Expression of transforming growth factor beta type II receptor reduces tumorigenicity in human gastric cancer cells.
Expression of transforming growth factor beta (TGF-beta) receptor type II (RII) is required for the growth-inhibitory effects of TGF-beta on proliferating epithelial cells. TGF-beta 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-beta resistance in cell lines derived from these tumors. In this study, the role of TGF-beta 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-beta RII. The SNU-638 cell line displays the DNA replication error phenotype and encodes a truncated, inactive TGF-beta RII protein. Infection of these cells with retroviral constructs expressing wild-type TGF-beta RII led to significant increases in TGF-beta RII mRNA and protein expression. These cells responded to exogenous TGF-beta with reduced proliferation compared to that of control cells infected with retroviral vector expressing chloramphenicol acetyltranferase. Addition of TGF-beta-neutralizing antibodies led to increased proliferation of wild-type TGF-beta RII-expressing SNU-638 cells but had no effect on control cells. The latter finding suggests that TGF-beta acts in an autocrine fashion to inhibit cell proliferation in SNU-638 cells. When transplanted into athymic nude mice, wild-type TGF-beta 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-beta RII and the degree of malignancy in human gastric cancer cells.
Chang
J
J
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892, USA.
Park
K
K
Bang
Y J
YJ
Kim
W S
WS
Kim
D
D
Kim
S J
SJ
D000818:Animals; D002455:Cell Division; D006801:Humans; D051379:Mice; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013274:Stomach Neoplasms / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D018125:Receptors, Transforming Growth Factor beta