Transcriptome Dysregulation in Hepatoblastoma: The Pivotal Role of Noncoding Rnas and Changes in Lipid Metabolism

Abstract Hepatoblastoma, the most common liver tumor in children and exhibited the lowest mutational burden among solid cancers, pointing to chromosomal and epigenetic changes as the main drivers of tumorigenesis. Previous studies explored hepatoblastoma transcriptomes focusing on risk stratification, but no consensual molecular signature emerged. We performed whole-transcriptome analysis with total RNA sequencing using 14 hepatoblastomas compared with control liver samples. A set of 1,492 differentially expressed genes (DEGs) was detected, 1,031 upregulated and 461 downregulated, comprising 920 protein-coding genes (62%). A strong dysregulation of non-coding RNA genes (ncRNAs) was revealed, mostly upregulated. Among the top 50 genes with the highest expression, 42% of them were ncRNAs, and three (MAGED4, SNO144-16, and RP11-431J24.2) were exclusively expressed by hepatoblastomas. Upregulated biological processes were linked to cell differentiation, communication and signaling pathways, as well as embryonic and developmental processes. Enriched biological processes in downregulated genes included mainly negative regulation of oxidation and metabolism inhibition, affecting amine, nicotinamide, and lipids. An integrative analysis between miRNA-mRNA and protein-protein interaction networks highlighted major biological processes associated with metabolism and oxidation reactions of lipids and carbohydrates, methylation-dependent chromatin silencing, and DNA methylation. Four upregulated miRNAs (miR-186, miR-214, miR-377, and miR-494) were disclosed, potentially targeting more than 10 protein-coding transcripts, which suggested a possible role in their negative regulation. In conclusion, the RNASeq analysis revealed the disruption of metabolic pathways, including lipids, amines, and nicotinamides, and disclosed a robust ncRNA transcriptome perturbation, highlighting a new epigenetic player in the control of hepatoblastoma gene expression, along with DNA methylation.