Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MicroRNA-146a limits tumorigenic inflammation in colorectal cancer.

ABSTRACT: Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.

SUBMITTER: Garo LP

PROVIDER: S-EPMC8065171 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Identification of Tumorigenic and Prognostic Biomarkers in Colorectal Cancer Based on microRNA Expression Profiles.

Project description:Objective:Although noncoding RNAs, especially the microRNAs, have been found to play key roles in CRC development in intestinal tissue, the specific mechanism of these microRNAs has not been fully understood. Methods:GEO and TCGA database were used to explore the microRNA expression profiles of normal mucosa, adenoma, and carcinoma. And the differential expression genes were selected. Computationally, we built the SVM model and multivariable Cox regression model to evaluate the performance of tumorigenic microRNAs in discriminating the adenomas from normal tissues and risk prediction. Results:In this study, we identified 20 miRNA biomarkers dysregulated in the colon adenomas. The functional enrichment analysis showed that MAPK activity and MAPK cascade were highly enriched by these tumorigenic microRNAs. We also investigated the target genes of the tumorigenic microRNAs. Eleven genes, including PIGF, TPI1, KLF4, RARS, PCBP2, EIF5A, HK2, RAVER2, HMGN1, MAPK6, and NDUFA2, were identified to be frequently targeted by the tumorigenic microRNAs. The high AUC value and distinct overall survival rates between the two risk groups suggested that these tumorigenic microRNAs had the potential of diagnostic and prognostic value in CRC. Conclusions:The present study revealed possible mechanisms and pathways that may contribute to tumorigenesis of CRC, which could not only be used as CRC early detection biomarkers, but also be useful for tumorigenesis mechanism studies.

| S-EPMC7424406 | biostudies-literature

Emerging functions of microRNA-146a/b in development and breast cancer: microRNA-146a/b in development and breast cancer.

Project description:MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression through translational repression or mRNA degradation. These molecules play critical roles in regulating normal developmental processes, but when deregulated, are causally linked to the pathogenesis of numerous diseases, including cancer. MicroRNA-146a and -146b are encoded by two different genes, but differ by only two bases and appear to function redundantly in many systems. Initial studies branded miR-146a/b as important mediators of inflammatory signaling, documenting the ability of these miRNAs to influence differentiation, proliferation, apoptosis and effector immune mechanisms within the hematopoietic system. Numerous contemporary studies now implicate miR-146a/b as pleiotropic regulators of tumorigenesis, as a polymorphism in miR-146a and altered expression of both miR-146a/b have been linked with cancer risk, tumor histogenesis and invasive and metastatic capacity in diverse cancers. Despite the numerous reports concerning miR-146a/b in human cancers, the mechanistic contributions of these miRNAs in both normal and neoplastic mammary gland development and biology remains poorly characterized.

| S-EPMC8276881 | biostudies-literature

MicroRNA-146a promote cell migration and invasion in human colorectal cancer via carboxypeptidase M/src-FAK pathway.

Project description:Colorectal cancer (CRC) is one of the most common cancers worldwide, and microRNAs play important roles in CRC progression. This study aimed to investigate the roles of miR-146a-5p in human CRC and their molecular mechanisms. First, we found that miR-146a-5p was significantly upregulated in CRC tissues and promoted the migration of CRC cells. Then, we identified carboxypeptidase M (CPM) as a direct target of miR-146a-5p, and found that it inhibited the migration and invasion of CRC cells. Our results also showed that CPM expression was positively correlated with overall survival and negatively correlated with recurrence, lymph node invasion, and N stage. Furthermore, we demonstrated that both miR-146a-5p and CPM regulated Src and FAK expression, while the Src-FAK signaling pathway is widely known to be associated with the migration and invasion of multiple tumor cells. This study is the first to demonstrate the functional and mechanistic relationship of the miR-146a-5p/CPM/Src-FAK axis and its effect on the migration and invasion of CRC cells. Thus, miR-146a-5p represents potential targets for CRC diagnosis and therapy.

| S-EPMC5410254 | biostudies-literature

microRNA-27a and microRNA-146a SNP in cerebral malaria.

Project description:BACKGROUND:During Plasmodium falciparum infection, microRNA expression alters in brain tissue of mice with cerebral malaria compared to noninfected controls. MicroRNA regulates gene expression post-transcriptionally to influence biological processes. Cerebral malaria pathology caused mainly by the immunological disorder. We hypothesize that single-nucleotide polymorphism in a microRNA influences microRNA biogenesis or target gene recognition and altering susceptibility to cerebral malaria. METHODS:We performed a literature search based on immunological mechanism and applied microRNA-related single-nucleotide polymorphisms database to examine candidate microRNA SNPs possibly responsible for cerebral malaria. MicroRNA-27a and microRNA-146a are supposed to involve in cerebral malaria pathology. To assess the relationship of microRNA SNP to cerebral malaria outcome, we performed TaqMan Genotyping Assays in 110 cerebral malaria and 207 uncomplicated malaria cases for three candidate microRNA SNPs (rs895819 of microRNA-27a, rs57095329 and rs2910164 of microRNA-146a). RESULTS:Our study detected no significant difference in genotype and allele frequency of individual microRNA SNPs as well as in haplotypes of microRNA-146a between these two groups of malaria patients in Thailand. Hardy-Weinberg disequilibrium of rs57095329 in the cerebral malaria group showed a heterozygous excess which might be due to natural selection. CONCLUSION:Our data supported that the candidate microRNA SNPs have no major role to develop cerebral malaria.

| S-EPMC6393659 | biostudies-literature

Rg6, a rare ginsenoside, inhibits systemic inflammation through the induction of interleukin-10 and microRNA-146a.

Project description:The immunobiological functions of Rg6, a rare ginsenoside from ginseng, have been largely unreported. In this paper, we demonstrate that Rg6 has a significant immunosuppressive function on Toll-like receptor (TLR) 4-induced systemic inflammatory responses. Rg6 was found to negatively regulate pro-inflammatory responses and severity in vivo, and thus induced recovery in mice with lipopolysaccharide (LPS)-induced septic shock and cecal ligation and puncture (CLP)-induced sepsis. Rg6 treatment also facilitated recovery in mice with LPS-induced lung damage via reduced neutrophil infiltration and tumor necrosis factor-α expression in lung tissues. Rg6 injection also downregulated pro-inflammatory cytokines and increased the levels of interleukin (IL)-10 in the serum of septic mice. Mechanistically, Rg6 did not induce TLR negative regulators, such as A20 and IRAK-M, in bone marrow-derived macrophages (BMDMs). Instead, addition of Rg6 to LPS-activated BMDMs augmented IL-10 expression, whereas it inhibited inflammatory signaling, such as by nuclear factor κB activation and mitogen-activated protein kinases. Furthermore, Rg6 significantly induced miR-146a, an operator miRNA for anti-inflammation, in BMDMs. Collectively, these data indicate that Rg6 inhibits inflammatory responses through the induction of IL-10 and miR-146a.

| S-EPMC6416268 | biostudies-literature

Distinct tumorigenic pathways within hereditary nonpolyposis colorectal cancer

Project description:Gene expression profiling has discriminated between sporadic microsatellite instable (MSI) and microsatellite stable (MSS) colorectal cancers (CRCs), whereas the expression pattern of familial colorectal cancer type X (FCCTX) and Lynch syndrome (LS) associated CRCs remain largely unknown. The purpose of this study is to use gene expression profiling of formalin-fixed paraffin-embedded (FFPE) tumor specimens from FCCTX, LS and sporadic CRC as a control to detect expression patterns and to identify signaling pathways differing between FCCTX and LS tumors. RNA extracted from 132 FFPE specimens (40 FCCTX, 42 LS, 50 sporadic) were profiled for differential gene expression by the whole genome cDNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay containing 18626 genes.

2012-03-08 | E-GEOD-36335 | biostudies-arrayexpress

Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis.

Project description:Roquin is an RNA-binding protein that prevents autoimmunity and inflammation via repression of bound target mRNAs such as inducible costimulator (Icos). When Roquin is absent or mutated (Roquin(san)), Icos is overexpressed in T cells. Here we show that Roquin enhances Dicer-mediated processing of pre-miR-146a. Roquin also directly binds Argonaute2, a central component of the RNA-induced silencing complex, and miR-146a, a microRNA that targets Icos mRNA. In the absence of functional Roquin, miR-146a accumulates in T cells. Its accumulation is not due to increased transcription or processing, rather due to enhanced stability of mature miR-146a. This is associated with decreased 3' end uridylation of the miRNA. Crystallographic studies reveal that Roquin contains a unique HEPN domain and identify the structural basis of the 'san' mutation and Roquin's ability to bind multiple RNAs. Roquin emerges as a protein that can bind Ago2, miRNAs and target mRNAs, to control homeostasis of both RNA species.

| S-EPMC4346627 | biostudies-literature

Increased exosomal microRNA-21 and microRNA-146a levels in the cervicovaginal lavage specimens of patients with cervical cancer.

Project description:Well-run screening programs for cervical cancer in the population at risk have been shown to result in a sharp decrease in the incidence and mortality of cervical cancer in a number of large populations. Expression patterns of a recently identified biomarker family, microRNA, appear to be characteristic of tumor type and developmental origin. Several tumors have been reported to actively release exosomes carrying microRNAs. The present study has determined the association of microRNAs with cervical cancer-derived exosomes. The cervical cancer-derived exosomes were enriched in the cervicovaginal lavages specimens and the abundance of exosomes and exosomal microRNAs was detected by electron microscopy, western blot analysis, RT-qPCR and microRNA target reporter vector. The microRNA-21 and microRNA-146a, which were up-regulated in cervical cancer patients, were associated with the high levels of cervical cancer-derived exosomes. In conclusion, we demonstrated the abundance of exosomes in the cervicovaginal lavage specimens of women with cervical cancer. Furthermore, our results indicated that abnormally high levels of microRNA-21 and microRNA-146a existed in the cervical cancer-derived exosomes and the two microRNAs were functional in 293T cells.

| S-EPMC3907836 | biostudies-other

Association between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer risk: A meta-analysis.

Project description:Many observational studies have found that microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 are associated with esophageal cancer risk. However, the results were mixed and inconsistent among these studies. We conducted a meta-analysis to assess the relationship between the polymorphisms of three microRNAs and esophageal cancer susceptibility. We systematically searched the PubMed and EMBASE databases to screen relevant studies. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to compute the risk of esophageal cancer. Because of the differences in ethnicities, sources of controls, and genotyping methods, the meta-analysis was conducted using a random-effect model regardless of heterogeneity. To further explore potential heterogeneity, we performed subgroup and sensitivity analyses, and publication bias was also evaluated. A total of 6 case-control studies on microRNA-196a2 rs11614913, 4 studies on microRNA-146a rs2910164, and 4 studies on microRNA-423 rs6505162 were considered eligible in the meta-analysis. No statistical association was found between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphisms and esophageal cancer susceptibility in any genetic model. Subgroup and sensitivity analyses showed similar results. In summary, based on the currently limited proof, no association exists between microRNA-196a2 rs11614913, microRNA-146a rs2910164, and microRNA-423 rs6505162 polymorphism and esophageal cancer risk. However, the result should be cautiously interpreted because of the heterogeneity among studies. Large, high quality clinical trials are required to verify our findings.

| S-EPMC4722486 | biostudies-literature

microRNA-146a controls age-related bone loss.

Project description:Bone loss is one of the consequences of aging, leading to diseases such as osteoporosis and increased susceptibility to fragility fractures and therefore considerable morbidity and mortality in humans. Here, we identify microRNA-146a (miR-146a) as an essential epigenetic switch controlling bone loss with age. Mice deficient in miR-146a show regular development of their skeleton. However, while WT mice start to lose bone with age, animals deficient in miR-146a continue to accrue bone throughout their life span. Increased bone mass is due to increased generation and activity of osteoblasts in miR-146a-deficient mice as a result of sustained activation of bone anabolic Wnt signaling during aging. Deregulation of the miR-146a target genes Wnt1 and Wnt5a parallels bone accrual and osteoblast generation, which is accompanied by reduced development of bone marrow adiposity. Furthermore, miR-146a-deficient mice are protected from ovariectomy-induced bone loss. In humans, the levels of miR-146a are increased in patients suffering fragility fractures in comparison with those who do not. These data identify miR-146a as a crucial epigenetic temporal regulator which essentially controls bone homeostasis during aging by regulating bone anabolic Wnt signaling. Therefore, miR-146a might be a powerful therapeutic target to prevent age-related bone dysfunctions such as the development of bone marrow adiposity and osteoporosis.

| S-EPMC7681058 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data