A Comprehensive Genomic Analysis Constructs miRNA–mRNA Interaction Network in Hepatoblastoma

Abstract

Hepatoblastoma (HB) is a rare disease but nevertheless the most common hepatic tumor in the pediatric population. For patients with advanced HB, the prognosis is dismal and there are limited therapeutic options. Multiple microRNAs (miRNAs) were reported to be involved in HB development, but the miRNA–mRNA interaction network in HB remains elusive. Through a comparison between HB and normal liver samples in the GSE131329 dataset, we detected 580 upregulated differentially expressed mRNAs (DE-mRNAs) and 790 downregulated DE-mRNAs. As for the GSE153089 dataset, the first cluster of differentially expressed miRNAs (DE-miRNAs) were detected between fetal-type tumor and normal liver groups, while the second cluster of DE-miRNAs were detected between embryonal-type tumor and normal liver groups. Through the intersection of these two clusters of DE-miRNAs, 33 upregulated hub miRNAs, and 12 downregulated hub miRNAs were obtained. Based on the respective hub miRNAs, the upstream transcription factors (TFs) were detected via TransmiR v2.0, while the downstream target genes were predicted via miRNet database. The intersection of target genes of respective hub miRNAs and corresponding DE-mRNAs contributed to 250 downregulated candidate genes and 202 upregulated candidate genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated the upregulated candidate genes mainly enriched in the terms and pathways relating to the cell cycle. We constructed protein–protein interaction (PPI) network, and obtained 211 node pairs for the downregulated candidate genes and 157 node pairs for the upregulated candidate genes. Cytoscape software was applied for visualizing the PPI network and respective top 10 hub genes were identified using CytoHubba. The expression values of hub genes in the PPI network were subsequently validated through Oncopression database followed by quantitative real-time polymerase chain reaction (qRT-PCR) in HB and matched normal liver tissues, resulting in six significant downregulated genes and seven significant upregulated genes. The miRNA–mRNA interaction network was finally constructed. In conclusion, we uncover various miRNAs, TFs, and hub genes as potential regulators in HB pathogenesis. Additionally, the miRNA–mRNA interaction network, PPI modules, and pathways may provide potential biomarkers for future HB theranostics.

DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis

“… 42 Interestingly, a hub between cell cycle actors and miRNAs within the DLK1/DIO3 locus has also been inferred by bioinformatics analysis of HB datasets. 43 Here, our study supports that the proliferative impact of the DLK1/DIO3 locus in preneoplastic hepatocytes is dependent on the β-catenin-driven DLK1-WRE enhancer and the subsequent redistribution of FoxM1 at the promoters of cell cycle actors. Meg3 appears as a potential guiding partner for FoxM1 at these promoters to regulate their transcription.…”

Summary of biological research on hepatoblastoma: a scoping review

“…Dysregulation in miRNA expression is closely linked to the initiation, progression, and metastasis of cancer. A comprehensive genomic analysis of hepatoblastoma tumors has unveiled 33 upregulated hub miRNAs; and 12 downregulated hub miRNAs, underscoring the significant role of miRNAs in hepatoblastoma formation ( 71 ). Ongoing research has demonstrated that mir-624-5p can markedly inhibit HB tumor growth by suppressing the transcriptional activity of Wnt pathway oncogenes ( 72 ).…”

Epigenetics and genetics of hepatoblastoma: Linkage and treatment

“…Each miRNA can regulate multiple target genes and influence the activity of signaling pathways, corresponding to the fact that many different miRNAs regulate a particular gene and that a gene might have more than half a hundred miRNA binding sites ( Okugawa et al, 2015 ). In a comprehensive genomic analysis of the Hepatoblastoma miRNA-mRNA interaction network, clusters of differentially expressed miRNAs were detected between fetal-type tumors, embryonic-type tumors, and corresponding normal liver groups, with 33 upregulated and 12 downregulated hub miRNAs in the intersection of these two clusters ( Chen et al, 2021 ).…”