Aberrant transforming growth factor-β signaling in azoxymethane-induced mouse colon tumors

被引:29
作者
Guda, K
Giardina, C
Nambiar, P
Cui, HY
Rosenberg, DW
机构
[1] Univ Connecticut, Ctr Hlth, Ctr Mol Med, Farmington, CT 06030 USA
[2] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA
关键词
transforming growth factor-beta; transforming growth factor-beta type II receptor; c-myc; p15; mouse colon; tumorigenesis;
D O I
10.1002/mc.1055
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
Alterations in the transforming growth factor-beta (TGF-beta) pathway are implicated in the pathogenesis of colorectal cancer. We hypothesize that alterations in the TGF-beta pathway contribute to differential sensitivity of mice to the colon carcinogen azoxymethane (AOM). A/J (sensitive) and AKR/J (resistant) mice were injected intraperitoneally with AOM (10 mg/kg of body weight once a week for 6 wk). Twenty-four weeks after AOM exposure, mutational analysis of TGF-beta type II receptor (T betaR-II) from normal colons and from tumors showed no AOM-induced alterations. A significant decrease (1.5-fold, P<0.05) in T<beta>R-II mRNA levels, however, was found in A/J tumors with the RNase protection assay. Immunofluorescence of T betaR-II showed marked loss of staining in A/J tumors. The RNase protection assay and sequence analysis of the downstream signaling molecule Smad3 revealed no carcinogen-induced alterations in either strain. To gain further insight into the functionality of the pathway, expression of TGF-beta, TGF-beta type I receptor (T betaR-1), and several downstream targets of TGF-beta signaling, including Smad7, c-myc, and p15, was examined. Although no alterations in TGF-beta, T betaR-1, or Smad7 were found in tumors, a significant increase in c-myc expression (2.5-fold, P<0.05) and a significant decrease in p15 expression (4.5-fold, P<0.05) were noted. Concomitant repression of T betaR-II and overexpression of c-myc may render epithelial cells insensitive to TGF-beta -mediated growth arrest, a possibility that also is suggested by this model. The significant decrease in p15 expression in tumors provides additional evidence that TGF-beta signaling may be markedly attenuated during colon tumorigenesis. (C) 2001 Wiley-Liss, Inc.
引用
收藏
页码:204 / 213
页数:10
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