Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA292391 | ENA |
REPOSITORIES: ENA
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Project description:A growing body of literature has proposed cell-autonomous tumor suppressor functions for the mir-143~145 cluster in a variety of human cancers, including lung adenocarcinoma, and has reported therapeutic benefits of delivering mir-143 and mir- 145 to tumors. In contrast to these studies, we found that depletion or forced expression of mir-143 and mir-145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. Surprisingly, we observed that loss of mir-143~145 from the tumor microenvironment significantly reduced tumor burden, indicating a non-cell- autonomous role for these miRNAs in promoting tumorigenesis. By examining the expression patterns of different cell populations isolated in vivo from tumor-bearing lungs using an integrated computational approach, we identified a role for mir-145 in stimulating the proliferation of endothelial cells by downregulating an inhibitory kinase, Camk1d, which prevents mitotic entry. As a consequence, tumors in mir-143~145- deficient animals exhibited diminished hallmarks of neo-angiogenesis, increased apoptosis and their expansion appeared limited by the tumor’s ability to co-opt the alveolar vasculature. These findings show that expression of the mir-143~145 cluster in the tumor stroma promotes rather than suppresses tumorigenesis and cautions against the use of these miRNAs as agents in cancer therapeutics.
2016-05-21 | GSE71877 | GEO
Project description:To assess the transcriptomic response associated with upregulation of the miR-143/-145 cluster, BRAFV600E mutant human melanoma cells M238P cells were transduced for stable expression of miR-143/145 cluster or with a control vector. Forty-eight hours after transduction, cells were treated with 1 μg/mL of puromycin for one week. RNA samples were then harvested. Two independent experiments were carried out.
2021-12-29 | GSE171881 | GEO
Project description:Lineage dedifferentiation towards a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and resistance to targeted therapy in melanoma. Here we show that the anti-fibrotic drug Nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy and delay tumor relapse in a pre-clinical model of melanoma. Acquisition of this resistant phenotype and its reversion by Nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p collaborated to mediate transition towards a drug resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof-of-principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.
2021-12-29 | GSE171883 | GEO
Project description:Transforming growth factor (TGF)-β is one of the major inducers of epithelial to mesenchymal transition (EMT), a crucial program that plays a critical role in promoting carcinoma’s metastasis formation. MicroRNAs-143 and -145, which are both TGF-β direct transcriptional targets, are essential for the differentiation of vascular smooth muscle cells (VSMC) during embryogenesis, a TGF-β-dependent process reminiscent of EMT. Their role in adult tissues is however less well defined and even ambiguous, since their expression was correlated both positively and negatively with tumor progression. Here we show that high expression of both miRs-143 and -145 in mouse mammary tumor cells expressing constitutively active STAT3 (S3C) is involved in mediating their disrupted cell-cell junctions. Additionally, miR-143 appears to play a unique role in tumorigenesis by enhancing cell migration in vitro and extravasation in vivo while impairing anchorage-independent
growth, which may explain the contradictory reports about its role in tumors. Accordingly, we demonstrate that overexpression of either miRNA in the non-transformed mammary epithelial NMuMG cells leads to upregulation of EMT markers and of several endogenous TGF-β targets, downmodulation of several junction proteins and increased motility. This correlates with enhanced basal and TGF-β-induced activity of SMAD transcription factors, suggesting that miR-143 and -145 can help promoting TGF-β mediated EMT via a positive feedback loop. Moreover, pervasive transcriptome perturbation consistent with the described phenotype was observed. In particular, the expression of several transcription factors involved in the mitogenic responses, of MAPK family members and, importantly, of several tight junction proteins and the SMAD co-repressor TGIF was significantly reduced. Our results provide important mechanistic insight into the non-redundant role played by miRs-143 and -145 in EMT-related processes in both transformed and non-transformed cells, and suggest that their expression must be finely coordinated to warrant optimal migration/invasion while not interfering with cell growth.
2017-07-19 | GSE98689 | GEO
Project description:In a series of mouse genetic studies, we concluded that miR-143/145 expression in intestinal subepithelial myofibroblasts (ISEMFs) promotes epithelial regeneration after DSS-mediated injury in the colon. This experiment aims to identify miR-143/145 target genes that are involved in this function. We generated primary ISEMFs from wildtype and miR-143/145 null mouse colons and analyzed their gene expression profile. We further subjected ISEMFs to LPS treatment, in order to measure gene expression changes that are only revealed after inflammatory stress.
2014-05-22 | GSE55651 | GEO
Project description:mRNA profiling of mouse ureters comparing wild-type ureter vs. ureters from mice having whole body deletion of miR-143 and miR-145 which results in abnormal ureter peristalsis and hydronephrosis We used microarrays to detail the global program of gene expression in wild-type and miR-143/145-deficient ureters which revealed dysregulation of genes linked to smooth muscle morphology and function. Two condition experiment: wild type vs miR-143/145 KO; biological replicates: individual mice - 2 wild type, 2 mutant. One replicate per array.
2014-10-08 | E-GEOD-58274 | biostudies-arrayexpress
Project description:In a series of mouse genetic studies, we concluded that miR-143/145 expression in intestinal subepithelial myofibroblasts (ISEMFs) promotes epithelial regeneration after DSS-mediated injury in the colon. This experiment aims to identify miR-143/145 target genes that are involved in this function. We generated primary ISEMFs from wildtype and miR-143/145 null mouse colons and analyzed their gene expression profile. We further subjected ISEMFs to LPS treatment, in order to measure gene expression changes that are only revealed after inflammatory stress. Three wild-type and three miR-143/145 null ISEMF cell lines were isolated from mouse colons. Cells were treated with or without 1 ug/mL LPS for 24 hours and total RNA was isolated. Gene expression was profiled using Illumina microarrays.
2014-05-22 | E-GEOD-55651 | biostudies-arrayexpress
Project description:The contribution of altered posttranscriptional gene silencing (PTGS) to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. We have described that expression of microRNAs (miR)-143 and -145 is dysregulated in genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, causes insulin resistance and impaired insulin-stimulated AKT activation. We used microarrays to analyze the underlying molecular mechanisms of miR-143-mediated development of insulin resistance.
2011-04-08 | GSE26460 | GEO
Project description:mRNA profiling of mouse ureters comparing wild-type ureter vs. ureters from mice having whole body deletion of miR-143 and miR-145 which results in abnormal ureter peristalsis and hydronephrosis We used microarrays to detail the global program of gene expression in wild-type and miR-143/145-deficient ureters which revealed dysregulation of genes linked to smooth muscle morphology and function.
2014-10-08 | GSE58274 | GEO
Project description:The contribution of altered posttranscriptional gene silencing (PTGS) to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. We have described that expression of microRNAs (miR)-143 and -145 is dysregulated in genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, causes insulin resistance and impaired insulin-stimulated AKT activation. We used microarrays to analyze the underlying molecular mechanisms of miR-143-mediated development of insulin resistance. miR-143DOX mice (n=3) and wildtype littermate controls (n=3) were treated with doxycycline via the drinking water to induce miR-143 overexpression in the transgenic animals. Primary hepatocytes were isolated for RNA extraction and hybridization on Affymetrix microarrays.
2011-04-08 | E-GEOD-26460 | biostudies-arrayexpress