UP-REGULATION OF CYCLOOXYGENASE-2 GENE-EXPRESSION IN HUMAN COLORECTALADENOMAS AND ADENOCARCINOMAS

Background/Aims: Several clinical, epidemiological, and animal studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may alter the incidence of colorectal cancer. A likely target for NSAIDs is cyc looxygenase, a key enzyme in arachidonic acid metabolism. Two isoforms of this enzyme have been identified; cyclooxygenase (COX) 1 and COX-2 . The present study was undertaken to determine if there is differenti al expression of these isoforms in colorectal neoplasia, and, if so, a t what stage in malignant transformation this occurs. Methods: COX-1 a nd COX-2 messenger RNA (mRNA) levels were determined by Northern blot analysis of poly(A)(+) RNA isolated from human colorectal cancers, ade nomas, and accompanying normal mucosa. Results: There was a marked inc rease in COX-2 mRNA levels in 12 of 14 carcinomas (86%) compared with paired normal mucosa. In contrast, there was equivalent intensity of t he COX-1 mRNA transcript between the normal mucosa and cancer in all 1 4 cases. In six pairs of colorectal adenomas and normal mucosa, three showed up-regulation of COX-2 in the adenoma compared with the normal mucosa. Because COX-2 expression is low to undetectable in normal colo rectal mucosa, 14 unpaired adenomas were examined for COX-2 expression ; a clearly detectable transcript was identified in six (43%). Conclus ions: COX-2, but not COX-1, gene expression is markedly elevated in mo st human colorectal cancers compared with accompanying normal mucosa. Furthermore, COX-2 expression seems to be increased in a subset of ade nomas. COX-2 may provide an attractive therapeutic target in colorecta l neoplasia.