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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors

Molecular Cancer > Ausgabe 1/2012
Ivonne Regel, Melanie Eichenmüller, Saskia Joppien, Johanna Liebl, Beate Häberle, Josef Müller-Höcker, Angelika Vollmar, Dietrich von Schweinitz, Roland Kappler
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-9) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

IR carried out the processing of clinical samples, expression measurements, migration assays, 5-Aza-dC treatments, and the methylation-specific PCR, and she participated in the analysis and interpretation of the data. ME performed the Western blot and apoptosis assays. SJ conducted the bisulfite-sequencing study and interpreted the methylation data. JL performed the invasion and migration assays. BH collected the clinical samples and carried out the statistical analyses of the clinical data. JMH performed the pathological diagnosis and staging of tumor specimens. AV participated in the design of the study and helped in the analysis and interpretation of the data. DvS participated in the design of the study and helped to draft the manuscript. RK designed the study, participated in the analysis and interpretation of data, and drafted the manuscript. All of the authors read and approved the final version of this manuscript.



Hepatoblastoma (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.


The 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.


This 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.
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