The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E 2 (PGE 2 ) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE 2 synthesis was enhanced. Inhibition of PGE 2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin downregulation. In contrast, addition of PGE 2 or the EP2 receptor agonist butaprost to PMK produced a dose-and timedependent decrease in E-cadherin. We also show that UV irradiation, via the PGE 2 -EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating Ecadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE 2 -EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. [Cancer Res 2007;67(16):7654-64]
Inhibition or deletion of cyclooxygenase (COX)-2 has been demonstrated to protect against squamous cell cancer in many studies. Although much effort has focused on COX-2 inhibition, recent work indicates that COX-1 deletion may be nearly as protective. In this study, we used SKH-1 hairless mice in which COX-1 was selectively deleted to examine the role of COX-1 in photocarcinogenesis. After UV exposure, 40 -60% less prostaglandin E 2 was detected in COX-1 ؊/؊ animals compared with wild-type (WT) controls. A 4-fold induction of keratinocyte apoptosis was observed in knockouts relative to WT animals, as documented by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and caspase-3 staining. Proliferation was not significantly different in COX-1 ؉/؉ , COX-1 ؉/؊ , and COX-1 ؊/؊ animals. When susceptibility to UVinduced tumor formation was studied, tumor number, average tumor size, and time of tumor onset in COX-1 ؊/؊ animals were identical to WT controls. Thus, enhanced apoptosis did not alter UV-induced skin carcinogenesis, suggesting other effects are key to nonsteroidal anti-inflammatory drug chemoprevention. These results contrast sharply with data obtained using the classic 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate cancer model in which a prominent protective effect of COX-1 ؊/؊ is present. The lack of protection observed here confirms cancer mechanisms are distinct in UV-and tumor promotorinduced cancer models and indicates that chemoprevention strategies must specifically address cancer causes to be effective.
Aldo-keto reductase 1C3 (AKR1C3) has been shown to mediate the metabolism of sex hormones and prostaglandin D2 (PGD2), a lipid mediator that promotes skin inflammation in atopic dermatitis (AD). Since both play a role in skin function and pathology, we first sought to investigate the expression pattern of AKR1C3 in normal human epidermis. Immunofluorescence revealed a strong expression of AKR1C3 in the differentiated suprabasal layers compared with the basal layer. Western blot and quantitative PCR confirmed that AKR1C3 expression was also upregulated in differentiation-induced primary human keratinocytes (PHK). To investigate the functional role of AKR1C3 during PHK differentiation, its expression and activity (measured as PGD2 reduction to 9α,11β-PGF2 by ELISA) were impaired by siRNA or 2′-hydroxyflavanone, respectively. Cytokeratin 10 (K10) and loricrin expression were then examined by western blot revealing altered expression of these differentiation markers. Finally, following an observation that the AD-associated mediator, PGD2 upregulated AKR1C3 expression in PHK, we used immunofluorescence to examine AKR1C3 expression in AD and psoriasis lesions. AKR1C3 was found to be upregulated in AD but not in psoriasis lesions compared with non-lesional skin. Our work demonstrates a function for AKR1C3 in differentiation-associated gene regulation and also suggests a role in supporting inflammation in AD.
A 670-nm LED red light source accelerates healing in skin of SKH-1 hairless mice after incisional injuries, but is not as effective for burn injuries. These data that suggest red light exposure may be helpful in postoperative wound repair.
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