Abstract
Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.
Highlights
The UVB part of solar UV radiation is directly absorbed by DNA
UV-light-induced DNA damage typically leads to the formation of two major DNA lesions: cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine photoproducts (6-4 PPs).[5,6,7]
CPDs form the majority of the DNA mutations which occur as a result of UV-light-induced DNA damage.[8,9]
Summary
The UVB part of solar UV radiation is directly absorbed by DNA. UV-light-induced DNA damage typically leads to the formation of two major DNA lesions: cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine photoproducts (6-4 PPs).[5,6,7] CPDs form the majority of the DNA mutations which occur as a result of UV-light-induced DNA damage.[8,9]. To protect from skin carcinogenesis keratinocytes exhibit a preventive mechanism called DNA damage response (DDR), which can have different physiological outcomes such as cell cycle arrest, activation of the DNA repair machinery, apoptosis or senescence; depending upon the level of DNA damage and the ability of keratinocytes to repair the damage.[13,14] The ATRChk[1] pathway is primarily activated in UV-light-induced DDR.[15] Cells with severe DNA damage are partially eliminated by apoptosis. UV-light-induced keratinocyte apoptosis results in the formation of sunburn cells in the epidermis.[16,17] Sunburn cells are apoptotic keratinocytes possessing severely and irreversibly damaged DNA as a result of UV radiation These sunburn cells are destined to death and exhibit characteristic morphological features: a dark pyknotic nucleus and scanty, eosinophilic cytoplasm.[16,17] UV-light-induced keratinocyte apoptosis is thought to involve the intrinsic and the extrinsic pro apoptotic signaling pathways, depending on the activation of caspases[9] and -8, respectively. In several experimental settings and in different cell types, Rac[1] has been shown to have an important role in either pro-apoptotic or anti-apoptotic mechanisms.[21,22,23,24] Inhibition or deletion of Rac[1] in HeLa cells and pancreatic cancer cells attenuated the DDR upon UV-irradiation or ionizing radiation, whereas the DDR was enhanced in a hepatic tumor model.[25,26,27]
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