Cyclooxygenase-2 expression is critical for chronic UV-induced murine skin carcinogenesis.
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.
Fischer
Susan M
SM
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Pavone
Amy
A
Mikulec
Carol
C
Langenbach
Robert
R
Rundhaug
Joyce E
JE
D000818:Animals; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D015971:Gene Expression Regulation, Enzymologic; D015994:Incidence; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000209:etiology* / Q000517:prevention & control; D014466:Ultraviolet Rays
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2