The hsa-miR-125a/hsa-let-7e/hsa-miR-99b cluster is potentially implicated in Cystic Fibrosis pathogenesis

Ahanda, Marie-Laure Endale; Bienvenu, Thierry; Sermet‐Gaudelus, Isabelle; Mazzolini, Laurent; Edelman, Aleksander; Zoorob, Rima; Davezac, Noélie

doi:10.1016/j.jcf.2015.02.011

Cited by 13 publications

(9 citation statements)

References 50 publications

(52 reference statements)

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“…The hsa-miR-125a/let-7e/miR-99b cluster is located within the 19q13.2–19q13.4 region (21). Further understanding of hsa-miR-125a/let-7e/miR-99b cluster biogenesis and function is required.…”

Section: Discussionmentioning

confidence: 99%

Low expression of miR‑125a‑5p is associated with poor prognosis in patients with gastric cancer

Guan

Hou

et al. 2019

Oncol Lett

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microRNAs (miRs) serve critical roles in tumor progression. Low expression of miR-125a in gastric carcinoma (GC) may promote tumor development. In the present study, low expression of miR-125a was confirmed in cancer tissues using The Cancer Genome Atlas database. Additionally, the expression and clinical significance of miR-125a-5p was investigated using reverse transcription-quantitative PCR in 150 cases of GC. The results of the present study demonstrated that the level of miR-125a-5p expression was decreased in GC biopsies compared with that in matched adjacent normal tissues. Low expression of miR-125a-5p was associated with increased tumor diameter, high Ki67 expression and poor overall survival of patients with GC. Multivariate survival analysis demonstrated that low miR-125a-5p expression may be used as an independent prognostic factor for patients with GC. However, no effects on the cell viability in a Cell Counting kit-8 assay, and cell migration and invasion in Transwell assays were detected in response to treatment using miR-125a-5p mimics or inhibitors in vitro. Therefore, the results of the present study provide evidence that low expression of miR-125a-5p may be associated with a poor prognosis, suggesting its value as a tumor biomarker for patients with GC.

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Section: Discussionmentioning

confidence: 99%

Low expression of miR‑125a‑5p is associated with poor prognosis in patients with gastric cancer

Guan

Hou

et al. 2019

Oncol Lett

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“…An upregulation of the hsa-miR-99b/let-7e/miR-125a cluster or single miRNA cluster members was described in innate immune cells under different inflammatory conditions ( 41 , 42 ). The miR cluster was shown to be induced through LPS stimulation in monocytes ( 43 ) and several publication show the TLR4- and TLR2-dependent induction of miR-125a and let-7e in macrophages ( 44 – 46 ).…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells

et al. 2018

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Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death-ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor-mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.

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“…The implication of miRNAs in CFTR expression is also controlled by the highly variable, and compelling information on phenotypic variability and lack of genotype-phenotype correlation among patients with the same mutation in the CFTR gene. Thus, three polymorphisms have been identified in the miR-99b/let-7e/miR-125a cluster that modulates the expression of these miRNAs and may be associated with patient phenotypes ( Endale Ahanda et al, 2015 ). In addition, polymorphisms present in the 3′-UTR region of CFTR mediate the binding of miR-509-3p and cause a decrease in CFTR expression ( Amato et al, 2013 ).…”

Section: Mirnas: Cftr and Other Associated Channel Proteinsmentioning

confidence: 99%

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

et al. 2018

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Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains the most common life-shortening diseases affecting the exocrine organs. The absence of this channel results in an imbalance of ion concentrations across the cell membrane and results in more abnormal secretion and mucus plugging in the gastrointestinal tract and in the lungs of CF patients. The direct introduction of fully functional CFTR by gene therapy has long been pursued as a therapeutical option to restore CFTR function independent of the specific CFTR mutation, but the different clinical trials failed to propose persuasive evidence of this strategy. The last ten years has led to the development of new pharmacotherapies which can activate CFTR function in a mutation-specific manner. Although approximately 2,000 different disease-associated mutations have been identified, a single codon deletion, F508del, is by far the most common and is present on at least one allele in approximately 70% of the patients in CF populations. This strategy is limited by chemistry, the knowledge on CFTR and the heterogenicity of the patients. New research efforts in CF aim to develop other therapeutical approaches to combine different strategies. Targeting RNA appears as a new and an important opportunity to modulate dysregulated biological processes. Abnormal miRNA activity has been linked to numerous diseases, and over the last decade, the critical role of miRNA in regulating biological processes has fostered interest in how miRNA binds to and interacts explicitly with the target protein. Herein, this review describes the different strategies to identify dysregulated miRNA opens up a new concept and new opportunities to correct CFTR deficiency. This review describes therapeutic applications of antisense techniques currently under investigation in CF.

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The hsa-miR-125a/hsa-let-7e/hsa-miR-99b cluster is potentially implicated in Cystic Fibrosis pathogenesis

Cited by 13 publications

References 50 publications

Low expression of miR‑125a‑5p is associated with poor prognosis in patients with gastric cancer

Low expression of miR‑125a‑5p is associated with poor prognosis in patients with gastric cancer

Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

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