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Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

Oncogene volume 18, pages 855–867 (1999)Cite this article

Abstract

The precise role of TGF-β in colorectal carcinogenesis is not clear. The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-β in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by >75% following TGF-β1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-β1. These `TGF-β-resistant' cells (RIE-Tr) were continuously exposed to TGF-β for >50 days. Unlike the parental RIE cells, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in soft agarose. RIE-Tr cells demonstrated TGF-β-dependent invasive potential in an in vitro assay and were resistant to Matrigel and Na-butyrate-induced apoptosis. The RIE-Tr cells were also tumorigenic in nude mice. The transformed phenotype of RIE-Tr cells was associated with a 95% decrease in the level of the type II TGF-β receptor (TβRII) protein, a 40-fold increase in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the production of prostacyclin. Most RIE-Tr subclones that expressed low levels of TβRII and high levels of COX-2 were tumorigenic. Those subclones that express abundant TβRII and low levels of COX-2 were not tumorigenic in nude mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in culture and tumor growth in nude mice. The reduced expression of TβRII, increased expression of COX-2, and the ability to form colonies in Matrigel were all reversible upon withdrawal of exogenous TGF-β1 for the RIE-Tr cells.

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Abbreviations

TGF-β:

transforming growth factor β

TβRII:

type II TGF-β receptor

COX-2:

cyclooxygenase-2

RIE-1:

rat intestinal epithelial cell

SC-58125:

{1-[(4-methylsulfonyl)phenyl]-3-trifluoromethyl-5-[(4-fluoro)phenyl]pyrazole}

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Acknowledgements

This work was supported in part by the United State Public Health Services Grants CA68485 (Vanderbilt Cancer Center), DK-52334 and CA-69457 (RDB); and DK-47297 and ES-00267 (RND). American Cancer Society Clinical Career Development Award 96-09 (DHB). We thank Dr Jason D Morrow for quantitation of eicosanoids. Mary E Aakre for performing soft agarose assay.

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Authors and Affiliations

  1. Department of Surgery, The Vanderbilt Cancer Center, Vanderbilt University Medical Center, and VA Medical Center, Nashville, 37232, Tennessee, USA

    Hongmiao Sheng, Jinyi Shao & R Daniel Beauchamp

  2. Department of Medicine, The Vanderbilt Cancer Center, Vanderbilt University Medical Center, and VA Medical Center, Nashville, 37232, Tennessee, USA

    Jinyi Shao & Raymond N DuBois

  3. Department of Cell Biology, The Vanderbilt Cancer Center, Vanderbilt University Medical Center, and VA Medical Center, Nashville, 37232, Tennessee, USA

    Raymond N DuBois & R Daniel Beauchamp

  4. Department of Pathology, The Vanderbilt Cancer Center, Vanderbilt University Medical Center, and VA Medical Center, Nashville, 37232, Tennessee, USA

    Laura Lamps

  5. Department of Inflammatory Disease Research, Searle R & D, St Louis, Missouri

    Peter C Isakson

  6. 63198, USA

    Peter C Isakson

  7. Department of Surgery, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania, USA

    Christine A O'Mahony, Daniel Albo & David H Berger

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Sheng, H., Shao, J., O'Mahony, C. et al. Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2. Oncogene 18, 855–867 (1999). https://doi.org/10.1038/sj.onc.1202397

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