxidative DNA damage, cell membrane oxidation, and can result in immunosuppression. UVA indirectly causes oxidative DNA damage through the generation of ROS. The oxidation of guanine bases to 8-hydroxy-2'deoxyguanine (8-OH-dG) is primarily associat‐ ed with UVA irradiation. UVB can induce oxidative stress indirectly through the activa‐ tion of the inflammatory cells. Signature mutagenic DNA lesions caused by UVB consistently found in skin cancers are cyclobutane pryimidine dimers (CPD), pyrimidine- (6-4)-pyrimidine photoproducts, and C → T transitions [6, 7, 11-16]. Signature UVB mutations, CPDs and G:C → A:T transitions, have been found to localize in the superfi‐ cial epithelial layers of human SCC samples, while signature UVA mutations, 8-OH-dG and A:T → C:G transversions, localized in the basal layers [15]. This distribution of DNA lesions is consistent with knowledge that UVA penetration into the skin is deeper than UVB penetration. Signature gene mutations found in skin cancers are those of tumor protein 53 (p53) tumor suppressor gene and proto-oncogene B-raf. Mutations to p53 are particularly detrimental because p53 plays a central role in pausing the cell cycle to allow time for DNA repair [2, 13]. UVR exposure can induce signal transduction pathways, such as mitogenactivated protein kinase (MAPK) and activation of transcription factor AP-1 that regulate cell growth, differentiation, apoptosis, and production of pro-inflammatory cytokines [17].

Inappropriate cell proliferation and survival contributes to carcinogenesis. Severely damaged DNA that cannot be repaired triggers skin cells to undergo apoptosis. Cells that survive the

**2. Photocarcinogenesis**

212 Highlights in Skin Cancer

UV exposure causes immunosuppression that promotes the development of skin cancer because the immune system is less likely to detect and eliminate cancer cells. UVA and UVB separately can suppress cutaneous immune responses in humans, and the magnitude of immunosuppression is greater when they are combined [20]. UVR induces physical alterations to cell surface proteins in the epidermis. These structural changes create neoantigens that would be attacked by the immune system. It is believed that the human adaptive immune system has evolved such that recognition of antigens is suppressed by UVR, thus reducing the risk of auto-sensitization. Langerhans cells, the antigen presenting cells of the skin, migrate out of the epidermis to local lymph nodes for several days after UV exposure [18]. The Langerhans cells activate T helper type 2 cells, which suppress immune reactions by releasing immunosuppressive cytokines [13, 21]. The downside to this mechanism is that cancer detection capabilities are suppressed in addition to autoimmune reactions [18].

UVR is considered to be a complete carcinogen since it can induce tumor formation by itself, and both UVA and UVB contribute to skin carcinogenesis. Since UVB is a more potent and direct inducer of DNA damage than UVA, it is thought to play more of a role in the initiation stage of tumorigenesis while the effects of UVA are thought to promote the development of the tumor [7]. UVR can be coupled with other chemical carcinogens to promote tumor development. The combination of solar UV and sodium arsenite causes SCC in mice, but sodium arsenite alone cannot cause SCC. This is an example of how UVR can act as a cocarcinogen [22].
