Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations
Open Access
- 18 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Zeitschrift für Krebsforschung und Klinische Onkologie
- Vol. 146 (5), 1153-1167
- https://doi.org/10.1007/s00432-020-03182-1
Abstract
Background Hepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are the most common malignant liver tumors in childhood. Both tumor types exhibit genetic and epigenetic alterations in the WNT/β-catenin signaling pathway, which is a key regulator of liver progenitor cells in embryonic development. The tumors demonstrate a high rate of β-catenin mutations and gene expression changes of several WNT antagonists. However, the role of the WNT inhibitory factor secreted frizzled-related protein 1 (SFRP1) has not been addressed in pediatric liver cancer so far. Results In our study, we investigated the gene expression level, DNA methylation status and functional relevance of SFRP1 in HB cell lines and in pediatric liver tumor patient samples. SFRP1 was downregulated due to DNA promoter methylation in all tested HB cell lines. Overexpression of SFRP1 in HB cell lines diminished tumor cell proliferation, colony formation and migration potential. In addition, the SFRP1-expressing HB cell lines showed reduced WNT/β-catenin signaling pathway activity and decreased expression of WNT target genes. To evaluate the utility of SFRP1 as a biomarker in pediatric liver cancer, we determined the gene expression level and DNA methylation status of SFRP1 in 45 pediatric liver tumor patient samples. The correlation analysis of different clinical parameters and tumor characteristics revealed a significant correlation of reduced SFRP1 expression with the presence of mutant β-catenin. The methylation status of SFRP1 was furthermore associated to a pediatric liver tumor type with HCC-like characteristics, TERT mutations and an older age at diagnosis. Conclusion Altogether, our data demonstrate that the epigenetic suppression of the WNT/β-catenin antagonist SFRP1 has an important impact on the malignant behavior of HB cells. Although SFRP1 methylation is a common event in HCC-like pediatric liver tumors, its potential as a prognostic or diagnostic biomarker needs to be further investigated.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (KA2274/3-1)
- Mehr LEBEN für Krebskranke Kinder – Bettina-Bräu-Stiftung
- Gänseblümchen Foundation
This publication has 44 references indexed in Scilit:
- Blocking the hedgehog pathway inhibits hepatoblastoma growthHepatology, 2008
- Frequent epigenetic inactivation of Wnt antagonist genes in breast cancerBritish Journal of Cancer, 2008
- Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinomaBMC Cancer, 2007
- SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathwayInternational Journal of Cancer, 2007
- Promoter methylation of the secreted frizzled‐related protein 1 gene SFRP1 is frequent in hepatocellular carcinomaCancer, 2006
- Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancerOncogene, 2006
- Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancerOncogene, 2005
- Functional Epigenomics Identifies Genes Frequently Silenced in Prostate CancerCancer Research, 2005
- Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancerNature Genetics, 2004
- Secreted antagonists of the Wnt signalling pathwayJournal of Cell Science, 2003