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Imprinted M6p/Igf2 receptor is mutated in rat liver tumors
J J Mills1, J G Falls, A T De Souza
1Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
We have previously shown that inactivation of mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is a common early event in both human liver and breast carcinogenesis. The M6p/Igf2r is imprinted in mice while expression is biallelic in most humans. In this investigation the M6p/Igf2r gene is shown to also be imprinted in the liver of Fischer 344, Lewis and Brown Norway rats. In addition, we have identified mutations in the expressed allele of the M6p/Igf2r in 40% of diethylnitrosamine-initiated rat liver tumors. These results provide further evidence that the M6P/IGF2R functions as a liver tumor suppressor gene. They also suggest that mice and rats would be more sensitive than humans to those hepatocarcinogens in which the M6p/Igf2r is mechanistically involved in transformation since one rather than two alleles would need to be inactivated.
Insights
Inactivation of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is crucial in liver cancer. This study shows M6P/IGF2R is imprinted in rats and mutated in rat liver tumors, supporting its tumor suppressor role.
Area of Science:
- Molecular biology
- Genetics
- Oncology
Background:
- Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) inactivation is an early event in human liver and breast cancer.
- M6P/IGF2R is imprinted in mice but biallelically expressed in most humans.
Purpose of the Study:
- To investigate M6P/IGF2R imprinting in rat liver.
- To identify mutations in the expressed M6P/IGF2R allele in rat liver tumors.
Main Methods:
- Analysis of M6P/IGF2R imprinting in rat liver.
- Mutation analysis of the expressed M6P/IGF2R allele in diethylnitrosamine-initiated rat liver tumors.
Main Results:
- M6P/IGF2R is imprinted in the liver of Fischer 344, Lewis, and Brown Norway rats.
- Mutations were identified in 40% of the expressed M6P/IGF2R alleles in rat liver tumors.
Conclusions:
- These findings provide further evidence for M6P/IGF2R acting as a liver tumor suppressor gene.
- Mice and rats may be more sensitive to certain hepatocarcinogens due to M6P/IGF2R imprinting.
