title: Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C.
abstract: Despite advances in chronic hepatitis C treatment, a proportion of patients respond poorly to treatment. This study aimed to explore hepatic mRNA and microRNA signatures involved in hepatitis C treatment resistance. Global hepatic mRNA and microRNA expression profiles were compared using microarray data between treatment responses. Quantitative real-time polymerase chain reaction validated the gene signatures from 130 patients who were infected with hepatitis C virus genotype 1b and treated with pegylated interferon-alpha and ribavirin combination therapy. The correlation between mRNA and microRNA was evaluated using in silico analysis and in vitro siRNA and microRNA inhibition/overexpression experiments. Multivariate regression analysis identified that the independent variables IL28B SNP rs8099917, hsa-miR-122-5p, hsa-miR-17-5p, and MAP3K8 were significantly associated with a poor virologic response. MAP3K8 and miR-17-5p expression were inversely correlated with treatment response. Furthermore, miR-17-5p repressed HCV production by targeting MAP3K8. Collectively, the data suggest that several molecules and the inverse correlation between mRNA and microRNA contributed to a host genetic refractory hepatitis C treatment response.
authors.affiliation: Institute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Kashiwa, Chiba, Japan; Division of Gastroenterology and Hepatology, Kashiwa Hospital, The Jikei University School of Medicine, Kashiwa, Chiba, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsubota
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Aizaki
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Miyaguchi
authors.affiliation: Institute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Kashiwa, Chiba, Japan; Division of Gastroenterology and Hepatology, Kashiwa Hospital, The Jikei University School of Medicine, Kashiwa, Chiba, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagatsuma
authors.affiliation: Institute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Kashiwa, Chiba, Japan; Division of Gastroenterology and Hepatology, Kashiwa Hospital, The Jikei University School of Medicine, Kashiwa, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsudaira
authors.affiliation: National Bioscience Database Center, Japan Science and Technology Agency, Chiyoda-ku, Tokyo, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kushida
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Science, Chiba University, Chiba, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Laboratory Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuura
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D004347:Drug Interactions; D024882:Drug Resistance, Viral / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000821:virology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human