C/EBPa-Mediated Activation of MicroRNAs 34a and 223 Inhibits Lef1 Expression To Achieve Efficient Reprogramming into Macrophages

Rodríguez-Ubreva, Javier; Ciudad, Laura; Oevelen, Chris van; Parra, Maribel; Graf, Thomas; Ballestar, Esteban

doi:10.1128/mcb.01487-13

Cited by 25 publications

(21 citation statements)

References 41 publications

(50 reference statements)

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“…The predominance of upregulated miRNAs may suggest that their primary role is to repress or ensure the maintenance of low levels of OC-inappropriate genes that could also be repressed through other mechanisms. Previous data from our group have already shown this type of behavior in B cell-to-macrophage transdifferentiation [ 36 ]. Our analysis of the functional effects of the depletion of the miRNAs within the miR-99b/let-7e/125a and miR-212/132 clusters, as well the analysis of their targets, shows that these molecules have a direct role in repressing MO-specific and immunomodulatory genes like TNFAIP3 , IGF1R and IL15 .…”

Section: Discussionmentioning

confidence: 57%

NF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation

et al. 2015

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BackgroundMonocyte-to-osteoclast conversion is a unique terminal differentiation process that is exacerbated in rheumatoid arthritis and bone metastasis. The mechanisms implicated in upregulating osteoclast-specific genes involve transcription factors, epigenetic regulators and microRNAs (miRNAs). It is less well known how downregulation of osteoclast-inappropriate genes is achieved.ResultsIn this study, analysis of miRNA expression changes in osteoclast differentiation from human primary monocytes revealed the rapid upregulation of two miRNA clusters, miR-212/132 and miR-99b/let-7e/125a. We demonstrate that they negatively target monocyte-specific and immunomodulatory genes like TNFAIP3, IGF1R and IL15. Depletion of these miRNAs inhibits osteoclast differentiation and upregulates their targets. These miRNAs are also upregulated in other inflammatory monocytic differentiation processes. Most importantly, we demonstrate for the first time the direct involvement of Nuclear Factor kappa B (NF-κB) in the regulation of these miRNAs, as well as with their targets, whereby NF-κB p65 binds the promoters of these two miRNA clusters and NF-κB inhibition or depletion results in impaired upregulation of their expression.ConclusionsOur results reveal the direct involvement of NF-κB in shutting down certain monocyte-specific genes, including some anti-inflammatory activities, through a miRNA-dependent mechanism for proper osteoclast differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0561-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 57%

NF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation

et al. 2015

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“…None of these associations, however, have been reported in the literature. On the other hand, studies have demonstrated hits on the gene regulation between hsa-miR-142-5p and CD24 [86], hsa-miR-29 and DNMT3B [87, 88], hsa-miR-142-3p and EGR2 [89], hsa-miR-150 and EGR2 [90], hsa-miR-34a and IKZF3 [91], hsa-miR-150 and MIAT [92], hsa-miR-342-3p and PSMG3 [93, 94], hsa-miR-17 and TIMP3 [95]. Our results further suggested an important correlation between miRNAS and gene expression values in both Basal I and Basal II, identified by this in silico approach.…”

Section: Discussionmentioning

confidence: 99%

Basal-like breast cancer: molecular profiles, clinical features and survival outcomes

et al. 2017

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BackgroundBasal-like constitutes an important molecular subtype of breast cancer characterised by an aggressive behaviour and a limited therapy response. The outcome of patients within this subtype is, however, divergent. Some individuals show an increased risk of dying in the first five years, and others a long-term survival of over ten years after the diagnosis. In this study, we aim at identifying markers associated with basal-like patients’ survival and characterising subgroups with distinct disease outcome.MethodsWe explored the genomic and transcriptomic profiles of 351 basal-like samples from the METABRIC and ROCK data sets. Two selection methods, labelled Differential and Survival filters, were employed to determine genes/probes that are differentially expressed in tumour and control samples, and are associated with overall survival. These probes were further used to define molecular subgroups, which vary at the microRNA level and in DNA copy number.ResultsWe identified the expression signature of 80 probes that distinguishes between two basal-like subgroups with distinct clinical features and survival outcomes. Genes included in this list have been mainly linked to cancer immune response, epithelial-mesenchymal transition and cell cycle. In particular, high levels of CXCR6, HCST, C3AR1 and FPR3 were found in Basal I; whereas HJURP, RRP12 and DNMT3B appeared over-expressed in Basal II. These genes exhibited the highest betweenness centrality and node degree values and play a key role in the basal-like breast cancer differentiation. Further molecular analysis revealed 17 miRNAs correlated to the subgroups, including hsa-miR-342-5p, -150, -155, -200c and -17. Additionally, increased percentages of gains/amplifications were detected on chromosomes 1q, 3q, 8q, 10p and 17q, and losses/deletions on 4q, 5q, 8p and X, associated with reduced survival.ConclusionsThe proposed signature supports the existence of at least two subgroups of basal-like breast cancers with distinct disease outcome. The identification of patients at a low risk may impact the clinical decisions-making by reducing the prescription of high-dose chemotherapy and, consequently, avoiding adverse effects. The recognition of other aggressive features within this subtype may be also critical for improving individual care and for delineating more effective therapies for patients at high risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0250-9) contains supplementary material, which is available to authorized users.

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“…It has been demonstrated by Pulikkan et al that this is the case for miR-223 and E2F1 regulation ( 84 ). E2F1, an important response element in G1/S, can repress transcription of miR-223 which in turn can repress E2F1 ( 84 , 94 , 95 ). The differentiation block observed in APL may be further exacerbated by miRNAs like miR-223 (Figure 3 ; Table 2 ).…”

Section: Mirna and Cell Cycling In Aml Resistancementioning

confidence: 99%

microRNAs and Acute Myeloid Leukemia Chemoresistance: A Mechanistic Overview

Gabra

Salmena

2017

Front. Oncol.

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Up until the early 2000s, a functional role for microRNAs (miRNAs) was yet to be elucidated. With the advent of increasingly high-throughput and precise RNA-sequencing techniques within the last two decades, it has become well established that miRNAs can regulate almost all cellular processes through their ability to post-transcriptionally regulate a majority of protein-coding genes and countless other non-coding genes. In cancer, miRNAs have been demonstrated to play critical roles by modifying or controlling all major hallmarks including cell division, self-renewal, invasion, and DNA damage among others. Before the introduction of anthracyclines and cytarabine in the 1960s, acute myeloid leukemia (AML) was considered a fatal disease. In decades since, prognosis has improved substantially; however, long-term survival with AML remains poor. Resistance to chemotherapy, whether it is present at diagnosis or induced during treatment is a major therapeutic challenge in the treatment of this disease. Certain mechanisms such as DNA damage response and drug targeting, cell cycling, cell death, and drug trafficking pathways have been shown to be further dysregulated in treatment resistant cancers. miRNAs playing key roles in the emergence of these drug resistance phenotypes have recently emerged and replacement or inhibition of these miRNAs may be a viable treatment option. Herein, we describe the roles miRNAs can play in drug resistant AML and we describe miRNA-transcript interactions found within other cancer states which may be present within drug resistant AML. We describe the mechanisms of action of these miRNAs and how they can contribute to a poor overall survival and outcome as well. With the precision of miRNA mimic- or antagomir-based therapies, miRNAs provide an avenue for exquisite targeting in the therapy of drug resistant cancers.

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C/EBPa-Mediated Activation of MicroRNAs 34a and 223 Inhibits Lef1 Expression To Achieve Efficient Reprogramming into Macrophages

Cited by 25 publications

References 41 publications

NF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation

NF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation

Basal-like breast cancer: molecular profiles, clinical features and survival outcomes

microRNAs and Acute Myeloid Leukemia Chemoresistance: A Mechanistic Overview

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