Cyclooxygenase-2 alters transforming growth factor-beta 1 response during intestinal tumorigenesis.

O'Mahony CA, Beauchamp RD, Albo D, Tsujii M, Sheng HM, Shao J, Dubois RN, Berger DH
Surgery. 1999 126 (2): 364-70

PMID: 10455907

BACKGROUND - Recent investigation suggests that cyclooxygenase-2 plays an important role in colorectal carcinogenesis. Transforming growth factor-beta1 (TGF-beta 1) is one of the most potent stimulators of cyclooxygenase-2 expression. A key step in intestinal tumorigenesis involves alteration of the normal cellular response to TGF-beta 1. We have hypothesized that overexpression of cyclooxygenase-2 alters intestinal epithelial response to TGF-beta 1.

METHODS - RIE-1 cells were stably transfected with rat cyclooxygenase-2 complementary DNA in either the sense (RIE-S) or antisense (RIE-AS) orientation. Tumor cell invasion was assessed with a modified Boyden collagen type I invasion assay in the presence of TGF-beta 1, antibody to urokinase plasminogen activator (uPA), or the selective cyclooxygenase-2 inhibitor SC-58125. Expression of uPA, uPA receptor, and plasminogen activator inhibitor-1 were determined by Western blot and enzyme-linked immunosorbent assay.

RESULTS - RIE-1 and RIE-AS did not invade although RIE-S cells were minimally invasive at baseline. TGF-beta 1 had no effect on RIE-1 or RIE-AS invasion; however, TGF-beta 1 significantly upregulated RIE-S cell invasion. All 3 RIE cell lines produce minimal uPA under basal conditions. TGF-beta 1 upregulated uPA production only in the RIE-S cells. Both antibody to uPA and SC-58125 reversed TGF-beta-mediated RIE-S cell invasion. SC-58125 inhibited TGF-beta-mediated RIE-S uPA production.

CONCLUSIONS - These results demonstrate that overexpression of cyclooxygenase-2 alters intestinal epithelial response to TGF-beta 1, which may be a mechanism by which cyclooxygenase-2 promotes colon carcinogenesis.

MeSH Terms (10)

Animals Cells, Cultured Cyclooxygenase 2 Intestinal Neoplasms Isoenzymes Neoplasm Invasiveness Prostaglandin-Endoperoxide Synthases Rats Transforming Growth Factor beta Urokinase-Type Plasminogen Activator

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