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

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Abstract
Alterations in the transforming growth factor‐β (TGF‐β) pathway are implicated in the pathogenesis of colorectal cancer. We hypothesize that alterations in the TGF‐β 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‐β type II receptor (TβR‐II) from normal colons and from tumors showed no AOM‐induced alterations. A significant decrease (1.5‐fold, P < 0.05) in TβR‐II mRNA levels, however, was found in A/J tumors with the RNase protection assay. Immunofluorescence of TβR‐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‐β, TGF‐β type I receptor (TβR‐I), and several downstream targets of TGF‐β signaling, including Smad7, c‐myc, and p15, was examined. Although no alterations in TGF‐β, TβR‐I, 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 TβR‐II and overexpression of c‐myc may render epithelial cells insensitive to TGF‐β‐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‐β signaling may be markedly attenuated during colon tumorigenesis.