Cyclooxygenase-2 Expression in Murine and Human Nonmelanoma Skin Cancers: Implications for Therapeutic Approaches¶

Abstract

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 UVBinduced 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 cy- ¶Posted on the website on 3 May 2002. tea polyphenols; IRB, institutional review board; MED, minimum erythema dose; MOM, mouse-on-mouse; NMSC, nonmelanoma skin cancers; NSAID, nonsteroidal anti-inflammatory drugs; OCT, optimum cutting temperature compound; PG, prostaglandin; PKC, protein kinase C; SCC, squamous cell carcinoma; TPA, 12-Otetradecanoyl 13-phorbol acetate.toplasmic 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 ؋ 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/cm 2 ) 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 UVBinduced skin cancer.

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

“…As reported previously (27,74), UV irradiation markedly up-regulated COX-2 within 24 h in diluent-treated control cells (Fig. 3b and Fig.…”

“…3b and Fig. S5), the time of maximal UV light-induced COX-2 protein expression reported by others in this cell type (27,74).…”

“…1b and Fig. S1f), the time of maximal UV light-induced COX-2 protein expression reported by others (27,63). After UV irradiation, maximal p53 induction and activation are reported to occur at ϳ2-24 h (depending on UV light dose) (64).…”

“…In relation to skin cancer, UVB irradiation increases both mRNA and protein levels of COX-2 in human keratinocytes (25). Recent studies have shown increased COX-2 expression in human skin in response to acute UVB exposure as well as increased COX-2 expression in human and murine tumors that were induced by chronic UVB exposure (26,27). Furthermore, specific inhibitors of Cox-2 such as celecoxib have been shown not only to decrease tumorigenesis and increase tumor latency in hairless mice models (28) but also to decrease tumor growth in hairless mice with pre-existing UVB-induced tumors (29).…”

Caffeine Promotes Ultraviolet B-induced Apoptosis in Human Keratinocytes without Complete DNA Repair

“…Second, cyclooxygenase-2 (COX-2), the rate-limiting enzyme in arachidonic acid metabolism leading to prostaglandin synthesis, is up-regulated in murine and human NMSC (28). Overexpression of COX-2 promotes UV-induced skin tumorigenesis in mice (29).…”