Transformation of intestinal epithelial cells by chronic TGF-beta 1 treatment results in downregulation of the type II TGF-beta receptor and induction of cyclooxygenase-2
Hm. Sheng et al., Transformation of intestinal epithelial cells by chronic TGF-beta 1 treatment results in downregulation of the type II TGF-beta receptor and induction of cyclooxygenase-2, ONCOGENE, 18(4), 1999, pp. 855-867
The precise role of TGF-P in colorectal carcinogenesis is not clear, The pu
rpose of this study was to determine the phenotypic alterations caused by c
hronic 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 t
reatment 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 cell
s, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in so
ft agarose, RIE-Tr cells demonstrated TGF-beta-dependent invasive potential
in an in vitro assay and were resistant to Matrigel and Na-butyrate-induce
d apoptosis, The RIE-Tr cells were also tumorigenic in nude mice. The trans
formed 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 increas
e in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the product
ion of prostacyclin, Most RIE-Tr subclones that expressed low levels of T b
eta RII and high levels of COX-2 were tumorigenic. Those subclones that exp
ress abundant T beta RII and low levels of COX-2 were not tumorigenic in nu
de mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in cultur
e and tumor growth in nude mice. The reduced expression of T beta RII, incr
eased expression of COX-2, and the ability to form colonies in Matrigel mer
e all reversible upon withdrawal of exogenous TGF-beta 1 for the RIE-Tr cel
ls.