Genetic alterations and reduced expression of the DPC4 molucule in colorectal cancers and relationship to liver metastasis

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The isolated Smad genes constitute an evolutionarily conserved gene family. The smads proteins have been shown to be essential intracellular mediators of the growth inhibitory effects of TGF-β. These proteins are phosphorylated by the respective transmembrane serine threonine kinase receptor, and translocates to nucleus, where it acts as a regulator of transcription. To investigate the role of DPC4 gene and Madr2 genes in advanced colorectal cancers, we analyzed 29 colorecrtal specimens for alterations in DPC4 gene and Madr2 genes. An alterstion of the DPC4 gene sequence was identified in 6 (20.7%) of 29 colorectal cancers, and the distinct Madr2 gene mobility shifts were present in 3 (10.3%) cancers.We established a monoclonal antibody that specifically reacts with DPC4 products, using a fusion protein of DPC4 products for immunization. Immunoblots of samples from 64 paires of colorectal cancers and adjacent normal tissues revealed that all normal colorectal tissues significantly expressed the DPC4 protein, whereas colorectal cancer tissues showed poor expression. The ratio of DPC4 protein (cancer/normal) in colorectal cancer patients with liver metastasis expressed significantly low levels than those without. There were no significant differences between the ratio of DPC4 protein and the other clinicopathological findings.Our findings suggest that TGF-β-Smads pathway may be important determinants for tumorigenesis and liver metastasis in colorectal cancers