Ultraviolet radiation-induced inflammation activates β-catenin signaling in mouse skin and skin tumors.
UVB-induced inflammation, in particular the overexpression of cyclooxygenase-2 (COX-2) and prostaglandin (PG) E2, has been implicated in photocarcinogenesis. UVB-induced COX-2 has been associated with β-catenin signaling in keratinocytes. However, a definitive role for COX-2 in the activation of β-catenin signaling as well as its role in UVB-induced skin tumors has not been established. We report that exposure of the skin to UVB resulted in a time- and dose-dependent activation of β-catenin in C3H/HeN mice. This response was COX-2-dependent as UVB-exposed COX-2-deficient mice exhibited significantly lower levels of UVB-induced activation of β-catenin. Moreover, treatment of mice with indomethacin, a COX-2 inhibitor, and an EP2 antagonist inhibited UVB-induced β-catenin signaling. Exposure of SKH-1 hairless mice to UVB radiation (180 mJ/cm2) 3 times a week for 24 weeks resulted in activation of β-catenin signaling in UVB-irradiated skin as well as UVB-induced skin tumors. Concomitantly, the levels of CK1α and GSK-3β, which are responsible for β-catenin signaling, were reduced while the levels of c-Myc and cyclin D1, which are downstream targets of β-catenin, were increased. To further verify the role of UVB-induced inflammation in activation of β-catenin signaling, a high-fat-diet model was used. Administration of high-fat diet exacerbated UVB-induced inflammation. Administration of the high-fat diet enhanced β-catenin signaling and the levels of its downstream targets (c-Myc, cyclin D1, cyclin D2, MMP-2 and MMP-9) in UVB-exposed skin and skin tumors in SKH-1 mice. These data suggest that UV-induced COX-2/PGE2 stimulates β-catenin signaling, and that β-catenin activation may contribute to skin carcinogenesis.
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Ram
R
Prasad
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Santosh K
SK
Katiyar
D000818:Animals; D047389:Casein Kinase I / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D056742:Cyclin D2 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D059305:Diet, High-Fat; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D011458:Prostaglandins E / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000096:biosynthesis; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000096:biosynthesis; D015398:Signal Transduction; D012867:Skin / Q000276:immunology* / Q000473:pathology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects; D051176:beta Catenin / Q000096:biosynthesis / Q000276:immunology*
C530105:Ccnd1 protein, mouse; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D052246:Cyclooxygenase 2 Inhibitors; C489428:Myc protein, mouse; D011458:Prostaglandins E; D016271:Proto-Oncogene Proteins c-myc; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051176:beta Catenin; D019938:Cyclin D1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D047389:Casein Kinase I; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007213:Indomethacin