IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors
<p>Abstract</p> <p>Background</p> <p>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 <it>insulin-...
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doaj-fdd2d2d020c349bca85e7401af97ce912020-11-24T21:08:16ZengBMCMolecular Cancer1476-45982012-03-01111910.1186/1476-4598-11-9IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumorsRegel IvonneEichenmüller MelanieJoppien SaskiaLiebl JohannaHäberle BeateMüller-Höcker JosefVollmar Angelikavon Schweinitz DietrichKappler Roland<p>Abstract</p> <p>Background</p> <p>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 <it>insulin-like growth factor 2 </it>(<it>IGF2</it>), loss of imprinting at the <it>IGF2</it>/<it>H19 </it>locus, and amplification of <it>pleomorphic adenoma gene 1 </it>(<it>PLAG1</it>) 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.</p> <p>Results</p> <p>The <it>IGFBP3 </it>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 <it>IGFBP3 </it>promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of <it>IGFBP3 </it>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 <it>IGFBP3 </it>expression. Interestingly, <it>IGFBP3 </it>promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring <it>IGFBP3 </it>expression in HB cells resulted in reduced colony formation, migration, and invasion.</p> <p>Conclusion</p> <p>This study provides the first direct evidence that the reactivation of <it>IGFBP3 </it>decreases aggressive properties of pediatric liver cancer cells and that <it>IGFBP3 </it>promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.</p> http://www.molecular-cancer.com/content/11/1/9HepatoblastomaEpigeneticsMethylationInvasionIGF2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Regel Ivonne Eichenmüller Melanie Joppien Saskia Liebl Johanna Häberle Beate Müller-Höcker Josef Vollmar Angelika von Schweinitz Dietrich Kappler Roland |
spellingShingle |
Regel Ivonne Eichenmüller Melanie Joppien Saskia Liebl Johanna Häberle Beate Müller-Höcker Josef Vollmar Angelika von Schweinitz Dietrich Kappler Roland IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors Molecular Cancer Hepatoblastoma Epigenetics Methylation Invasion IGF2 |
author_facet |
Regel Ivonne Eichenmüller Melanie Joppien Saskia Liebl Johanna Häberle Beate Müller-Höcker Josef Vollmar Angelika von Schweinitz Dietrich Kappler Roland |
author_sort |
Regel Ivonne |
title |
IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors |
title_short |
IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors |
title_full |
IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors |
title_fullStr |
IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors |
title_full_unstemmed |
IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors |
title_sort |
igfbp3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2012-03-01 |
description |
<p>Abstract</p> <p>Background</p> <p>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 <it>insulin-like growth factor 2 </it>(<it>IGF2</it>), loss of imprinting at the <it>IGF2</it>/<it>H19 </it>locus, and amplification of <it>pleomorphic adenoma gene 1 </it>(<it>PLAG1</it>) 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.</p> <p>Results</p> <p>The <it>IGFBP3 </it>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 <it>IGFBP3 </it>promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of <it>IGFBP3 </it>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 <it>IGFBP3 </it>expression. Interestingly, <it>IGFBP3 </it>promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring <it>IGFBP3 </it>expression in HB cells resulted in reduced colony formation, migration, and invasion.</p> <p>Conclusion</p> <p>This study provides the first direct evidence that the reactivation of <it>IGFBP3 </it>decreases aggressive properties of pediatric liver cancer cells and that <it>IGFBP3 </it>promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.</p> |
topic |
Hepatoblastoma Epigenetics Methylation Invasion IGF2 |
url |
http://www.molecular-cancer.com/content/11/1/9 |
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