Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA378249 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Prospective epidemiological studies have consistently supported that pancreatic cancer associated new-onset diabetes mellitus (PC-DM) is probably an important clue for early diagnosis of pancreatic cancer (PC). However, the mechanism underlying remains fragmentary. In this study, two types of exosomes released by murine pancreatic cancer cells and murine pancreatic ductal epithelial cells were isolated，and their effects on skeletal muscle cells were invested. The results showed that PC-derived exosomes can readily enter C2C12 myotubes, and then induce lipidosis, glucose intake inhibition. We also found that PC-derived exosomes can inhibit Insulin and PI3K/Akt signaling, in which insulin-induced FoxO1 nuclear exclusion is preserved while Glut4 trafficking is impaired. In addition, further microarray and Kyoto encyclopedia of genes and genomes (KEGG) analysis prompted that exosomal microRNAs (miRNAs) probably play an critical role in this process, which also has been preliminarily demonstrated in vitro. Taking together, these results suggest that PC-derived exosomes induce insulin resistance (IR) of skeletal muscle cells through Insulin and PI3K/Akt/FoxO1 signaling pathway, and exosomal miRNAs are probably involved. The novel findings also support the theories of cancer “metabolic reprogramming” and “metabolic crosstalk”.
2017-08-11 | GSE95741 | GEO
Project description:Mice pancreatic cancer derived exosomes(KPC-exosomes) could induce skeletal muscle cells(C2C12) insulin resistance and exosomal microRNAs (miRNAs) may exert an important effect (Sci Rep. 2017;7(1):5384). The data set GSE95741 provided the differentially expressed micro RNAs. In this work, we aim to detect the differentially expressed genes and explore the intrinsic link.
2022-01-01 | GSE174058 | GEO
Project description:C2C12 mouse myoblasts were transduced with either PAX3-FOXO1 expression vector (P3F-C2C12), a system that is commonly used to study the more aggressive alveolar rhabdomyosarcoma subtype, or empty vector (Ctrl-C2C12). Exosomes were isolated from both cell lines by differential centrifugation, and exosomal markers were characterized by western blot. Then, the Affymetrix GeneChip miRNA 3.0 array was used to identify the miRNA content of the extracted exosomes where the differentially deregulated miRNA (either enriched or depleted) in P3F-C2C12 exosomes were determined relative to Ctrl-C2C12 exosomes. Results showed that PAX3-FOXO1 fusion gene alters the content of exosomes and that the enriched miR-486-5p is a downstream effector of PAX3-FOXO1 in mediating the oncogenic effects of exosome-mediated paracrine signaling in this setting.
2019-12-01 | E-MTAB-7646 | biostudies-arrayexpress
Project description:Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism, however the molecular mechanosensor remains unknown. Here, we show that SWELL1 (LRRC8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. SWELL1 over-expression in SWELL1 KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle targeted SWELL1 KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to WT mice. These results reveal that the SWELL1-LRRC8 complex regulates insulin-PI3K-AKT-mTOR signaling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.
2020-08-22 | GSE156667 | GEO
Project description:Through small RNA sequencing, we finded that a total of 8 miRNAs, including miR-133a-3p and miR-1a-3p cluster, showed differential expression after guanidineacetic acid supplement. To further study the function of miR-133a-3p and miR-1a-3p in guanidineacetic acid induce myotube hypertrophy, we transfected miR-133a-3p and miR-1a-3p mimics, that also induce myotube hypertrophy. Through bioinformatics and dual-luciferase reporter system, the target gene of miR-133a-3p and miR-1a-3p were respectively determined. Meanwhile, miR-133a-3p and miR-1a-3p modulate PI3K-Akt-mTOR signaling pathway by restraining target gene expression.
2019-05-17 | GSE118528 | GEO
Project description:FOXO1 acts as a tumor suppressor in solid tumors. The oncogenic PI3K pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B cell derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations which prevent AKT targeting and lock the transcription factor in the nucleus are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development we demonstrate pro-proliferative and anti-apoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B cell derived lymphomagenesis.
2018-12-21 | GSE119437 | GEO
Project description:One major effect of PI3-kinase activation downstream of the serine/threonine kinase Akt is the phosphorylation of the transcription factor FOXO1 and its neutralization. FOXO1 has several ubiquitous targets genes in many cell types that control cell quiescence, oxydative stress or apoptosis. However, it has been demonstrated that FOXO1 also has specific targets depending of the cellular context. The role of FOXO1 to regulate specific genes in T lymphocytes has not been investigated yet. To examine this point, we used the CD4+ leukemia Jurkat T-cell line, in which the PI3K pathway is constitutively turned-on and FOXO1 transcriptional activity strongly repressed. These cells were transduced with lentiviruses coding for a constitutively active form of FOXO1 fused to GFP and having the three AKT phosphorylation sites mutated to alanine (FOXO1-AAA-GFP) to restore its transcriptional activity. GFP-transduced cells were used as a control and the gene activation levels in the two cell populations analyzed 48 hours post-infection.
2008-12-01 | E-TABM-391 | biostudies-arrayexpress
Project description:Hyperinsulinemia is often viewed as compensatory to insulin resistance, but studies have shown that high levels of insulin may contribute to insulin resistance. The precise mechanisms by which hyperinsulinemia contributes to insulin resistance remain poorly defined. To understand direct effects of prolonged exposure to excess insulin in muscle cells, we incubated differentiated C2C12 myotubes with elevated insulin for 16 hours, followed by 6 hours serum starvation, before examining key insulin signaling nodes. Using this model, we found that prolonged high insulin treatment significantly increased the phosphorylation of insulin receptor (INSR) and AKT, but not ERK. After starvation, acute AKT and ERK signaling stimulated by 0.2 - 20 nM insulin was attenuated. INSR protein was significantly downregulated by hyperinsulinemia in a insulin-dose-dependent manner. Surface INSR was reduced proportionally to total INSR levels. Mechanistically, we found that hyperinsulinemia strongly downregulated Insr mRNA, which was correlated with increased threonine 24 phosphorylation of FOXO1. Interestingly, 6h starvation reversed the effects of high insulin on basal phosphorylation of INSR, AKT and FOXO1, and Insr transcription. Using RNAseq, bioinformatics, and follow-up RNAi studies, we identified SIN3A as a negative regulator of Insr mRNA levels and JUND, MAX and MXI as positive regulators of Irs2 mRNA. We validated our in vitro results by determining that INSR levels in mouse skeletal muscle were negatively correlated with circulating insulin in vivo. Together, our findings shed new light on the mechanisms underlying hyperinsulinemia-induced insulin resistance in muscle cells, which are likely to be relevant in the pathogenesis of type 2 diabetes.
2020-12-31 | GSE147422 | GEO
Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.
2016-06-13 | E-MTAB-4263 | biostudies-arrayexpress
Project description:Healthy skeletal muscle can regenerate after ischaemic, mechanical, or toxin-induced injury, but ageing impairs that regeneration potential. This has been largely attributed to dysfunctional satellite cells and reduced myogenic capacity. Understanding which signalling pathways are associated with reduced myogenesis and impaired muscle regeneration can provide valuable information about the mechanisms driving muscle ageing and prompt the development of new therapies. To investigate this, we developed a high-throughput in vitro model to assess muscle regeneration in chemically injured C2C12 and human myotube-derived young and aged myoblast cultures. We observed a reduced regeneration capacity of aged cells, as indicated by an attenuated recovery towards preinjury myotube size and myogenic fusion index at the end of the regeneration period, in comparison with younger muscle cells that were fully recovered. RNA-sequencing data showed significant enrichment of KEGG signalling pathways, PI3K-Akt, and downregulation of GO processes associated with muscle development, differentiation, and contraction in aged but not in young muscle cells. Data presented here suggests that repair in response to in vitro injury is impaired in aged vs. young muscle cells. Our study establishes a framework that enables further understanding of the factors underlying impaired muscle regeneration in older age.
2023-07-05 | E-MTAB-12248 | biostudies-arrayexpress