Induction of cyclooxygenase-2 and invasiveness by transforming growth factor-beta(1) in immortalized mouse colonocytes expressing oncogenic Ras.
Cyclooxygenase-2 (COX-2) expression appears to be important in colorectal carcinogenesis. Elevated COX-2 expression and activity have been observed in several different transformed cell types. Prior studies implicating involvement of the Ras oncogene and growth factors on COX-2 expression were largely derived from rat small intestinal cell lines. We have investigated whether mouse colonocyte COX-2 levels are regulated by oncogenic Ras or transforming growth factor-beta(1) (TGF-beta(1)), and whether these factors also serve to regulate cellular invasiveness. Young adult mouse colonocyte cells are colonocytes derived from the "Immortomouse" and immortalized by the SV40 large T antigen. Young adult mouse colonocyte Ras cells were derived by transfection of young adult mouse colonocyte cells with oncogenic Ha-Ras and are known to be tumorigenic. We found that the induction of COX-2 and eicosanoid release were augmented in the presence of activated Ras and that TGF-beta(1) caused a further increase in COX-2 in the Ras-transformed mouse colonocytes. Increased COX-2 expression was correlated with increased release of prostaglandins E(2) and I(2). Activated Ras and TGF-beta increased the invasiveness of the young adult mouse colonocyte cells, but treatment with a COX-2 inhibitor did not inhibit invasiveness. Thus we found that transforming growth factor-beta collaborates to increase COX-2 expression, protaglandin release, and invasiveness in mouse colonocytes, but the increased COX-2 activity does not appear to contribute to the invasive response.
Roman
Christopher D
CD
Department of Surgery, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-2730, USA.
Morrow
Jason
J
Whitehead
Robert
R
Beauchamp
R Daniel
RD
D000818:Animals; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2; D015972:Gene Expression Regulation, Neoplastic; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1
D007527:Isoenzymes; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015689:Oncogene Protein p21(ras)