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

肝细胞癌 生物 癌症研究 癌症 癌变 内科学 转录组 基因
作者
Anna Wojcicka,Michal Swierniak,Oskar Kornasiewicz,Wojciech Gierlikowski,Monika Maciag,Monika Kolanowska,Marta Kotlarek,Barbara Górnicka,Lukasz Koperski,Grzegorz Niewiński,Marek Krawczyk,Krystian Jazdzewski
出处
期刊:The International Journal of Biochemistry & Cell Biology [Elsevier BV]
卷期号:53: 208-217 被引量:71
标识
DOI:10.1016/j.biocel.2014.05.020
摘要

a b s t r a c t 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 func- tionally 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 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 miR- NAs, 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.
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