Identification of miRNA-mRNA associations in hepatocellular carcinoma using hierarchical integrative model

Abstract

Background: 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. Hierarchical integrative models (HIM) offer the opportunity to uncover the relationships between disease and the levels of different molecules measured in multiple omic studies. Methods: The 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. Results: mRNA-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. Conclusion: The 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.

Cross‐talk of four types of RNA modification writers defines the immune microenvironment in severe asthma

“…46 TRMT6 is involved in hepatocellular carcinoma via regulation of the cell cycle and apoptosis. 47 These results demonstrate that TRMT6/61A plays important roles in the regulation of cell development and differentiation.…”

MicroRNA-483-5p Inhibits Hepatocellular Carcinoma Cell Proliferation, Cell Steatosis, and Fibrosis by Targeting PPARα and TIMP2

“…Total RNAs were isolated from samples as previously described [ 36 ]. Briefly, RNA samples were isolated using the RNeasy Plus Universal Mini Kit (Qiagen, Hilden, Germany) following the manufacturer’s instructions.…”

A Bayesian two-step integrative procedure incorporating prior knowledge for the identification of miRNA-mRNAs involved in hepatocellular carcinoma

“…In this paper we focused on a subset of 106 mRNAs from the mRNA-seq data that are selected in previous comparisons using the same dataset and are known to have some association with liver disease [8], [5], [6], [9]. Student t-tests with multiple testing adjustment were used to identify miRNAs with significant changes in their levels between HCC and CIRR.…”

“…Gaining insights into the mechanistic differences between HCC and CIRR contributes greatly to improving the detection of important biological features. In this paper, we introduce a Bayesian two-step integrative procedure extending the hierarchical integrative model (HIM) proposed by [4], [3], and adapted by [5], for analyzing miRNA-seq and mRNA-seq data from patients with HCC or CIRR. The goals are to improve the knowledge about the relationships between miRNAs and mRNAs, as well as among mRNAs after considering the effects of miRNAs, and to identify relevant disease-associated miRNA-mRNA pairs.…”