[Apoptosis, UV-radiation, precancerosis and skin tumors]

Abstract

Apoptosis plays an important role in regulating skin development and homeostasis, as well as carcinogenesis. Apoptosis balances epidermal proliferation to maintain epidermal thickness and may eliminate mutated, premalignant cells. Skin carcinomas are the most common cancers in Western population. The risk is closely related to UV exposure and the relation between exposure to UV radiation and development of skin cancer has been well established. Apoptosis and carcinogenesis in skin can be triggered by UV irradiation, and tumor suppressor gene p53 plays the most important role in these two processes. The p53 gene is involved in the cell cycle arrest and activation of apoptosis. It has been shown that p53 could protect skin cells from DNA-damage due to UVB exposure. UV-induced DNA damage activates the mechanisms for removal of DNA damage, delay in cell cycle progression, DNA repair, or apoptosis by transcriptional activation of p-53 related genes, such as p21 and bax. Several studies have shown that UVB also induces mutations in p53 gene.The induced mutations are unique (C toT and CC to TT transition) for UVB radiation and are not commonly induced by other carcinogens. Mutations in the p53 gene have been detected in 50% of all human cancers and in the majority of skin carcinomas. A high frequency of p53 mutation was reported in pre-malignant actinic keratosis lesions that is considered to be pre-squamous cell carcinoma, and in Bowen's disease that is considered to be in situ squamous cell carcinoma (SCC) of the skin. The majority of these mutations were characteristic UVB mutations and these findings suggested that p53 mutations might be involved in the malignant conversion of precancerous lesions to SCC. Several studies have demonstrated the continued and discontinued regimens of chronic UVB treatment to ultimately result in skin tumor development with 100% incidence, although the kinetics of tumor occurrence is delayed in the latter. Thus, these studies suggest that skin cancer development can be delayed but not stopped with further avoidance of UV exposure. More recent studies have shown that besides UVB, UVA component of solar irradiation could also be an important carcinogen but in the stem cell compartment of the skin. This knowledge will lead to development of new apoptosis-based therapeutics; several have recently been tested in SCC. It can be expected that new apoptosis-based drugs are to be introduced soon to the daily medical practice; however, prevention of excessive UVB exposure remains the main curative factor against skin cancer.