Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas 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 cyclooxygenase, 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 differential expression of these isoforms in colorectal neoplasia, and, if so, at what stage in malignant transformation this occurs.

METHODS

COX-1 and COX-2 messenger RNA (mRNA) levels were determined by Northern blot analysis of poly(A)+ RNA isolated from human colorectal cancers, adenomas, and accompanying normal mucosa.

RESULTS

There was a marked increase in COX-2 mRNA levels in 12 of 14 carcinomas (86%) compared with paired normal mucosa. In contrast, there was equivalent intensity of the COX-1 mRNA transcript between the normal mucosa and cancer in all 14 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 colorectal mucosa, 14 unpaired adenomas were examined for COX-2 expression; a clearly detectable transcript was identified in six (43%).

CONCLUSIONS

COX-2, but not COX-1, gene expression is markedly elevated in most human colorectal cancers compared with accompanying normal mucosa. Furthermore, COX-2 expression seems to be increased in a subset of adenomas. COX-2 may provide an attractive therapeutic target in colorectal neoplasia.