Recent findings demonstrate that the TGF-beta receptor complex is a new addition to the family of human tumor suppressor genes and that inactivation of these receptors is important in multiple human malignancies. Because human cancer cells frequently demonstrate resistance to the normal growth inhibitory effects of TGF-beta, it has been proposed that the development of such TGF-beta resistance represents a significant step during carcinogenesis. We have demonstrated a strong correlation between the resistance to TGF-beta and gross structural abnormalities in the TGF-beta type II receptor (RII) gene in human gastric cancers. In addition, we have reported that mutation and transcriptional repression of the TGF-beta RII receptor is correlated with the loss of responsiveness of tumor cell lines to TGF-beta. Transcriptional repression of the TGF-beta RII receptor gene is one of several mechanisms leading to TGF-beta resistance. Our research has suggested that a pharmacologic augmentation of TGF-beta signaling pathways in human cancers, such as gastric cancer, may be a potential therapeutic strategy. Previously, we showed that MS-275, a synthetic inhibitor of histone deacetylase (HDAC), specifically induces the expression of the TGF-beta RII receptor gene and restores the TGF-beta signaling in human breast cancer cell lines. In our recent study, we demonstrated that treatment with the HDAC inhibitor induces TGF-beta RII receptor promoter activity by the recruitment of PCAF protein to the NF-Y complex interacting with the inverted CCAAT box in the TGF-beta RII receptor promoter. To study the role of the TGF-beta signaling pathway during carcinogenesis in vivo, transgenic mice expressing a dominant-negative mutant form of the TGF-beta RII (dnRII) targeted to the colon using the ITF promoter, and to the stomach and using pS2 promoter, have been generated. Mice lacking in TGF-beta signaling, specifically in the stomach, showed a significantly higher proliferation cell nuclear antigen-labeling index and developed a gastric adenocarcinoma when infected with H.pylori. ITF-dnRII transgenic mice showed an increased susceptibility to inflammatory diseases and significantly higher incidences of aberrant crypt foci and colon cancers than wild-type littermates when mice were treated with azoxymethane. These results suggest that maintaining normal TGF-beta signaling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.
Showing the most recent 10 out of 31 publications
