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

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. Results: We detected 374 microRNAs expressed in liver, including miR-122-5p that constituted over 39% ofthe hepatic miRnome. Among the liver expressed miRs, the levels of 64 significantly differed between tumor and control samples (FDR 2). 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. Conclusions: 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. Overall design: We employed next-generation sequencing to comprehensively analyze microRNA transcriptome in HCCtumors (n = 24) and unaffected tissue adjacent to tumors (n = 24), including samples with (n = 15) and without cirrhosis (n = 9).