miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells

Lim, Clarice X.; Lee, Bernett; Geiger, Olivia; Passegger, Christina; Beitzinger, Michaela; Romberger, Johann; Stracke, Anika; Högenauer, Christoph; Stift, Anton; Stoiber, Heribert; Zebisch, Armin; Meister, Gunter; Williams, Adam; Flavell, Richard A.; Henao‐Mejia, Jorge; Strobl, Herbert

doi:10.1016/j.celrep.2020.02.077

Cited by 17 publications

(9 citation statements)

References 69 publications

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“…Reduced miR-181a levels in older people are associated with a failure of T cell response against weak antigenic stimuli [ 14 ]. Relevant actions driven by miR-181 were also reported in B cell development as well as in macrophages and dendritic cells, showing anti-inflammatory effects by targeting IL1a [ 26 , 27 ], and confirming its complex role in the immune system development and immune response modulation.…”

Section: Micrornas In the Immune System Developmentmentioning

confidence: 84%

MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

et al. 2022

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Treatments aimed to reverse the tumor-induced immune tolerance represent a promising approach for advanced hepatocellular carcinoma (HCC). Notwithstanding, primary nonresponse, early, and late disease reactivation still represent major clinical challenges. Here, we focused on microRNAs (miRNAs) acting both as modulators of cancer cell hallmarks and immune system response. We outlined the bidirectional function that some oncogenic miRNAs play in the differentiation and program activation of the immune system development and, at the same time, in the progression of HCC. Indeed, the multifaceted spectrum of miRNA targets allows the modulation of both immune-associated factors and oncogenic or tumor suppressor drivers at the same time. Understanding the molecular changes contributing to disease onset, progression, and resistance to treatments might help to identify possible novel biomarkers for selecting patient subgroups, and to design combined tailored treatments to potentiate antitumor approaches. Preliminary findings seem to argue in favor of a bidirectional function of some miRNAs, which enact an effective modulation of molecular pathways driving oncogenic and immune-skipping phenotypes associated with cancer aggressiveness. The identification of these miRNAs and the characterization of their ‘dual’ role might help to unravel novel biomarkers identifying those patients more likely to respond to immune checkpoint inhibitors and to identify possible therapeutic targets with both antitumor and immunomodulatory functions. In the present review, we will focus on the restricted panel of miRNAs playing a bidirectional role in HCC, influencing oncogenic and immune-related pathways at once. Even though this field is still poorly investigated in HCC, it might represent a source of candidate molecules acting as both biomarkers and therapeutic targets in the setting of immune-based treatments.

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Section: Micrornas In the Immune System Developmentmentioning

confidence: 84%

MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

et al. 2022

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“…In our study, it was demonstrated that miR-181A was highly expressed in BMSC-derived exosomes, and miR-181A, miR-181b, miR-181c, and miR-181D jointly formed the miR-181 family, which is one of the most abundant miRNAs in lymphatic tissues [ 39 ]. mir-181a plays an important role in B cell development in bone marrow [ 40 , 41 ] and immune function [ 42 ]. We found that miR-181A can be internalized by CD4 + cells and that miR-181A in CD4 + cells directly target SIRT1.…”

Section: Discussionmentioning

confidence: 99%

Bone Mesenchymal Stem Cell-Derived Exosome-Enclosed miR-181a Induces CD4+CD25+FOXP3+ Regulatory T Cells via SIRT1/Acetylation-Mediated FOXP3 Stabilization

Wang

et al. 2022

Journal of Oncology

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Bone marrow mesenchymal stem cells (BMSCs) have been identified as a potential therapeutic approach to immune-related diseases. Here, we show that BMSC-derived exosomes promote FOXP3 expression and induce the conversion of CD4+ T cells into CD4+CD25+FOXP3+ Treg cells, which is significant for immunosuppressive activity. We found that miR-181a-5p is upregulated in BMSC-derived exosomes and can be transferred to CD4+ T cells. In CD4+ cells, miR-181a directly targets SIRT1 and suppresses its expression. Moreover, downregulated SIRT1 enhances FOXP3 via protein acetylation. In conclusion, our data demonstrated that BMSC-derived exosomal miR-181a is critical in the maintenance of immune tolerance. Furthermore, our results reveal that BMSC-derived exosomal miR-181a induces the production of CD4+CD25+FOXP3+ Treg cells via SIRT1/acetylation/FOXP3.

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“…More recently, high expression of miR-181a has been shown as one of the features exhibited in iCluster 1 tumours that were associated with a worse prognosis [ 4 ]. However, miR-181a modulation could act via either tumour suppression or oncogene induction via different miRNA targets in different cellular compartments [ 15 , 20 , 21 ]. The roles of miR-181 in tumour initiation and progression and its underlying mechanisms need to be further examined with robust approaches [ 11 , 16 – 19 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7

Chen

Zhao

Zhang

et al. 2022

Cell. Mol. Life Sci.

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MiR-181 expression levels increased in hepatocellular carcinoma (HCC) compared to non-cancerous tissues. MiR-181 has been widely reported as a possible driver of tumourigenesis but also acts as a tumour suppressor. In addition, the miR-181 family regulates the development and function of immune and vascular cells, which play vital roles in the progression of tumours. More complicatedly, many genes have been identified as miR-181 targets to mediate the effects of miR-181. However, the role of miR-181 in the development of primary tumours remains largely unexplored. We aimed to examine the function of miR-181 and its vital mediators in the progression of diethylnitrosamine-induced primary liver cancers in mice. The size of liver tumours was significantly reduced by 90% in global (GKO) or liver-specific (LKO) 181ab1 knockout mice but not in hematopoietic and endothelial lineage-specific knockout mice, compared to WT mice. In addition, the number of tumours was significantly reduced by 50% in GKO mice. Whole-genome RNA-seq analysis and immunohistochemistry showed that epithelial-mesenchymal transition was partially reversed in GKO tumours compared to WT tumours. The expression of CBX7, a confirmed miR-181 target, was up-regulated in GKO compared to WT tumours. Stable CBX7 expression was achieved with an AAV/Transposase Hybrid-Vector System and up-regulated CBX7 expression inhibited liver tumour progression in WT mice. Hepatic CBX7 deletion restored the progression of LKO liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iClust2 and 3 subclasses of human HCC compared to iClust1. Gene expression profiles of GKO tumours overlapped with low-proliferative peri-portal-type HCCs. Liver-specific loss of miR-181ab1 inhibited primary liver tumour progression via up-regulating CBX7 expression, but tumour induction requires both hepatic and non-hepatic miR-181. Also, miR-181ab1-deficient liver tumours may resemble low-proliferative periportal-type human HCC. Graphical abstract

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miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells

Abstract: Highlights d miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation d miR-181a limits DC-SIGN + mo-DC responsiveness to inflammatory stimuli d miR-181a fine-tunes terminal mo-DC differentiation by modulating ERK-MAPK signaling

Cited by 17 publications

References 69 publications

MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

Bone Mesenchymal Stem Cell-Derived Exosome-Enclosed miR-181a Induces CD4+CD25+FOXP3+ Regulatory T Cells via SIRT1/Acetylation-Mediated FOXP3 Stabilization

Liver-specific deletion of miR-181ab1 reduces liver tumour progression via upregulation of CBX7

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