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Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to
1Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-5055, USA.
Abstract:
The transforming growth factor-beta (TGF-beta) receptor complex and its downstream signaling intermediates constitute a tumor suppressor pathway. In many cancers, expression of TGF-beta type II receptor (TbetaR-II) is markedly decreased. In the present study, we show that the hepatocytes isolated from 15-day-old, but not 9-month-old, mice heterozygous for the deletion of the TbetaR-II gene are slightly less sensitive to the growth-inhibitory effect of TGF-beta when compared with wild-type littermates of same age. In addition, the proliferation index of hepatocytes as indicated by bromodeoxyuridine incorporation is mildly increased in the heterozygous mice. These subtle changes in cellular phenotype did not result in either gross or microscopic abnormality of the liver. The treatment of these mice with the chemical carcinogen, diethylnitrosamine, results in a significantly enhanced tumorigenesis in the liver when compared with the wild-type littermates. Our results demonstrate the gene-dosage effect of TbetaR-II and indicate that the reduced expression of TbetaR-II in mice increases susceptibility to tumorigenesis in the liver.
Insights
Reduced expression of the transforming growth factor-beta type II receptor (TbetaR-II) in mice impairs TGF-beta signaling, increasing liver tumor susceptibility. This highlights TbetaR-II
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The transforming growth factor-beta (TGF-beta) receptor complex is a critical tumor suppressor pathway.
- Decreased expression of the TGF-beta type II receptor (TbetaR-II) is observed in numerous cancers.
- The role of TbetaR-II gene dosage in cancer susceptibility requires further investigation.
Purpose of the Study:
- To investigate the functional consequences of reduced TbetaR-II expression on TGF-beta signaling.
- To determine the impact of TbetaR-II gene dosage on liver cell proliferation and tumorigenesis.
- To elucidate the role of TbetaR-II in liver cancer development.
Main Methods:
- Hepatocytes were isolated from mice heterozygous for TbetaR-II deletion and age-matched wild-type littermates.
- Sensitivity to TGF-beta growth inhibition and hepatocyte proliferation (bromodeoxyuridine incorporation) were assessed.
- Liver tumorigenesis was evaluated following diethylnitrosamine (DEN) exposure in heterozygous and wild-type mice.
Main Results:
- Hepatocytes from young (15-day-old) TbetaR-II heterozygous mice showed reduced sensitivity to TGF-beta growth inhibition.
- A mild increase in hepatocyte proliferation was observed in TbetaR-II heterozygous mice.
- Diethylnitrosamine treatment resulted in significantly enhanced liver tumorigenesis in TbetaR-II heterozygous mice compared to wild-types.
Conclusions:
- These findings demonstrate a gene-dosage effect for TbetaR-II in vivo.
- Reduced TbetaR-II expression confers increased susceptibility to liver tumorigenesis.
- The TGF-beta type II receptor plays a crucial role in suppressing liver cancer development.