Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches.
Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose x 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer.
An
Kathy P
KP
Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Athar
Mohammad
M
Tang
Xiuwei
X
Katiyar
Santosh K
SK
Russo
Justin
J
Beech
J
J
Aszterbaum
Michelle
M
Kopelovich
Levy
L
Epstein
Ervin H
EH
Mukhtar
Hasan
H
Bickers
David R
DR
D000328:Adult; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012867:Skin / Q000201:enzymology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D014466:Ultraviolet Rays / Q000009:adverse effects
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases