Cancers, Vol. 12, Pages 2294: SP8 Promotes an Aggressive Phenotype in Hepatoblastoma via FGF8 Activation

Cancers, Vol. 12, Pages 2294: SP8 Promotes an Aggressive Phenotype in Hepatoblastoma via FGF8 Activation Cancers doi: 10.3390/cancers12082294 Authors: Wagner Schwarzmayr Häberle Vokuhl Schmid Schweinitz Kappler 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 ess...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research