Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations.
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.
['Regel|Ivonne|I|', 'Eichenmüller|Melanie|M|', 'Mahajan|Ujjwal Mukund|UM|', 'Hagl|Beate|B|', 'Benitz|Simone|S|', 'Häberle|Beate|B|', 'Vokuhl|Christian|C|', 'von Schweinitz|Dietrich|D|', 'Kappler|Roland|R|']
D000368:Aged D045744:Cell Line, Tumor D019175:DNA Methylation D015536:Down-Regulation D005260:Female D056945:Hep G2 Cells D018197:Hepatoblastoma D006801:Humans D036341:Intercellular Signaling Peptides and Proteins D008113:Liver Neoplasms D008297:Male D008565:Membrane Proteins D008875:Middle Aged D009154:Mutation D011401:Promoter Regions, Genetic D060449:Wnt Signaling Pathway D051176:beta Catenin
SFRP1 Hepatoblastoma Hepatocellular carcinoma Epigenetics Pediatric liver cancer DNA methylation APC DKK1 WIF1 WNT signaling