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Int J Biochem Cell Biol. 2014 Aug;53:208-17. doi: 10.1016/j.biocel.2014.05.020. Epub 2014 May 27.

Next generation sequencing reveals microRNA isoforms in liver cirrhosis and hepatocellular carcinoma.

Author information

1
Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; Laboratory of Human Cancer Genetics, Centre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, Poland.
2
Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; Department of Nuclear Medicine and Endocrine Oncology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, 44-101 Gliwice, Poland.
3
Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland.
4
Department of Pathology, Medical University of Warsaw, 02-091 Warsaw, Poland.
5
Second Department of Anaesthesiology and Intensive Therapy, Medical University of Warsaw, 02-091 Warsaw, Poland.
6
Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; Laboratory of Human Cancer Genetics, Centre of New Technologies, CENT, University of Warsaw, 02-089 Warsaw, Poland. Electronic address: krystian.jazdzewski@wum.edu.pl.

Abstract

Hepatocellular carcinoma (HCC) represents the major histological subtype of liver cancer. Tumorigenic changes in hepatic cells potentially result from aberrant expression of microRNAs (miRNAs). Individual microRNA gene may give rise to miRNAs of different length, named isomiRNAs that proved to be functionally relevant. Since microRNA length heterogeneity in hepatic tissue has not been described before, we employed next-generation sequencing to comprehensively analyze microRNA transcriptome in HCC tumors (n=24) and unaffected tissue adjacent to tumors (n=24), including samples with (n=15) and without cirrhosis (n=9). We detected 374 microRNAs expressed in liver, including miR-122-5p that constituted over 39% of the hepatic miRnome. Among the liver expressed miRs, the levels of 64 significantly differed between tumor and control samples (FDR<0.05, fold change>2). Top deregulated miRNAs included miR-1269a (T/N=22.95), miR-3144-3p (T/N=5.24), miR-183-5p (T/N=4.63), miR-10b-5p (T/N=3.87), miR-490-3p (T/N=0.13), miR-199a-5p (T/N=0.17), miR-199a-3p/miR-199b-3p (T/N=0.19), miR-214-5p (T/N=0.20) and miR-214-3p (T/N=0.21). Almost all miRNA genes produced several mature molecules differing in length (isomiRNAs). The reference sequence was not the most prevalent in 38.6% and completely absent in 10.5% of isomiRNAs. Over 26.1% of miRNAs produced isoforms carrying≥2 alternative seed regions, of which 35.5% constituted novel, previously unknown seeds. This fact sheds new light on the percentage of the human genome regulated by microRNAs and their variants. Among the most deregulated miRNAs, miR-199a-3p/miR-199b-3p (T/N fold change=0.18, FDR=0.005) was expressed in 9 isoforms with 3 different seeds, concertedly leading to upregulation of TGF-beta signaling pathway (OR=1.99; p=0.004). In conclusion, the study reveals the comprehensive miRNome of hepatic tissue and provides new tools for investigation of microRNA-dependent pathways in cirrhotic liver and hepatocellular carcinoma. This article is part of a Directed Issue entitled: Rare Cancers.

KEYWORDS:

Deep sequencing; HCC; Isoforms; Liver cancer; miRs

PMID:
24875649
DOI:
10.1016/j.biocel.2014.05.020
[Indexed for MEDLINE]

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