{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T03:45:08Z","timestamp":1771472708179,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,15]],"date-time":"2020-08-15T00:00:00Z","timestamp":1597449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["668596 (ChiLTERN)"],"award-info":[{"award-number":["668596 (ChiLTERN)"]}]},{"name":"Bettina Br\u00e4u foundation Munich","award":["R.K."],"award-info":[{"award-number":["R.K."]}]},{"name":"G\u00e4nsebl\u00fcmchen foundation Voerde","award":["R.K."],"award-info":[{"award-number":["R.K."]}]},{"name":"Elterninitiative Ebersberg","award":["I.S."],"award-info":[{"award-number":["I.S."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hepatoblastoma (HB) is the most common malignant liver tumor in childhood and it generally has a good prognosis. However, if associated with aggressive metastatic disease, outcome is still poor. The molecular mechanisms leading to metastatic spread in HB patients are still unknown. By combining RNA-sequencing and a genome-wide methylome analysis, we identified the transcription factor SP8 and the growth factor FGF8 among the most strongly upregulated genes in metastatic HB cases, with a concomitant robust demethylation of the respective promoter regions. Of note, high expression of both candidates was associated with the aggressive C2 subtype of the 16-gene signature and poor survival. Chromatin immunoprecipitation revealed a direct transcriptional regulation of FGF8 through binding of SP8 to the FGF8 promoter. Gain- and loss-of-function experiments proved promoting effects of SP8 on motility, self-renewal, migration, and the invasive potential of HB cells. Moreover, stable overexpression of SP8 in Hep3B cells resulted in the acquisition of a mesenchymal phenotype and a strong upregulation of epithelial-mesenchymal transition-associated genes. Using KRAB-mediated CRISPR-dCas9 interference directed against FGF8, we could show that FGF8 is essential for the SP8-mediated aggressive tumor behavior. Treatment of HB cell lines with the pan SP family inhibitor mithramycin A resulted in a significant inhibition of their clonogenic growth. In summary, we identified SP8 and FGF8 as key players in aggressive traits of HB and propose SP8 inhibiting drugs as a new effective treatment strategy especially for metastatic tumors.<\/jats:p>","DOI":"10.3390\/cancers12082294","type":"journal-article","created":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T04:35:51Z","timestamp":1597638951000},"page":"2294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["SP8 Promotes an Aggressive Phenotype in Hepatoblastoma via FGF8 Activation"],"prefix":"10.3390","volume":"12","author":[{"given":"Alexandra","family":"Wagner","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Schwarzmayr","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beate","family":"H\u00e4berle","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Vokuhl","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4514-5767","authenticated-orcid":false,"given":"Markus","family":"Kaller","sequence":"additional","affiliation":[{"name":"Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heiko","family":"Hermeking","sequence":"additional","affiliation":[{"name":"Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany"},{"name":"German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dietrich","family":"von Schweinitz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-2803","authenticated-orcid":false,"given":"Roland","family":"Kappler","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1053\/j.sempedsurg.2011.10.011","article-title":"Hepatoblastoma: Recent developments in research and treatment","volume":"21","year":"2012","journal-title":"Semin. 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