A Comprehensive Genomic Analysis Constructs miRNA-mRNA Interaction Network in Hepatoblastoma.

Tong Chen,Jiangbin Liu,Zhibao Lv,Xiuhao Zhao,Linlin Zhu,Linlin Tian,Jianglong Chen,Ting Guo,Jing Zhou,Qingfeng Sheng

doi:10.3389/fcell.2021.655703

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.

Highlights

Hepatoblastoma (HB) is a rare disease with an annual incidence of 1.5 cases per million children per year (Spector and Birch, 2012)
The extreme rarity of HB has hindered our understanding of its underlying molecular mechanisms, and the majority of potential hub genes, DE-miRNAs and Transcription factors (TFs) in this study were reported for the first time in HB pathogenesis
The dysregulation of miRNA–messenger RNAs (mRNAs) interaction network in liver is associated with various liver diseases, such as liver regeneration (Wang et al, 2019) and hepatocellular carcinoma (Zhang and Du, 2017; Lou et al, 2019)

Summary

Introduction

Hepatoblastoma (HB) is a rare disease with an annual incidence of 1.5 cases per million children per year (Spector and Birch, 2012). It is the predominant hepatic tumor in the pediatric population (Schnater et al, 2003). Surgical resection and chemotherapy have dramatically improved the prognosis for HB children, with the 3-years event-free survival (EFS) > 80% (Aronson et al, 2014). There are limited therapeutic strategies for advanced HB children, with the 3-years EFS of only 34% (Semeraro et al, 2013). There is an urgent need to unveil the molecular mechanisms underlying this rare tumor in order to identify novel biomarkers for therapeutic tailoring

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