UVB radiation-induced β-catenin signaling is enhanced by COX-2 expression in keratinocytes.

UVB radiation is the major carcinogen responsible for skin carcinogenesis, thus elucidation of the molecular pathways altered in skin in response to UVB would reveal novel targets for therapeutic intervention. It is well established that UVB leads to upregulation of cyclooxygenase 2 (COX-2) in the skin which contributes to skin carcinogenesis. Overexpression of COX-2 has been shown to promote colon cancer cell growth through beta-catenin signaling, however, little is known about the connection between UVB, COX-2, and beta-catenin in the skin. In the present study, we have identified a novel pathway in which UVB induces beta-catenin signaling in keratinocytes, which is modulated by COX-2 expression. Exposure of the mouse 308 keratinocyte cell line (308 cells) and primary normal human epidermal keratinocytes (NHEKs) to UVB resulted in increased protein levels of both N-terminally unphosphorylated and total beta-catenin. In addition, we found that UVB-enhanced beta-catenin-dependent TOPflash reporter activity and expression of a downstream beta-catenin target gene. We demonstrated that UVB-induced beta-catenin signaling is modulated by COX-2, as treatment of keratinocytes with the specific COX-2 inhibitor NS398 blocked UVB induction of beta-catenin. Additionally, beta-catenin target gene expression was reduced in UVB-treated COX-2 knockout (KO) MEFs compared to wild-type (WT) MEFs. Furthermore, epidermis from UVB-exposed SKH-1 mice exhibited increased N-terminally unphosphorylated and total beta-catenin protein levels and increased staining for total beta-catenin, and both responses were reduced in COX-2 heterozygous mice. Taken together, these results suggest a novel pathway in which UVB induces beta-catenin signaling in keratinocytes which is enhanced by COX-2 expression. (c) 2011 Wiley Periodicals, Inc.