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

Hongmiao Sheng, Jinyi Shao, Christine A. O'Mahony, Laura Lamps, Daniel Albo, Peter C. Isakson, David H. Berger, Raymond N. DuBois, R. Daniel Beauchamp

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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.

Original languageEnglish (US)
Pages (from-to)855-867
Number of pages13
JournalOncogene
Volume18
Issue number4
DOIs
StatePublished - Jan 28 1999

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Keywords

  • Carcinogenesis
  • Cyclooxygenase-2
  • Intestinal epithelial cells
  • Transforming growth factor β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Sheng, H., Shao, J., O'Mahony, C. A., Lamps, L., Albo, D., Isakson, P. C., Berger, D. H., DuBois, R. N., & Beauchamp, R. D. (1999). 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(4), 855-867. https://doi.org/10.1038/sj.onc.1202397