Regulation of human lung alveolar multipotent cells by a novel p38α MAPK/miR-17-92 axis
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PROVIDER: S-EPMC3419937 | biostudies-literature | 2012 Aug
REPOSITORIES: biostudies-literature
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Project description:The cellular and molecular mechanisms that control lung homeostasis and regeneration are still poorly understood. It has been proposed that a population of cells exists in the mouse lung with the potential to differentiate into all major lung bronchioalveolar epithelium cell types in homeostasis or in response to virus infection. A new population of E-Cad/Lgr6(+) putative stem cells has been isolated, and indefinitely expanded from human lungs, harbouring both, self-renewal capacity and the potency to differentiate in vitro and in vivo. Recently, a putative population of human lung stem cells has been proposed as being c-Kit(+). Unlike Integrin-α6(+) or c-Kit(+) cells, E-Cad/Lgr6(+) single-cell injections in the kidney capsule produce differentiated bronchioalveolar tissue, while retaining self-renewal, as they can undergo serial transplantations under the kidney capsule or in the lung. In addition, a signalling network involving the p38α pathway, the activation of p53 and the regulation of the miR-17-92 cluster has been identified. Disruption of the proper cross-regulation of this signalling axis might be involved in the promotion of human lung diseases.
| S-EPMC3419929 | biostudies-literature
Project description:The terminal stages of pulmonary development, called sacculation and alveologenesis, involve both differentiation of distal lung endoderm progenitors and extensive cellular remodeling of the resultant epithelial lineages. These processes are coupled with dramatic expansion of distal airspace and surface area. Despite the importance of these late developmental processes and their relation to neonatal respiratory diseases, little is understood about the molecular and cellular pathways critical for their successful completion. We show that a histone deacetylase 3 (Hdac3)-mediated epigenetic pathway is critical for the proper remodeling and expansion of the distal lung saccules into primitive alveoli. Loss of Hdac3 in the developing lung epithelium leads to a reduction of alveolar type 1 cell spreading and a disruption of lung sacculation. Hdac3 represses miR-17-92 expression, a microRNA cluster that regulates transforming growth factor β (TGF-β) signaling. De-repression of miR-17-92 in Hdac3-deficient lung epithelium results in decreased TGF-β signaling activity. Importantly, inhibition of TGF-β signaling and overexpression of miR-17-92 can phenocopy the defects observed in Hdac3 null lungs. Conversely, loss of miR-17-92 expression rescues many of the defects caused by loss of Hdac3 in the lung. These studies reveal an intricate epigenetic pathway where Hdac3 is required to repress miR-17-92 expression to allow for proper TGF-β signaling during lung sacculation.
| S-EPMC4750387 | biostudies-literature
Project description:Although androgen-deprivation treatment (ADT) is the main treatment for advanced prostate cancer (PCa), it eventually fails. This failure invariably leads to castration-resistant prostate cancer (CRPC) and the development of the neuroendocrine (NE) phenotype. The molecular basis for PCa progression remains unclear. Previously, we and others have demonstrated that the sex-determining region Y-box 4 (SOX4) gene, a critical developmental transcription factor, is overexpressed and associated with poor prognosis in PCa patients. In this study, we show that SOX4 expression is associated with PCa progression and the development of the NE phenotype in androgen deprivation conditions. High-throughput microRNA profiling and bioinformatics analyses suggest that SOX4 may target the miR-17-92 cluster. SOX4 transcriptionally upregulates miR-17-92 cluster expression in PCa cells. SOX4-induced PCa cell proliferation, migration, and invasion are also mediated by miR-17-92 cluster members. Furthermore, RB1 is a target gene of miR-17-92 cluster. We found that SOX4 downregulates RB1 protein expression by upregulating the miR-17-92 expression. In addition, SOX4-knockdown restrains NE phenotype and PCa cell proliferation. Clinically, the overexpression of miR-17-92 members is shown to be positively correlated with SOX4 expression in PCa patients, whereas RB1 expression is negatively correlated with SOX4 expression in patients with the aggressive PCa phenotype. Collectively, we propose a novel model of a SOX4/miR-17-92/RB1 axis that may exist to promote PCa progression.
| S-EPMC6593351 | biostudies-literature
Project description:MiR-17-92 cluster is an oncogenic miRNA cluster that is implicated in several cancers, although its role in hepatocarcinogenesis has not been clearly defined. In this study, we show that the miR-17-92 cluster is highly expressed in human hepatocellular carcinoma (HCC) tissues compared to the non-tumorous liver tissues by RT-PCR and in situ hybridization analyses. Increased miR-17-92 cluster expression in HCC tissues was further confirmed by analysis of the RNA-sequencing data of 319 patients available from the Cancer Genome Atlas (TCGA) Data Portal (https://tcga-data.nci.nih.gov/tcga/). To create an animal model that resembles enhanced miR-17-92 in the liver, we developed liver-specific miR-17-92 transgenic mice and the animals were treated with the hepatic carcinogen, diethylnitrosamine (DEN). We observed that the liver-specific miR-17-92 transgenic mice showed significantly increased hepatocellular cancer development compared to the matched wild-type control mice. Forced overexpression of the miR-17-92 cluster in cultured human hepatocellular cancer cells enhanced tumor cell proliferation, colony formation and invasiveness in vitro, whereas inhibition of the miR-17-92 cluster reduced tumor cell growth. By analyzing the miRNA and mRNA sequencing data from the 312 hepatocellular cancer patients available from the TCGA database, we observed that the expression levels of the miR-17-92 cluster members and host gene in the tumor tissues are negatively correlated with several target genes, including CREBL2, PRRG1, NTN4. Our findings demonstrate an important role of the miR-17-92 cluster in hepatocarcinogenesis and suggest the possibility of targeting this pivotal miRNA cluster for potential therapy.
| S-EPMC4794620 | biostudies-literature
Project description:MYC regulates tumorigenesis by coordinating the expression of thousands of genes. We found that MYC appears to regulate the decisions between cell survival versus death and self-renewal versus senescence through the microRNA miR-17-92 cluster. Addiction to the MYC oncogene may therefore in fact be an addiction to miR-17-92.
| S-EPMC4905255 | biostudies-other
Project description:RationaleIdiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. In organ repair and remodeling, epigenetic events are important. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and can target epigenetic molecules important in DNA methylation. The miR-17~92 miRNA cluster is critical for lung development and lung epithelial cell homeostasis and is predicted to target fibrotic genes and DNA methyltransferase (DNMT)-1 expression.ObjectivesWe investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue.MethodsExpression and DNA methylation patterns of miR-17~92 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-17~92 cluster and DNMT-1 expression was examined in vitro. Using a murine model of pulmonary fibrosis, we examined the therapeutic potential of the demethylating agent, 5'-aza-2'-deoxycytidine.Measurements and main resultsCompared with control samples, miR-17~92 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-17~92 promoter was increased. Several miRNAs from the miR-17~92 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-17~92 expression was reduced in the lungs of bleomycin-treated mice. Treatment with 5'-aza-2'-deoxycytidine in a murine bleomycin-induced pulmonary fibrosis model reduced fibrotic gene and DNMT-1 expression, enhanced miR-17~92 cluster expression, and attenuated pulmonary fibrosis.ConclusionsThis study provides insight into the pathobiology of IPF and identifies a novel epigenetic feedback loop between miR-17~92 and DNMT-1 in lung fibrosis.
| S-EPMC3603596 | biostudies-literature
Project description:B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.
| S-EPMC10859618 | biostudies-literature
Project description:Methionine COFRADIC combined with Arg and Lys SILAC labeling was used to quantify proteins upon induction of miR-17-92 in SHEP neuroblastoma cells. Differently labeled cells treated with tetracycline for 72 h or left untreated, were harvested and mixed lysates were analyzed by methionine COFRADIC to isolate methionyl peptides followed by identification of these peptides by LC-MS/MS and subsequent quantification.
2010-12-10 | PRD000321 | Pride
Project description:The overexpression of microRNA cluster miR-17-92 has been implicated in development of solid tumors and hematological malignancies. The role of miR-17-92 in lymphomagenesis has been extensively investigated; however, because of the developmental defects caused by miR-17-92 dysregulation, its ability to drive tumorigenesis has remained undetermined until recently. Here we demonstrate that overexpression of miR-17-92 in a limited number of hematopoietic cells is sufficient to cause B cell malignancies. In sum, our study provides a novel and physiologically relevant model that exposes the potent ability of miR-17-92 to act as a driver of tumorigenesis.
| S-EPMC4376677 | biostudies-literature
Project description:Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Emu-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt-mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.
| S-EPMC2800084 | biostudies-literature