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We and others have previously shown that the overexpression of <jats:italic>insulin-like growth factor 2<\/jats:italic> (<jats:italic>IGF2<\/jats:italic>), loss of imprinting at the <jats:italic>IGF2<\/jats:italic>\/<jats:italic>H19<\/jats:italic> locus, and amplification of <jats:italic>pleomorphic adenoma gene 1<\/jats:italic> (<jats:italic>PLAG1<\/jats:italic>) 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The <jats:italic>IGFBP3<\/jats:italic> 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 <jats:italic>IGFBP3<\/jats:italic> promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of <jats:italic>IGFBP3<\/jats:italic> 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 <jats:italic>IGFBP3<\/jats:italic> expression. Interestingly, <jats:italic>IGFBP3<\/jats:italic> promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring <jats:italic>IGFBP3<\/jats:italic> expression in HB cells resulted in reduced colony formation, migration, and invasion.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>This study provides the first direct evidence that the reactivation of <jats:italic>IGFBP3<\/jats:italic> decreases aggressive properties of pediatric liver cancer cells and that <jats:italic>IGFBP3<\/jats:italic> promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1476-4598-11-9","type":"journal-article","created":{"date-parts":[[2012,3,8]],"date-time":"2012-03-08T13:14:07Z","timestamp":1331212447000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors"],"prefix":"10.1186","volume":"11","author":[{"given":"Ivonne","family":"Regel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Eichenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Joppien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Liebl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"H\u00e4berle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"M\u00fcller-H\u00f6cker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Vollmar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietrich","family":"von Schweinitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Kappler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,3,8]]},"reference":[{"key":"1001_CR1","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/S0046-8177(83)80005-7","volume":"14","author":"AG Weinberg","year":"1983","unstructured":"Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. 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