Reactivation of the maternally imprinted IGF2 allele in TGFα induced hepatocellular carcinomas in mice

Abstract

The Insulin like growth factor 2 (IGF2) gene is expressed in several types of tumors in humans and mice and has been implicated as an important growth factor in tumor progression. IGF2 expression in the TGFa transgenic mice was analysed in liver and tumors from animals which also contained one or two functional IGF2 alleles. In a two by two mating experiment using transgenic mice containing either a TGFa transgene or a IGF2 gene knockout, we have investigated whether IGF2 imprinting is reversed during hepatocarcinogenesis and the consequences of IGF2 expression for tumor growth. We observed that: (1) 100% of the hepatocellular carcinomas expressed IGF2 (2) the normally imprinted maternal 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 tumors. We also observed that the total tumor burden of animals with two wild type IGF-2 alleles (paternal and maternal) was the same as the tumor burden in animals which contained only a single reactivated maternal allele. The 100% incidence of reactivation of the imprinted maternal allele suggests that IGF2 expression is selected during murine hepatocarcinogenesis and can substitute for the paternal allele when it is inactivated.

The H19 endodermal enhancer is required for Igf2 activation and tumor formation in experimental liver carcinogenesis

“…Interestingly, Igf2 imprinting was conserved also in the liver tumors developed in mice carrying a null paternal Igf2 allele (Igf2 +/7) and the SV40 Tag oncogene, but was lost in the TGFainduced Igf2 +/7 hepatocellular carcinomas and SV40 Tag-dependent Igf2 +/7 and Igf2 7/+ pancreatic b-cell carcinomas. These results suggest that the molecular events occurring in the various carcinogenesis systems di erentially a ect the maintenance of the Igf2 imprinting status (Haddad and Held, 1997; Harris et al, 1998;Christofori et al, 1994Christofori et al, , 1995.…”

Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis

“…The foetal promoters P2 -P4 were active in HCC, whereas transcription from the adult promoter P1 was reduced in such lesions (Nardone et al, 1996;Li et al, 1997). Hepatic overexpression of the IGF-2 gene has been observed in animal models of hepatocarcinogeneses (Norstedt et al, 1988;Harris et al, 1998) as well as in human HCC (Sohda et al, 1996;Cariani et al, 1988), often on the background of HBV-and HCV-related chronic disease (d'Arville et al, 1991;Nardone et al, 1996). In HCV-related cirrhosis, HCV replication was positively correlated with overexpression of IGF-2 (Tanaka et al, 1996).…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Although the physiological function of lowlevel IGF-II expression in adult liver has largely remained obscure, there is a large body of evidence for multiple protumorigenic functions during hepatocarcinogenesis such as antiapoptosis, stimulation of proliferation and activation of angiogenesis. IGF-II is overexpressed in 16-40% of human HCCs (Table 1), and possibly even in some premalignant lesions (Cariani et al, 1988;Ng et al, 1998;Aihara et al, 1996;Sohda et al, 1996;Breuhahn et al, 2004), in HCC cell lines (Li et al, 1997;Breuhahn et al, 2004;Lund et al, 2004) and in several HCC animal models (Schirmacher et al, 1991(Schirmacher et al, , 1992Harris et al, 1998). Elevated expression in HCC cells results from transcriptional activation such as loss of promoter-specific imprinting or re-activation of the fetal promoter (P2-P4) pattern (Li et al, 1997;Vernucci et al, 2000).…”