Altered expression of members of the IGF-axis in hepatoblastomas

Abstract

Summary Previous reports have demonstrated that expression of insulin-like growth factor 2 (IGF2) is altered in hepatoblastoma. Using RNAase protection analysis (RPA), we examined the gene expression for IGF1, IGF2, IGF1R, M6P/IGF2R, IGFBP-1 and IGFBP-2 in a series of hepatoblastomas with corresponding normal liver from the same individuals. The results show that the expression of the IGF-axis members included in the present study are altered between tumour and normal, and indicate that the IGF-axis may be involved in hepatoblastoma development.

Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma

“…Although the expression levels of IGF2 mRNA were reported to be higher in WTs with UPD than in WTs with ROI in two series of WTs (Wang et al, 1996;Haruta et al, 2008), conflicting results were reported in IGF2 mRNA levels between WTs with LOI and WTs with ROI (Wang et al, 1996;Ravenel et al, 2001). The present and earlier studies showed that all HB tumours with UPD and the majority of HB tumours with LOI or ROI expressed the higher levels of IGF2 mRNA than normal liver tissues (Li et al, 1998b;Gray et al, 2000;Hartmann et al, 2000). This study also showed that P3 transcripts predominated in total IGF2 mRNAs in HB tumours irrespective of the IGF2 status (i.e., UPD, 11p15 loss, LOI or ROI); these findings were similar to those reported in foetal liver tissues showing elevated expression of IGF2 mRNA with predominance of the P3 transcript (Li et al, 1998a).…”

“…Hepatoblastoma tumours can be classified into those with LOH and those with ROH, and tumours with ROH can be further classified into those with LOI and those with ROI. For data comparison, the frequencies of LOH and LOI in the earlier and present series of HB tumours are shown in Tables 2 and 3, respectively (Davies, 1993;Montagna et al, 1994;Li et al, 1995;Rainier et al, 1995;Fukuzawa et al, 1999;Gray et al, 2000;Hartmann et al, 2000;Ross et al, 2000;Albrecht et al, 2004;Suzuki et al, 2008). Both frequencies of LOH and LOI were similar between the earlier and present series of HB tumours.…”

“…To improve the mortality of these patients, innovative treatment based on a specific molecular target is needed. The molecular mechanism involved in the development and progression of HB includes overexpression of insulin-like growth factor-II (IGF2) (Li et al, 1998b;Gray et al, 2000;Hartmann et al, 2000), downregulation of RASSF1A by promoter hypermethylation (Sugawara et al, 2007;Honda et al, 2008) and alterations of genes in the Wnt signalling pathway; most notably, the high incidence of CTNNB1 (catenin, b1) mutation (Koch et al, 1999;Taniguchi et al, 2002).…”

“…It has been proved in many WTs that aberrant methylation of the maternal CTCF6 prevents the insulator binding and leads to loss of imprinting (LOI), resulting in the overexpression of IGF2 (Steenman et al, 1994;Ravenel et al, 2001). Although LOI of IGF2 was reported in HB, the mechanism of LOI, the concurrent overexpression of IGF2 mRNA and loss of H19 mRNA expression are uncertain because of the limited number of HB tumours examined and the low frequency of the heterozygous IGF2 polymorphic site in general populations (Davies, 1993;Montagna et al, 1994;Rainier et al, 1995;Li et al, 1995Li et al, , 1998bFukuzawa et al, 1999;Gray et al, 2000;Hartmann et al, 2000;Ross et al, 2000;Albrecht et al, 2004;Suzuki et al, 2008), and some investigators stated earlier that the mechanisms of IGF2 upregulation by LOI found in WT do not apply to HB (Li et al, 1995;Hartmann et al, 2000).…”

Therapeutic Innovations for Targeting Hepatoblastoma

“…Moreover, they found that PI3K/AKT/mTOR activation was actually central for hepatoblastoma survival as demonstrated by PI3K inhibition in vitro and subsequent reduction of AKT and GSK3β phosphorylation (45). Further, the IGF axis was also shown to be implicated in hepatoblastoma growth (49). This pathway was found to be overactivated as a result of IGF2 ligand overexpression, confering a constant anti-apoptotic signal to the cells mediated through the insulin-like growth factor 1 receptor (IGF1R) (50).…”