Cyclooxygenase‐2 expression is critical for chronic UV‐induced murine skin carcinogenesis

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Abstract
While it has been established that both the constitutive and inducible forms of cyclooxygenase (COX‐1 and COX‐2, respectively) play important roles in chemical initiation‐promotion protocols with phorbol ester tumor promoters, the contribution of these two enzymes to ultraviolet (UV) light‐induced skin tumors has not been fully assessed. To better understand the contribution of COX‐1 and COX‐2 to UV carcinogenesis, we transferred the null allele for each isoform onto the SKH‐1 hairless strain of mouse. Due to low viability on this background with complete knockout of COX‐2, heterozygous mice were used in UV carcinogenesis experiments. While the lack of one allele of COX‐1 had no effect on tumor outcome, the lack of one allele of COX‐2 resulted in a 50–65% reduction in tumor multiplicity and a marked decrease in tumor size. Additionally, transgenic SKH‐1 mice that overexpress COX‐2 under the control of a keratin 14 promoter developed 70% more tumors than wild‐type SKH‐1 mice. The lack of one allele of either COX‐1 or COX‐2 reduced prostaglandin (PG) E2 levels in response to a single UV treatment. The proliferative response to UV was significantly reduced in COX‐2, but not COX‐1, heterozygous mice. UV‐induced apoptosis, however, was greater in COX‐2 heterozygous mice. Collectively, these results clearly establish the requirement for COX‐2 in the development of skin tumors.