The MicroRNA-148/152 Family: Multi-faceted Players

Chen, Yue; Song, Yongxi; Wang, Zhenning

doi:10.1186/1476-4598-12-43

Cited by 141 publications

(134 citation statements)

References 70 publications

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“…Deregulated miR-148a expression can be detected in many tumors, for example from lung, stomach, prostate, brain, and pancreas, potentially affecting survival, proliferation, and cell migration by influencing the abundance of apoptotic proteins, transcription factors (such as Mitf and Runx3), and the feedback regulatory miR-148a/DNMT1 axis [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

et al. 2015

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B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into longlived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitfare essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1 + cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.Keywords: B cells r Blimp-1 r MicroRNAs r miR-148a r Plasma cell differentiation r Bach2, Mitf See accompanying article by Haftmann et al.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe generation of antibody-secreting plasma cells (PCs) and memory B cells is essential for eliminating pathogens and establishing Correspondence: Prof. Hans-Martin Jäck e-mail: hjaeck@molmed.uni-erlangen.de effective protection after vaccination. After antigen encounter, B cells are clonally expanded in the T-cell zone of a peripheral lymphatic organ and differentiate quickly into IgM-secreting short-lived PCs (extrafollicular pathway). If an antigen-activated * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1206-1215 Molecular immunology 1207B cell receives T-cell help, some of these cells move from the Tcell zone to a B-cell follicle located in the B-cell zone. There, they are further expanded, resulting in the formation of a germinal center (GC). During a GC reaction, B cells undergo somatic hypermutation (SHM) of their immunoglobulin variable region exons and class switch recombination (CSR). After B cells with highaffinity and class-switched antigen receptors have been selected, they leave the GC and differentiate either into memory B cells or long-lived PCs [1][2][3]. The differentiation of mature B cells into long-lived PCs via the GC pathway is tightly controlled by a regulatory network of mutually exclusive transcription factors; one set maintains the GC reaction, and the other is re...

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Section: Discussionmentioning

confidence: 99%

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

et al. 2015

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“…as reviewed. 19 These point to the fact that they may act as tumor suppressor in MM as well. As known, microRNAs are regulated at transcriptional level and at post-transcriptional level, 38 and mature miRNA has 2 arms, the 5p and 3p.…”

Section: Discussionmentioning

confidence: 99%

“…19 In our study, we assessed 4 miRNAs (miR-152, 15a, 34, and 223) in MM and non-MM groups. Our results suggested that miR-152 expression was significantly downregulated in the majority of MM patients and cell lines compared with non-MM; consistent with the reports from other cancers.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

Chen

George

et al. 2015

RNA Biology

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Multiple myeloma (MM) induced bone lesion is one of the most crippling characteristics, and the MM secreted Dickkopf-1 (DKK1) has been reported to play important role in this pathologic process. However, the underlying regulation mechanisms involved in DKK1 expression are still unclear. In this study, we validated the expression patterns of microRNA (miR) 15a, 34a, 152, and 223 in MM cells and identified that miR-152 was significantly downregulated in the MM group compared with the non-MM group, and that miR-152 level was negatively correlated with the expression of DKK1 in the MM cells. Mechanistic studies showed that manipulating miR-152 artificially in MM cells led to changes in DKK-1 expression, and miR-152 blocked DKK1 transcriptional activity by binding to the 3 0 UTR of DKK1 mRNA. Importantly, we revealed that MM cells stably expressing miR-152 improved the chemotherapy sensitivity, and counteracted the bone disruption in an intrabone-MM mouse model. Our study contributes better understanding of the regulation mechanism of DKK-1 in MM, and opens up the potential for developing newer therapeutic strategies in the MM treatment.

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“…Indeed, a number of these miRNAs were recognized to promote cell proliferation and regulate apoptosis and were linked to the regulation of immune cell activation (e.g., miR-148/152 family, miR-132/212, miR-19 superfamily, and miR-7 family). Among these miRNAs, the miR-148/ 152 family (e.g., miR-148a, miR-148b, and miR-152) is involved in the regulation of cell proliferation, differentiation, and growth, as well as immune responses by suppressing the expression of proinflammatory molecules (e.g., IL-12, IL-6, TNF-a, and IFN-b) (25,26). miR-132/212 belongs to a gene cluster whose expression is regulated by CREB, a transcription factor that provides survival signals for many cells, including macrophages (21).…”

mentioning

confidence: 99%

MicroRNA-487b Is a Negative Regulator of Macrophage Activation by Targeting IL-33 Production

Xiang

Eyers

Herbert

et al. 2016

The Journal of Immunology

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MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including immune responses. Although the contributions of miRNAs to the function of immune cells are beginning to emerge, their specific roles remain largely unknown. IL-33 plays an important role in macrophage activation for innate host defense and proinflammatory responses. In this study, we report that miR-487b can suppress the levels of mRNA and protein for IL-33 during the differentiation of bone marrow–derived macrophages (BMDMs). This results in inhibition of IL-33–induced expression of Ag-presenting and costimulatory molecules and proinflammatory mediators. A luciferase assay showed that miR-487b binds to the IL-33 3′-untranslated region. We also confirmed that IL-33 directly promotes the activation of BMDMs by increasing the expression of MHC class I, MHC class II, CD80/CD86, and inducible NO synthase (iNOS) in a dose-dependent manner. Exposure of BMDMs to the TLR4 ligand, LPS, decreased miR-487b expression, increased IL-33 transcript levels, and induced the production of proinflammatory mediators (e.g., iNOS, IL-1β, IL-6, and TNF-α). Treatment with a specific inhibitor of miR-487b function also resulted in increased levels of IL-33 mRNA, which augmented LPS-induced expression of these inflammatory mediators in macrophages. Collectively, our results indicate that miR-487b plays a negative regulatory role in macrophages by controlling the levels of IL-33 transcript and protein to fine-tune innate immune host defense and proinflammatory responses of these cells. Thus, miR-487b plays an important role in the regulation of macrophage homeostasis and activation by targeting IL-33 transcripts.

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The MicroRNA-148/152 Family: Multi-faceted Players

Cited by 141 publications

References 70 publications

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

MicroRNA-487b Is a Negative Regulator of Macrophage Activation by Targeting IL-33 Production

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