Expression of transforming growth factor β (TGF-β) receptor type II (RII) is required for the growth-inhibitory effects of TGF-β on proliferating epithelial cells. TGF-β RII mutations have been identified in a broad spectrum of human epithelial malignancies, including colon and gastric cancers, and are highly correlated with development of TGF-β resistance in cell lines derived from these tumors. In this study, the role of TGF-β RII in regulating the tumorigenic potential of the SNU-638 human gastric cancer cell line was investigated by infecting these cells with retroviral construct (MFG) expressing TGF-β RII. The SNU-638 cell line displays the DNA replication error phenotype and encodes a truncated, inactive TGF-β RII protein. Infection of these cells with retroviral constructs expressing wild-type TGF-β RII led to significant increases in TGF-β RII mRNA and protein expression. These cells responded to exogenous TGF-β with reduced proliferation compared to that of control cells infected with retroviral vector expressing chloramphenicol acetyltransferase. Addition of TGF-β-neutralizing antibodies led to increased proliferation of wild-type TGF-β RII-expressing SNU-638 cells but had no effect on control cells. The latter finding suggests that TGF-β acts in an autocrine fashion to inhibit cell proliferation in SNU-638 cells. When transplanted into athymic nude mice, wild-type TGF-β RII-expressing SNU-638 cells showed decreased and delayed tumorigenicity compared with control cells. This study suggests a strong association between the expression of wild-type TGF-β RII and the degree of malignancy in human gastric cancer cells.
Supported in part by HAN Project of Korean Ministry of Science and Technology (MOST 8-1-10). J. C. and K. P. contributed equally to this work.