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Altered expression of the receptor and ligand in the TGF beta signaling pathway in diffusely infiltrating colon carcinoma.

A diffusely infiltrating colorectal carcinoma (DICC) is a distinct clinicopathological entity demonstrating invasive growth with extensive matrix production and associated with an extremely poor prognosis. The factors producing these peculiar features, however, remain to be determined. Here we investigated the receptor and ligand of the transforming growth factor (TGF) beta signaling pathway in 32 DICCs and 60 common type colorectal carcinomas (CCCs). Immunohistochemical analysis revealed that the expression of TGF beta 1 was markedly increased in DICC, especially of the schirrous type, compared to CCC, whereas the expression of the TGF beta type II receptor (RII) was significantly decreased in DICC compared to CCC. The molecular basis for the reduced expression of RII was further investigated in 15 cases of DICC with a diminished RII expression. Two somatic mutations were found: one was a missense mutation in the kinase domain (Cys533Tyr), and the other was a G to C transition at the putative Sp1 binding site in the core promoter region. The latter mutation reduced the promoter activity, which may be due to a reduced affinity of the mutant sequence to the putative transcriptional regulator, which was neither Sp1 nor Sp3. No methylated cytosine was found at any CpG sites in the promoter region. These results suggested the presence of unidentified mechanisms for the diminished expression of RII in DICC cases.