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

Surgery. 1999 Aug;126(2):364-70.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclooxygenase 2
  • Intestinal Neoplasms / enzymology
  • Intestinal Neoplasms / etiology
  • Intestinal Neoplasms / pathology*
  • Isoenzymes / physiology*
  • Neoplasm Invasiveness
  • Prostaglandin-Endoperoxide Synthases / physiology*
  • Rats
  • Transforming Growth Factor beta / pharmacology*
  • Urokinase-Type Plasminogen Activator / biosynthesis


  • Isoenzymes
  • Transforming Growth Factor beta
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Urokinase-Type Plasminogen Activator