Wildtype Kras2 can inhibit lung carcinogenesis in mice
1Division of Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center, 420 West 12th Avenue, Columbus, Ohio, USA.
Abstract:
Although the ras genes have long been established as proto-oncogenes, the dominant role of activated ras in cell transformation has been questioned. Previous studies have shown frequent loss of the wildtype Kras2 allele in both mouse and human lung adenocarcinomas. To address the possible tumor suppressor role of wildtype Kras2 in lung tumorigenesis, we have carried out a lung tumor bioassay in heterozygous Kras2-deficient mice. Mice with a heterozygous Kras2 deficiency were highly susceptible to the chemical induction of lung tumors when compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells and a mouse lung tumor cell line containing an activated Kras2 allele. Allelic loss of wildtype Kras2 was found in 67% to 100% of chemically induced mouse lung adenocarcinomas that harbor a mutant Kras2 allele. Finally, an inverse correlation between the level of wildtype Kras2 expression and extracellular signal-regulated kinase (ERK) activity was observed in these cells. These data strongly suggest that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression.
Insights
Wild-type Kras2 acts as a tumor suppressor in lung cancer, contrary to its proto-oncogene role. Its loss is frequent in lung tumors, increasing susceptibility to chemically induced lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ras genes are established proto-oncogenes, but their dominant role in cell transformation is debated.
- Loss of wild-type Kras2 alleles is frequently observed in lung adenocarcinomas.
Purpose of the Study:
- To investigate the potential tumor suppressor role of wild-type Kras2 in lung tumorigenesis.
- To analyze the impact of Kras2 deficiency on susceptibility to lung tumor induction.
Main Methods:
- Lung tumor bioassay in heterozygous Kras2-deficient mice and wild-type controls.
- Chemical induction of lung tumors.
- Detection of Kras2 mutations and analysis of wild-type Kras2 expression.
- Assessment of colony formation and tumor development in cell lines.
Main Results:
- Heterozygous Kras2-deficient mice showed increased susceptibility to chemically induced lung tumors.
- Activating Kras2 mutations were present in all induced lung tumors.
- Wild-type Kras2 inhibited colony formation and tumor development in cell lines.
- Allelic loss of wild-type Kras2 occurred in 67-100% of induced lung adenocarcinomas with mutant Kras2.
- An inverse correlation was observed between wild-type Kras2 expression and ERK activity.
Conclusions:
- Wild-type Kras2 exhibits tumor suppressor activity in lung tumorigenesis.
- Loss of wild-type Kras2 is a common event during lung tumor progression.
- These findings challenge the traditional view of ras genes solely as oncogenes.
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