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

被引:56
作者
Sheng, HM
Shao, JY
O'Mahony, CA
Lamps, L
Albo, D
Isakson, PC
Berger, DH
DuBois, RN
Beauchamp, RD
机构
[1] Vanderbilt Univ, Med Ctr N, Vanderbilt Canc Ctr, Dept Surg, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Vanderbilt Canc Ctr, Dept Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Med Ctr, Vanderbilt Canc Ctr, Dept Cell Biol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Vanderbilt Canc Ctr, Dept Pathol, Nashville, TN 37232 USA
[5] Vet Affairs Med Ctr, Nashville, TN 37232 USA
[6] Searle Res & Dev, Dept Inflammatory Dis Res, St Louis, MO 63198 USA
[7] Allegheny Univ Hlth Sci, Dept Surg, Philadelphia, PA 19102 USA
关键词
intestinal epithelial cells; transforming growth factor beta; cyclooxygenase-2; carcinogenesis;
D O I
10.1038/sj.onc.1202397
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The precise role of TGF-P in colorectal carcinogenesis is not clear, The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-beta in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by >75% following TGF-beta 1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-beta 1, These 'TGF-beta-resistant' cells (RIE-Tr) were continuously exposed to TGF-beta 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-beta-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-P receptor (T beta RII) 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 T beta RII and high levels of COX-2 were tumorigenic. Those subclones that express abundant T beta RII 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 T beta RII, increased expression of COX-2, and the ability to form colonies in Matrigel mere all reversible upon withdrawal of exogenous TGF-beta 1 for the RIE-Tr cells.
引用
收藏
页码:855 / 867
页数:13
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