Carcinogenesis, Vol. 20, No. 2, 185-191,
February 1999
© 1999 Oxford University Press
Coordinate regulation of cyclooxygenase-2 and TGF-ß1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors
1 Departments of Medicine,
2 Surgery,
5 Pathology and
6 Cell Biology, Vanderbilt University Medical Center,
7 Veterans Affairs Medical Center, Nashville, TN 37232,
3 Medical College of Ohio, Toledo, OH 43614 and
4 National Cancer Institute, Bethesda, MD 20892, USA
Evidence is accumulating which indicates that cyclooxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)-induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-ß1 staining pattern in these human and rat tumors was similar to that observed for COX-2. The role of TGF-ß in RER adenocarcinomas is complex because of the increased mutation rate of TGF-ß type II receptors. Northern analysis showed abundant TGF-ß1 mRNA in AOM-induced tumors, but not in paired mucosa. TGF-ß1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6). Chronic TGF-ß1 treatment caused a TGF-ß-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1). TGF-ß1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence.
Abbreviations: AOM, azoxymethane; COX, cyclooxygenase; HNPCC, non-polyposis colorectal cancer; NSAID, non-steroidal anti-inflammatory drug; PBS, phosphate-buffered saline; RER, replication error-positive; TGF-ß, transforming growth factor ß.
8 To whom correspondence should be addressed at: Department of Medicine/GI, MCN C-2104, Vanderbilt University Medical Center, Nashville, TN 27232-2279, USA Email: duboisrn{at}ctrvax.vanderbilt.edu
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