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MicroRNA 130 family regulates the hypoxia response signal through the P-body protein DDX6.

ABSTRACT: The transcription factor HIF-1? (hypoxia inducible factor 1?) has an essential role in the maintenance of oxygen homeostasis in metazoans. HIF-1? expression and activity in the hypoxic response is regulated at the translation and post-translational levels. However, the mechanism and modulator of HIF-1? translation during hypoxia is not fully understood. We found that HIF-1? expression during hypoxia was upregulated by the microRNA 130 (miR-130) family. Levels of the miR-130 family are elevated under hypoxia, and their target is DDX6 mRNA, which is a component of the P-bodies. Furthermore, we found that a decrease of DDX6 expression by the miR-130 family enhanced the translation of HIF-1? in an internal ribosome entry site element-dependent manner. These results reveal a new HIF-1? translational mechanism and a role for P-bodies in hypoxic stress.

SUBMITTER: Saito K

PROVIDER: S-EPMC3152344 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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MicroRNA 130 family regulates the hypoxia response signal through the P-body protein DDX6.

Saito Ken K Kondo Eisaku E Matsushita Masayuki M

Nucleic acids research 20110412 14

The transcription factor HIF-1α (hypoxia inducible factor 1α) has an essential role in the maintenance of oxygen homeostasis in metazoans. HIF-1α expression and activity in the hypoxic response is regulated at the translation and post-translational levels. However, the mechanism and modulator of HIF-1α translation during hypoxia is not fully understood. We found that HIF-1α expression during hypoxia was upregulated by the microRNA 130 (miR-130) family. Levels of the miR-130 family are elevated u ...[more]

PMID: 21486751

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Project description:BackgroundEmerging evidence shows that microRNA-130 (miRNA-130) family may be useful as prognostic biomarkers in cancer. However, there is no confirmation in an independent validation study. The aim of this study was to summarize the prognostic value of miRNA-130 family (miRNA-130a and miRNA-130b) for survival in patients with cancer.MethodsThe pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the association strength between miRNA-130 family expression and prognosis. Kaplan-Meier plotters were used to verify the miRNA-130b expression and overall survival (OS).ResultsA total of 2141 patients with OS and 1159 patients with disease-free survival (DFS)/progression-free survival (PFS) were analyzed in evidence synthesis. For the miRNA-130a, the overall pooled effect size (HR) was HR 1.58 (95% CI: 1.21-2.06, P?<?0.001). Tissue and serum expression of miRNA-130a was significantly associated with the OS (HR?=?1.54, 95% CI: 1.11-2.14, P?=?0.009; HR?=?1.65, 95% CI: 1.14-2.38, P?=?0.008), and in gastric cancer (HR?=?1.81, 95% CI: 1.34-2.45, P?<?0.001). For the miRNA-13b, a statistical correlation was observed between high miRNA-130b expression and poor OS in patients with cancer (HR?=?1.95, 95% CI: 1.47-2.59, P?<?0.001), especially in tissue sample (HR?=?2.01, 95% CI: 1.39-2.91, P?<?0.001), Asian (HR?=?2.55, 95% Cl: 1.77-3.69, P?<?0.001) and hepatocellular carcinoma (HR?=?1.87, 95% CI: 1.23-2.85, P?=?0.004). The expression of miRNA-130b was significantly correlated with DFS/PFS (HR?=?1.53, 95% CI: 1.31-1.77, P?<?0.001), in tissue (HR?=?1.98, 95% CI: 1.50-2.62, P?<?0.001) and serum (HR?=?1.37, 95% CI: 1.15-1.64, P?<?0.001), especially in HCC (HR?=?1.98, 95% CI: 1.50, 2.62, P?<?0.001). In database test, a significant correlation between high miRNA-130b expression and poor OS for HCC patients was observed (HR?=?1.55, 95% CI: 1.01, 2.35, P?=?0.0045).ConclusionThe high expression of miRNA-130 family might predict poor prognosis in cancer patients. Prospectively, combining miRNA-130a and miRNA-130b may be considered as powerful prognostic predictor for clinical application.

Project description:Purpose: Guided by an in silico combination of microRNA (miRNA) target prediction, analysis of transcriptomic changes in 137 human diseases, and advanced gene network modeling, we predicted the miR-130/301 family of miRNAs as a shared regulator of a fibrotic gene network across human diseases, thus orchestrating broad control over disease manifestation. The goals of this study are to compare the lung mRNA profile of mouse model of Pulmonary hypertension, one of the most fibrotic pathology uncovered by our in silico prediction, treated with an inhibitor of miR-130/301 (Short-130) to mice treated with a control inhibitor (Short-NC). Methods: Eight-week-old mice (C57BL/6) were injected with SU5416 (20 mg/kg/dose; Sigma-Aldrich), followed by exposure to normobaric hypoxia (10% O2; OxyCycler chamber, Biospherix Ltd.) for 2 weeks. After 2 weeks and confirmation of PH development in 5 mice (right heart catheterization), mice were further treated with 3 intrapharyngeal injections (every 4 days) of control or miR-130/301 shortmer oligonucleotides, designed as fully modified antisense oligonucleotides complementary to the seed sequence of the miR-130/301 miRNA family (10 mg/kg/dose; Regulus). Specifically, the control and miR-130/301 shortmer oligonucleotides were nontoxic, lipid-permeable, high-affinity oligonucleotides. The miR-130/301 shortmer carried a sequence complementary to the active site of the miR-130/301 miRNA family, containing a phosphorothioate backbone and modifications (fluoro-, methoxyethyl, and bicyclic sugar) at the sugar 2’ position. Three days after the last injection, right heart catheterization was performed followed by harvesting of lung tissue for RNA extraction. Lung mRNA profiles of those mice or control mice (Normoxia+SU5416) were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed at the gene-level count. The gene level counts were then normalized with the R/Bioconductor package limma using the voom /variance stabilization method. The data were quality controlled for outliers using principal component analysis (PCA). Differential expression analysis between transcriptome profiles of experimental groups was performed using the R / Bioconductor package limma. Results: Transcriptomic analyses of whole lung from mice with hypoxia+SU5416-induced PH revealed a generalized de-repression of miR-130/301 targets by Short-130 treatment. Importantly, although whole lung transcriptomics likely captured only a subset of the miR-130/301 targets affecting the diseased pulmonary vasculature, pathway enrichment nonetheless revealed pronounced representation of several pathways known to be involved in fibrosis. Thus, the miR-130/301 family indeed induces a programmatic shift at the molecular level toward the fibrotic pathophenotype in vivo

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MicroRNA 130 family regulates the hypoxia response signal through the P-body protein DDX6.

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MicroRNA 130 family regulates the hypoxia response signal through the P-body protein DDX6.

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