Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Intrahepatic miRNA/mRNA expression in non-responders to pegylated interferon plus ribavirin combination therapy for chronic hepatitis C (miRNA microarray data)

ABSTRACT: Despite advance in interferon-based treatment for chronic hepatitis C, difficult-to-treat patients remain in existence yet. To identify key genes involved in difficult-to-treat characteristics, gene expression patterns of miRNA and RNA were analyzed by profiling pretreatment liver tissues from five sustained virological responders (SVR), three relapsers (R) and four non-responders (NR). Expression levels of miRNA and mRNA were compared between SVR/R and NR groups by using microarray, respectively. Quantitative real-time reverse-transcriptase polymerase chain reaction and statistical analyses validated genes with significantly differential expression levels in 50 liver tissues: proliferation-, inflammation- and anti-apoptosis-related mRNA expression levels increased significantly in NR, compared to SVR/R. Of miRNA with significantly differential expression levels on microarray, several miRNA were correlated inversely with those significant mRNA. In vitro studies by using miRNA inhibitors and mimics verified the inverse correlation between the miRNA and mRNA. These findings enhance our understanding of the difficult-to-treat molecular mechanism and identification of target molecules for novel treatments. Moderated t-statistics based on the empirical Bayes approach were performed to identify miRNA differentially expressed between SVRs/relapses and NVRs using the M-bM-^@M-^\limmaM-bM-^@M-^] package from BioConductor software (http://www.bioconductor.org/) under R statistical software version 2.12.1 (http://www.r-project.org/). Because of multiple hypothesis testing, p values were adjusted by the Benjamini-Hochberg false discovery rate (FDR) method. Related mRNA expression data are in GSE42697.

ORGANISM(S): Homo sapiens

SUBMITTER: Kaoru Mogushi

PROVIDER: E-GEOD-45179 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C.

Tsubota Akihito A Mogushi Kaoru K Aizaki Hideki H Miyaguchi Ken K Nagatsuma Keisuke K Matsudaira Hiroshi H Kushida Tatsuya T Furihata Tomomi T Tanaka Hiroshi H Matsuura Tomokazu T

PloS one 20140512 5

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 ...[more]

PMID: 24819603

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Project description:Introduction: Systems vaccinology is a novel approach to predict immune response in vaccines. We have used a systems biology approach to identify early gene ‘signatures’ that predicted viral load control after analytical therapy interruption (ATI) in HIV-1 infected patients vaccinated with a dendritic cell-based (DC) HIV-1 vaccine. Methods: Frozen post-vaccination PBMC samples from participants of a previously published DC vaccine (DCV2) clinical trial were used for the study. mRNA and miRNA were extracted and gene expression was determined by microarray method. Differential gene expression analysis was performed on both mRNA and miRNA between responders (> 1 log10 copies/mL drop of VL after 12 weeks of ATI) and non-responders (<= 1 log10 copies/mL drop in VL at week 12 of ATI). Gene set enrichment analysis (GSEA) was carried out with the hallmark gene sets of the Broad Institute on the mRNA data. After the stand-alone analyses of mRNA and miRNA we performed an additional GSEA with gene sets defined by the genes regulated by significantly differentially expressed miRNAs. Statistical analysis was done using R and the GSEA software of the Broad Institute. Results: There were 15 responders and 20 non-responders. No differentially expressed mRNAs were observed between responders and non-responders. As compared with non-responders, responders showed an up-regulation of gene sets corresponding to TNF- alpha signaling via the NFkB pathway, inflammatory response, coagulation, the complement system, Il6 and Il2 JAK-STAT signaling, or reactive oxygen-species pathways were up-regulated, and a down-regulation of gene sets corresponding to E2F targets, oxidative phosphorylation, or interferon alpha response. We found 9 differentially expressed miRNAs between responders and non-responders: miR-32-3p, miR-185-3p, miR-223-3p, miR-500b-3p, miR-550a-3p, miR-1183, miR-1184, miR-4455, and miR-8063. Twelve Broad hallmark gene sets that were significantly deregulated in the GSEA showed significant overlap with genes regulated by one or more of these miRNAs, 10 of them with genes regulated by miR-223-3p. We also observed that the expression of genes regulated by miR-223-3p, miR-1183 and miR-8063 was significantly down-regulated in responders as compared with non-responders. Conclusions: Deregulation of certain gene sets related to inflammatory processes seems fundamental in viral control during ATI. miR-223-3p may be one of the miRNAs that fine tune part of these processes.

Project description:Dioxin-like chemicals are well-known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA levels in several systems, might be responsible for mRNA downregulation in dioxin/AHR pathways. We used the Exiqon miRNA array platform as well as quantitative RT-PCR to measure miRNA levels in dioxin-sensitive Long-Evans (Turku/AB; L-E) rats vs. dioxin-resistant Han/Wistar(Kuopio; H/W) rats. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo caused few changes in miRNA levels in rat livers and those changes that were statistically significant were of modest magnitude. AHR genotype had little effect on hepatic miRNA levels, either in constitutive expression or in response to TCDD – only a few miRNAs differed in expression between between L-E rats (that have wildtype AHR) compared to H/W rats (whose AHR has a large deletion in the transactivation domain). It is unlikely that mRNA downregulation by dioxins is mediated by miRNAs, nor are miRNAs likely to play a significant role in dioxin toxicity in adult rodent liver. We conducted a thorough investigation to address the following questions: (1) does AHR genotype itself affect constitutive expression of microRNAs? (2) does TCDD affect microRNA levels and, if so, is this response dependent on the AHR? (3) does TCDD affect microRNA levels differently in animals that are sensitive to dioxin toxicity versus those that are dioxin-resistant? We assessed the in vivo effect of TCDD on microRNA levels in liver at multiple time points after TCDD treatment using microRNA arrays along with quantitative RT-PCR. The cumulative results of our experiments indicate that downregulation of mRNA levels by dioxins in adult rodent livers is very unlikely to involve microRNAs. Manuscript Submitted: Moffat ID, Boutros PC, Celius T, Pohjanvirta R & Okey AB. Micro-RNAs in rodent liver are refractory to dioxin treatment. Toxicological Sciences May, 2007. Keywords: miRNA expression, Time course, response to xenobiotics, genetic modification, comparative genome hybridization We examined strain differences in miRNA expression independent of TCDD: 19-h vehicle-treated dioxin-resistant H/W AHRH/W/H/W rats (HC19) vs. vehicle- control dioxin-sensitive L-E AHRWT/WT rats (LC19). In the dioxin-sensitive rats we compared miRNA expression levels 3 h (LT3) or 19 h (LT19) post-TCDD treatment vs. LC19. In the dioxin-resistant rats we compared miRNA levels 3 h (HT3), 19 h (HT19), or 96 h (HT96) post-TCDD treatment vs. HC19.

Dataset Information

Intrahepatic miRNA/mRNA expression in non-responders to pegylated interferon plus ribavirin combination therapy for chronic hepatitis C (miRNA microarray data)

Publications

Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C.

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