Differentially Expressed miRNAs in Hepatocellular Carcinoma Target Genes in the Genetic Information Processing and Metabolism Pathways.

Thomas Thurnherr,Yu Jin,Zhengdeng Lei,Caroline G Lee,Steven G Rozen,Way-Champ Mah

doi:10.1038/srep20065

Abstract

To date, studies of the roles of microRNAs (miRNAs) in hepatocellular carcinoma (HCC) have either focused on specific individual miRNAs and a small number of suspected targets or simply reported a list of differentially expressed miRNAs based on expression profiling. Here, we seek a more in-depth understanding of the roles of miRNAs and their targets in HCC by integrating the miRNA and messenger RNA (mRNA) expression profiles of tumorous and adjacent non-tumorous liver tissues of 100 HCC patients. We assessed the levels of 829 mature miRNAs, of which 32 were significantly differentially expressed. Statistical analysis indicates that six of these miRNAs regulate a significant proportion of their in silico predicted target mRNAs. Three of these miRNAs (miR-26a, miR-122, and miR-130a) were down-regulated in HCC, and their up-regulated gene targets are primarily associated with aberrant cell proliferation that involves DNA replication, transcription and nucleotide metabolism. The other three miRNAs (miR-21, miR-93, and miR-221) were up-regulated in HCC, and their down-regulated gene targets are primarily involved in metabolism and immune system processes. We further found evidence for a coordinated miRNA-induced regulation of important cellular processes, a finding to be considered when designing therapeutic applications based on miRNAs.

Highlights

As miRNAs modulate gene expression through messenger RNA (mRNA) degradation or translational repression, we first examined a negative correlation in expression between miRNA and their gene targets
We evaluated if differentially expressed miRNAs or their relevant differentially expressed gene targets are associated with various clinical characteristics, such as gender, age, hepatitis infection status, liver cirrhosis, stage, grade, size, relapse status, encapsulation, and Alpha Fetoprotein (AFP) levels (Tables 4 and 5)
MiRNAs have been shown to be differentially expressed in the tumors of hepatocellular carcinoma (HCC) patients

Summary

Introduction

Six were consistently reported in several studies to be differentially expressed in tumorous compared to non-tumorous tissues of HCC patients (see review[5]). Two previous studies on breast cancer and a pan-cancer catalogue integrated miRNA and mRNA expression profiles of tumor tissues to study miRNA-regulation on a whole genome level[15,16]. We considered all miRNAs and mRNAs in tumor and non-tumorous tissues available from whole genome miRNA and mRNA expression profiling, together with in silico miRNA target prediction algorithms. Through integration of these data, we identified miRNAs that coordinately dys-regulate mRNAs to perturb specific pathways that may lead to tumorigenesis

Methods

Results

Conclusion