REACTIVATION OF THE MATERNALLY IMPRINTED IGF2 ALLELE IN TGF-ALPHA INDUCED HEPATOCELLULAR CARCINOMAS IN MICE

The Insulin like growth factor 2 (IGF2) gene is expressed in several t ypes of tumors in humans and mice and has been implicated as an import ant growth factor in tumor progression. IGF2 expression in the TGF alp ha transgenic mice was analysed in liver and tumors from animals which also contained one or two functional IGF2 alleles. In a two by two ma ting experiment using transgenic mice containing either a TGF alpha tr ansgene or a IGF2 gene knockout, we have investigated whether IGF2 imp rinting is reversed during hepatocarcinogenesis and the consequences o f IGF2 expression for tumor growth. We observed that: (1) 100% of the hepatocellular carcinomas expressed IGF2 (2) the normally imprinted ma ternal allele is active in the tumors in which the paternal allele is knocked out and (3) all three of the murine IGF2 promoters upstream of the reactivated maternal alleles are transcriptionally active in tumo rs. We also observed that the total tumor burden of animals with two w ild type IGF-2 alleles (paternal and maternal) was the same as the tum or burden in animals which contained only a single reactivated materna l allele. The 100% incidence of reactivation of the imprinted maternal allele suggests that IGF2 expression is selected during murine hepato carcinogenesis and can substitute for the paternal allele when it is i nactivated.