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Expression of transforming growth factor beta type II receptor reduces tumorigenicity in human gastric cancer cells
1Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
Restoring transforming growth factor beta (TGF-beta) receptor type II (RII) in gastric cancer cells reduced their proliferation and tumor growth. This suggests wild-type TGF-beta RII expression is crucial for controlling gastric cancer malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor beta (TGF-beta) receptor type II (RII) mutations are common in epithelial cancers, leading to TGF-beta resistance.
- SNU-638 gastric cancer cells have a DNA replication error phenotype and express an inactive TGF-beta RII.
Purpose of the Study:
- To investigate the role of TGF-beta RII in the tumorigenic potential of SNU-638 human gastric cancer cells.
- To determine if restoring wild-type TGF-beta RII expression can inhibit cancer cell growth and tumor formation.
Main Methods:
- SNU-638 cells were infected with retroviral constructs expressing wild-type TGF-beta RII.
- TGF-beta RII mRNA and protein expression levels were assessed.
- Cell proliferation was measured in response to TGF-beta and TGF-beta-neutralizing antibodies.
- Tumorigenicity was evaluated in athymic nude mice.
Main Results:
- Infection with wild-type TGF-beta RII retroviral constructs significantly increased TGF-beta RII expression in SNU-638 cells.
- TGF-beta treatment reduced proliferation in wild-type TGF-beta RII-expressing cells but not in control cells.
- TGF-beta-neutralizing antibodies increased proliferation in wild-type TGF-beta RII-expressing cells, indicating autocrine TGF-beta signaling.
- Wild-type TGF-beta RII-expressing SNU-638 cells exhibited decreased and delayed tumorigenicity in nude mice.
Conclusions:
- Restoration of wild-type TGF-beta RII expression suppresses the proliferation and tumorigenicity of SNU-638 gastric cancer cells.
- This study highlights a strong association between wild-type TGF-beta RII expression and reduced malignancy in human gastric cancer.