Abstract

BackgroundHepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. We and others have previously shown that the overexpression of insulin-like growth factor 2 (IGF2), loss of imprinting at the IGF2/H19 locus, and amplification of pleomorphic adenoma gene 1 (PLAG1) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis. In this study, we investigated the role of the insulin-like growth factor binding protein 3 (IGFBP3), a known competitor of the IGF axis, in pediatric liver cancers.ResultsThe IGFBP3 gene was highly expressed in normal pediatric livers but was heavily downregulated in four HB cell lines and the majority of HB primary tumors (26/36). Detailed methylation analysis of CpG sites in the IGFBP3 promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of IGFBP3 in HB cell lines. Consequently, the treatment of HB cell lines with 5-aza-2'-deoxycytidine resulted in DNA demethylation and reactivation of the epigenetically silenced IGFBP3 expression. Interestingly, IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring IGFBP3 expression in HB cells resulted in reduced colony formation, migration, and invasion.ConclusionThis study provides the first direct evidence that the reactivation of IGFBP3 decreases aggressive properties of pediatric liver cancer cells and that IGFBP3 promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.

Highlights

  • Hepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion

  • We demonstrate that the downregulation of insulin-like growth factor binding protein 3 (IGFBP3) expression is a common feature in HB, which is associated with CpG island promoter methylation in advanced, high-risk HB cases

  • Downregulation of IGFBP3 is a common event in pediatric liver tumors To define the IGF signaling status in our pediatric liver tumor collection, we initially investigated the endogenous expression of the ligand insulin-like growth factor 2 (IGF2) and its positive regulator pleomorphic adenoma gene 1 (PLAG1)

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Summary

Introduction

Hepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. The type 1 insulin-like growth factor receptor and its ligands, IGF1 and IGF2, are upregulated in a variety of human cancers [5] In pediatric tumors, such as rhabdomyosarcoma, nephroblastoma, and HB, the role of the IGF axis is important [6]. We and others have shown that the fetal growth factor IGF2 is upregulated in almost all HB cases [7,8], even though the underlying molecular mechanism is still not understood. This upregulation could be explained in part by the observation that the loss of imprinting at the IGF2/H19 locus is evident in approximately 20% of all IGF2

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