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

Research output: Contribution to journalArticle

65 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Cyclooxygenase 2
Down-Regulation
Epithelial Cells
Nude Mice
Growth
Contact Inhibition
Butyrates
Cyclooxygenase 2 Inhibitors
Epoprostenol
Sepharose
Carcinogenesis
Proteins
Apoptosis
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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

In: Oncogene, Vol. 18, No. 4, 28.01.1999, p. 855-867.

Research output: Contribution to journalArticle

Sheng, Hongmiao ; Shao, Jinyi ; O'Mahony, Christine A. ; Lamps, Laura ; Albo, Daniel ; Isakson, Peter C. ; Berger, David H. ; DuBois, Raymond N. ; Beauchamp, R. Daniel. / 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. In: Oncogene. 1999 ; Vol. 18, No. 4. pp. 855-867.
@article{23db37655d2942c1a0bfc5ed759a21c0,
title = "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",
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.",
keywords = "Carcinogenesis, Cyclooxygenase-2, Intestinal epithelial cells, Transforming growth factor β",
author = "Hongmiao Sheng and Jinyi Shao and O'Mahony, {Christine A.} and Laura Lamps and Daniel Albo and Isakson, {Peter C.} and Berger, {David H.} and DuBois, {Raymond N.} and Beauchamp, {R. Daniel}",
year = "1999",
month = "1",
day = "28",
doi = "10.1038/sj.onc.1202397",
language = "English (US)",
volume = "18",
pages = "855--867",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - 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

AU - Sheng, Hongmiao

AU - Shao, Jinyi

AU - O'Mahony, Christine A.

AU - Lamps, Laura

AU - Albo, Daniel

AU - Isakson, Peter C.

AU - Berger, David H.

AU - DuBois, Raymond N.

AU - Beauchamp, R. Daniel

PY - 1999/1/28

Y1 - 1999/1/28

N2 - 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.

AB - 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.

KW - Carcinogenesis

KW - Cyclooxygenase-2

KW - Intestinal epithelial cells

KW - Transforming growth factor β

UR - http://www.scopus.com/inward/record.url?scp=0033611576&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033611576&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1202397

DO - 10.1038/sj.onc.1202397

M3 - Article

C2 - 10023661

AN - SCOPUS:0033611576

VL - 18

SP - 855

EP - 867

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 4

ER -