MiR-26a attenuates colitis and colitis-associated cancer by targeting the multiple intestinal inflammatory pathways.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang W
PROVIDER: S-EPMC7985669 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Intestinal fibrosis is the most common complication of Crohn's disease (CD) that is one major disorder of inflammatory bowel disease (IBD), but the precise mechanism remains unclear. MiR-155 has been involved in fibrotic diseases. Here, we determined the role of miR-155 in regulating intestinal fibrosis. MiR-155 levels were significantly up-regulated in CD patients with intestinal stricture CD. The overexpression of miR-155 significantly aggravated TNBS-induced CD-associated intestinal fibrosis. Mechanistically, we identified that HBP1, a negative regulator of the Wnt/β-catenin signalling pathway, is a direct target of miR-155. Moreover, in vitro and in vivo experiments suggested that the miR-155/HBP1 axis activates Wnt/β-catenin signalling pathway to induce intestinal fibrosis. Taken together, we demonstrated that miR-155 directly targets HBP1 to induce CD-associated intestinal fibrosis via Wnt/β-catenin signalling pathway.
| S-EPMC8107084 | biostudies-literature
Project description:MicroRNAs are small non-coding RNA regulatory molecules that play an important role in the development and function of immune cells. MicroRNA-26a (miR-26a) exhibits anti-inflammatory immune effects on immune cells. However, the exact mechanism by which miR-26a plays an anti-inflammatory role remains unclear. Here, we report that miR-26a reduces inflammatory response via inhibition of prostaglandin E2 (PGE2) production by targeting cyclooxygenase-2 (COX-2). We found that miR-26a was downregulated in vitro and in vivo. The miR-26a mimic significantly decreased COX-2 protein levels, further inhibiting pro-inflammatory cytokine production in LPS-stimulated macrophages. We predicted that miR-26a could potentially target COX-2 in LPS-stimulated macrophages. Computational algorithms showed that the 3'-UTR of COX-2 mRNA contains a binding site for miR-26a. This putative targeting relationship between miR-26a and COX-2 was further confirmed by a dual-reporter gene assay. The anti-inflammatory effects of the miR-26a mimic were diminished by PGE2 supplementation. Importantly, miR-26a mimics protected mice from lethal endotoxic shock and attenuated pro-inflammatory cytokine production. Collectively, these results suggest that miR-26a may function as a novel feedback negative regulator of the hyperinflammatory response and as a drug target for the progression of inflammation.
| S-EPMC8791555 | biostudies-literature
Project description:Irreversible respiratory obstruction resulting from progressive airway damage, inflammation and fibrosis is a feature of several chronic respiratory diseases, including cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). The cytokine transforming growth factor ? (TGF-?) has a pivotal role in promoting lung fibrosis and is implicated in respiratory disease severity. In the present study, we show that a previously uncharacterized miRNA, miR-1343, reduces the expression of both TGF-? receptor 1 and 2 by directly targeting their 3'-UTRs. After TGF-? exposure, elevated intracellular miR-1343 significantly decreases levels of activated TGF-? effector molecules, pSMAD2 (phosphorylated SMAD2) and pSMAD3 (phosphorylated SMAD3), when compared with a non-targeting control miRNA. As a result, the abundance of fibrotic markers is reduced, cell migration into a scratch wound impaired and epithelial-to-mesenchymal transition (EMT) repressed. Mature miR-1343 is readily detected in human neutrophils and HL-60 cells and is activated in response to stress in A549 lung epithelial cells. miR-1343 may have direct therapeutic applications in fibrotic lung disease.
| S-EPMC4867233 | biostudies-literature
Project description:Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes, yet the mechanisms are not completely understood. Here, we demonstrated that serum LPS levels were significantly higher in newly diagnosed diabetic patients than in normal control. miR-145 level in peripheral blood mononuclear cells decreased in type 2 diabetics. LPS repressed the transcription of miR-143/145 cluster and decreased miR-145 levels. Attenuation of miR-145 activity by anti-miR-145 triggered liver inflammation and increased serum chemokines in C57BL/6 J mice. Conversely, lentivirus-mediated miR-145 overexpression inhibited macrophage infiltration, reduced body weight, and improved glucose metabolism in db/db mice. And miR-145 overexpression markedly reduced plaque size in the aorta in ApoE-/- mice. Both OPG and KLF5 were targets of miR-145. miR-145 repressed cell proliferation and induced apoptosis partially by targeting OPG and KLF5. miR-145 also suppressed NF-κB activation by targeting OPG and KLF5. Our findings provide an association of the environment with the progress of metabolic disorders. Increasing miR-145 may be a new potential therapeutic strategy in preventing and treating metabolic diseases such as type 2 diabetes and atherosclerosis.
| S-EPMC7109608 | biostudies-literature
Project description:BackgroundMultiple genes have been associated with IBD, and many of these can be linked to alterations in autophagy, UPR, ubiquitination, and metabolic and immune response pathways. The aim of this study was to analyze a transcriptomic panel of mediators associated with the inflammatory pathways in the colonic mucosa of UC patients. Patients and Methods. We studied a total of 100 patients with definitive diagnosis of UC (50 active and 50 in remission) and a control group (50 subjects) without endoscopic evidence of intestinal inflammation. Colonic mucosal biopsies were taken by colonoscopy and preserved in RNA later. Gene expression were measured by real-time polymerase chain reaction (RT-PCR).ResultsThe gene expressions of XBP1, AGR2, HSPA5, UBE2L3, TNFRSF14, LAMP3, FCGR2A, LSP1, CTLA4, SOD2, TDO2, and ALDOB mRNA levels were significantly higher in the colonic mucosa from UC patients (both quiescent and active) as compared to the control group (P < 0.05). Conversely, IRGM, ORDML3, UBD, CUL2, CYLD, FOXC2, FOXO4, DOK3, and SNX20 mRNA levels were found to be significantly lower in patients with active disease, as compared to those with active disease (P < 0.05). Gene expressions of IRGM, CTLA4, FOXO4, SLC26A3, SLC39A4, SOD2, TDO2, and ALDOB were associated with clinical outcomes, such as medical treatment in response to aminosalicylates, histological remission, clinical course, and evolution.Conclusions: The gene expressions of FOXO4, ALDOB, SOD2, TOD2, SLC26A3, and SLC39A4 were associated with the clinical course and histological activity and are of relevance since these provide the utility of new prognostic markers in IBD. Gene expression signature showed dysregulation in mediators associated with autophagy, ubiquitination, ER stress, oxidative stress, carbohydrate metabolism, solute transport, and T cell regulation in the colonic mucosa from patients with UC, suggesting that these genes could be involved in the pathogenesis of UC.
| S-EPMC7201440 | biostudies-literature
Project description:Inflammatory caspases are essential effectors of inflammation and cell death. Here, we investigated their roles in colitis and colorectal cancer and report a bimodal regulation of intestinal homeostasis, inflammation and tumorigenesis by caspases-1 and -12. Casp1-/- mice exhibited defects in mucosal tissue repair and succumbed rapidly after dextran sulfate sodium (DSS) administration. This phenotype was rescued by administration of exogenous interleukin-18 and was partially reproduced in mice deficient in the inflammasome adaptor ASC. Casp12-/- mice, in which the inflammasome is derepressed, were resistant to acute colitis and showed signs of enhanced repair. Together with their increased inflammatory response, the enhanced repair response of Casp12-/- mice rendered them more susceptible to colorectal cancer induced by azoxymethane (AOM)+DSS. Taken together, our results indicate that the inflammatory caspases are critical in the induction of inflammation in the gut following injury, which is necessary for tissue repair and maintenance of immune tolerance. Total RNA obtained from isolated tumors or normal colon tissue from wild type and caspase-12 deficient mice were compared.
2010-07-30 | E-GEOD-20407 | biostudies-arrayexpress
Project description:The multidrug resistance (MDR) acquired in human osteosarcoma is a huge obstacle for effective chemotherapy. Recently, microRNA-26a (miR-26a) has been associated with the pathogenesis and progression of osteosarcoma. However, whether it regulates MDR in osteosarcoma is unknown. We show here that miR-26a expression declines in chemoresistant osteosarcoma after neoadjuvant chemotherapy, and its expression correlates with clinical outcome. In addition, compared with sensitive parental cells, miR-26a expression also declines in osteosarcoma MDR cells, together suggesting a negative correlation between miR-26a expression and MDR development in osteosarcoma. We also show that the enforced expression of miR-26a reverses MDR in osteosarcoma cells, and conversely, miR-26a knockdown confers MDR in chemosensitive osteosarcoma cells treated with doxorubicin, methotrexate, or cisplatin. Mechanistically, miR-26a directly targets the pro-survival protein myeloid cell leukemia 1 (MCL1), and in turn, the enforced expression of MCL1 markedly antagonizes miR-26a-decreased MDR in osteosarcoma MDR cells, therefore demonstrating that miR-26a reverses MDR in osteosarcoma by targeting MCL1. Lastly, miR-26a reverses resistance to doxorubicin in osteosarcoma MDR cells xenografted in nude mice. Collectively, these results reveal a negative role and the underlying mechanism of miR-26a in the regulation of MDR in human osteosarcoma, implying a potential tactic of manipulating miR-26a for overcoming MDR in osteosarcoma chemotherapy.
| S-EPMC8012539 | biostudies-literature
Project description:miRNA, which involves in pathogenesis of thyroid cancer via different targets, has been found aberrantly expressed in thyroid cancer. Modes of actions of miR-26a in papillary thyroid carcinoma (PTC), however, have not been fully understood to this date. In vitro results obtained from this research confirmed miR-26a was down-regulated in PTC cells (i.e. TPC-1 and BCPAP) where the down-regulation of miR-26a was found to be able to promote cell proliferation. In order to explore the mechanisms, potential targets of miR-26a were postulated: cAMP regulated phosphoprotein 19 (ARPP19) turned out to be the target of miR-26a and it was by depleting ARPP19 was the cell proliferation be suppressed. This suggested that miR-26a regulated cell proliferation by targeting ARPP19. In addition, such a depletion of ARPP19 sensitized PTC cells to tamoxifen (TMX) treatment. The above findings indicated miR-26a was a target of interest regarding the treatment of refractory thyroid carcinomas.
| S-EPMC6048401 | biostudies-literature
Project description:Background:Tongue squamous cell carcinoma (TSCC) is the most common oral malignancy. Previous studies found that microRNA (miR)-26a and miR-26b were downregulated in TSCC tissues. The current study was designed to explore the effects of miR-26a/miR-26b on TSCC progression and the potential mechanism. Methods:Expression of miR-26a, miR-26b and p21 Activated Kinase 1 (PAK1) in TSCC tissues and cell lines was detected by reverse transcription- quantitative polymerase chain reaction (RT-qPCR). Flow cytometry analysis was performed to examine cell cycle and apoptosis. Transwell assay was conducted to evaluate the migrated and invasive abilities of SCC4 and Cal27 cells. In addition, western blot assay was employed to analyze the protein level. Glucose assay kit and lactate assay kit were utilized to analyze glycolysis. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were applied to explore the relationship between miR-26a/miR-26b and PAK1. Xenograft tumor model was constructed to explore the role of miR-26a/miR-26b in vivo. Results:Both miR-26a and miR-26b were underexpressed, while PAK1 was highly enriched in TSCC. Overexpression of miR-26a and miR-26b inhibited TSCC cell cycle, migration invasion and glycolysis, while promoted cell apoptosis. Both miR-26a and miR-26b directly targeted and negatively regulated PAK1 expression. Introduction of PAK1 partially reversed miR-26a/miR-26b upregulation-mediated cellular behaviors in TSCC cells. Gain of miR-26a/miR-26b blocked TSCC tumor growth in vivo. Conclusion:MiR-26a/miR-26b repressed TSCC progression via targeting PAK1 in vitro and in vivo, which enriched our understanding about TSCC development and provided new insights into the its treatment.
| S-EPMC7071636 | biostudies-literature
Project description:Endometritis is the failure of embryo implantation and an important cause of infertility in dairy cows. IFN-τ is a type I interferon unique to ruminants. In regulating the process of inflammatory response, IFN-τ can be expressed through MicroRNAs (miRNAs) to regulate the process of inflammation. However, IFN-τ regulates lipopolysaccharide (LPS)-induced inflammatory injury of bEECs through the highly conserved miR-26a in mammals, and the mechanism remains unclear. Bovine endometrial epithelial cells (bEECs)were isolated and cultured to establish an inflammatory injury model. RT-qPCR and ELISA were used to detect the secretion of inflammatory factors. Dual-luciferase assays and target gene silencing assays determine the regulatory role of miRNAs. The target protein was detected by immunofluorescence and western blotting. This study showed that the expression of miR-26a was significantly down-regulated in mouse endometrium inflammatory injury tissue and LPS stimulated bEECs; and IFN-τ reversed the expression of miR-26a. The study also showed that the overexpression of miR-26a significantly inhibited the secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. In addition, studies have shown that miR-26a inhibits its translation by targeting PTEN 3'-UTR, which in turn activates the Phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathway, so that nuclear factor kappa-B (NF-κB) signaling is inhibited. In summary, the results of this study further confirm that IFN-τ as an anti-inflammatory agent can up-regulate the expression of miR-26a and target the PTEN gene to inhibit the inflammatory damage of bEECs.
| S-EPMC9174273 | biostudies-literature