Abstract
BackgroundThe established role miRNA-mRNA regulation of gene expression has in oncogenesis highlights the importance of integrating miRNA with downstream mRNA targets. These findings call for investigations aimed at identifying disease-associated miRNA-mRNA pairs. Hierarchical integrative models (HIM) offer the opportunity to uncover the relationships between disease and the levels of different molecules measured in multiple omic studies.MethodsThe HIM model we formulated for analysis of mRNA-seq and miRNA-seq data can be specified with two levels: (1) a mechanistic submodel relating mRNAs to miRNAs, and (2) a clinical submodel relating disease status to mRNA and miRNA, while accounting for the mechanistic relationships in the first level.ResultsmRNA-seq and miRNA-seq data were acquired by analysis of tumor and normal liver tissues from 30 patients with hepatocellular carcinoma (HCC). We analyzed the data using HIM and identified 157 significant miRNA-mRNA pairs in HCC. The majority of these molecules have already been independently identified as being either diagnostic, prognostic, or therapeutic biomarker candidates for HCC. These pairs appear to be involved in processes contributing to the pathogenesis of HCC involving inflammation, regulation of cell cycle, apoptosis, and metabolism. For further evaluation of our method, we analyzed miRNA-seq and mRNA-seq data from TCGA network. While some of the miRNA-mRNA pairs we identified by analyzing both our and TCGA data are previously reported in the literature and overlap in regulation and function, new pairs have been identified that may contribute to the discovery of novel targets.ConclusionThe results strongly support the hypothesis that miRNAs are important regulators of mRNAs in HCC. Furthermore, these results emphasize the biological relevance of studying miRNA-mRNA pairs.
Highlights
The established role miRNA-mRNA regulation of gene expression has in oncogenesis highlights the importance of integrating miRNA with downstream mRNA targets
Comparing the miRNAmRNAs selected by Hierarchical integrative models (HIM) at the mechanistic submodel with the pairs selected by regularized generalized canonical correlation analysis (rgCCA), we found 104 experimentally verified pairs overlapped in the Georgetown University (GU) dataset
The model led to identification of key miRNA-mRNA pairs and associated pathways that are potentially involved in hepatocellular carcinoma (HCC) pathogenesis
Summary
The established role miRNA-mRNA regulation of gene expression has in oncogenesis highlights the importance of integrating miRNA with downstream mRNA targets. These findings call for investigations aimed at identifying disease-associated miRNA-mRNA pairs. MicroRNAs (miRNAs) play vital roles in many biological processes, including differentiation, cell signaling, and response to infection. MicroRNA dysregulation has been linked to cancer initiation and progression where miRNAs act as tumor suppressors or oncogenes, regulating multiple pathways including cell proliferation, differentiation, apoptosis, metastasis and angiogenesis [1]. Recent studies have highlighted several miRNAs that are differentially expressed in cancer stem cells establishing the role of miRNAs in targeting genes and pathways supporting cancer stemness [2]. Mature miRNAs are highly stable and have great utility as biomarkers of diagnosis/ prognosis and disease progression
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