Genomic imprinting and Igf2 influence liver tumorigenesis and loss of heterozygosity in SV40 T antigen transgenic mice.
Maternal-specific loss of heterozygosity (LOH) and allelic imbalances [i.e., partial LOH (pLOH)] observed in SV40 T/t antigen-induced liver tumors suggests that an imprinted gene on chromosome 7 is involved in liver tumorigenesis. Maternal-specific LOH/pLOH may reflect the loss of a maternally expressed tumor suppressor gene or the acquisition of paternally active alleles of a growth promoter. In addition, two oppositely imprinted genes on distal chromosome 7, Igf2 and H19, are re-expressed in most liver tumors from an SV40 T/t antigen transgenic line (M11T-G). Igf2 is a paternally expressed growth promoter, and H19 is a maternally expressed gene that can suppress growth in some tumor cell lines. We studied the role of Igf2 during liver tumorigenesis by creating Igf2 (+/-) M11T-G mice. These mice are essentially null for Igf2 expression because imprinting normally precludes maternal Igf2 expression. M11T-G, Igf2 (+/-) males exhibit a 15-fold reduction in the frequency of large tumors. Igf2 (+/-) tumors do not express maternal Igf2, indicating rigid imprinting control in the liver. LOH/pLOH analysis was performed on the tumors and indicates that acquisition of paternally active Igf2 alleles is a major selective event for M11T-G liver tumorigenesis. This also implies the existence of an imprinted, maternally expressed tumor suppressor gene on chromosome 7 that is unlikely to be H19.
Haddad
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Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Held
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D000483:Alleles; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D005819:Genetic Markers; D018392:Genomic Imprinting; D005838:Genotype; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013539:Simian virus 40 / Q000235:genetics*
D000957:Antigens, Viral, Tumor; D005819:Genetic Markers; D007335:Insulin-Like Growth Factor II