Transforming Growth Factor-β–Induced Endothelial-to-Mesenchymal Transition Is Partly Mediated by MicroRNA-21

Kumarswamy, Regalla; Volkmann, Ingo; Jazbutyte, Virginija; Dangwal, Seema; Park, Da-Hee; Thum, Thomas

doi:10.1161/atvbaha.111.234286

Cited by 260 publications

(198 citation statements)

References 67 publications

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“…The prosurvival protein ZEB1 has been identified as a direct target of miR-200c and miR-141, and ZEB1 is a key molecule involved in the processes of EMT and EndMT that directly suppress E-cadherin (34,40). Downregulation of miR-141 and miR-205 has been implicated in EMT progression, whereas upregulation of miR-21 and miR-9 has been linked to EndMT and EMT, respectively (30,37). Similar expression patterns for these miRNAs (Table 1, Fig.…”

Section: Mir-21 and The Mir-17-92 Clustermentioning

confidence: 99%

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Chakraborty

Zawieja

Davis

et al. 2015

American Journal of Physiology-Cell Physiology

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Chakraborty S, Zawieja DC, Davis MJ, Muthuchamy M. MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation. Am J Physiol Cell Physiol 309: C680 -C692, 2015. First published September 9, 2015; doi:10.1152/ajpcell.00122.2015.-The lymphatics have emerged as critical players in the progression and resolution of inflammation. The goal of this study was to identify specific microRNAs (miRNAs) that regulate lymphatic inflammatory processes. Rat mesenteric lymphatic endothelial cells (LECs) were exposed to the proinflammatory cytokine tumor necrosis factor-␣ for 2, 24, and 96 h, and miRNA profiling was carried out by real-time PCR arrays. Our data demonstrate a specific set of miRNAs that are differentially expressed (Ͼ1.8-fold and/or P Ͻ 0.05) in LECs in response to tumor necrosis factor-␣ and are involved in inflammation, angiogenesis, endothelial-mesenchymal transition, and cell proliferation and senescence. We further characterized the expression of miRNA 9 (miR-9) that was induced in LECs and in inflamed rat mesenteric lymphatics. Our results showed that miR-9 overexpression significantly repressed NF-B expression and, thereby, suppressed inflammation but promoted LEC tube formation, as well as expression of the prolymphangiogenic molecules endothelial nitric oxide synthase and VEGF receptor type 3. LEC viability and proliferation and endothelial-mesenchymal transition were also significantly induced by miR-9. This study provides the first evidence of a distinct profile of miRNAs associated with LECs during inflammation. It also identifies the critical dual role of miR-9 in fine-tuning the balance between lymphatic inflammatory and lymphangiogenic pathways.

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Section: Mir-21 and The Mir-17-92 Clustermentioning

confidence: 99%

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Chakraborty

Zawieja

Davis

et al. 2015

American Journal of Physiology-Cell Physiology

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“…We propose that this phenotypic evolution to CAF, exemplified by the formation of actin stress fibers and a massive cytokine release, is, to a large extent, driven by a complex mixture of small RNAs and proteins contained by CLL exosomes. Among the cargoes identified in exosomes, tetraspanins can promote cell activation, growth, and motility, 50 and the most abundant miRNAs (miR-21 and -146a) are known critical regulators of CAF induction, 51,52 MSC proliferation, 53 and EC angiogenic activities. 54 On uptake of CLL exosomes, cell signaling pathways are activated, and gene expression is altered in target cells.…”

Section: Cll Exosomes Induce Caf Formation 1113mentioning

confidence: 99%

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

Paggetti

Haderk

Seiffert

et al. 2015

Blood

387

377

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Luxembourg Key Points• CLL-derived exosomes are internalized by stromal cells, deliver functional microRNA and proteins, and activate key signaling pathways.• Stromal cells exposed to CLLderived exosomes demonstrate a CAF-like phenotype and secrete factors promoting CLL cell survival.Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumorsupportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected a-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts. (Blood. 2015;126(9):1106-1117

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“…At a molecular level, transforming growth factor (TGF)-β has been implicated in the induction of EndMT [17,18], with a reduction in TGF-β signalling being associated with reduced neo-intima formation and decreased contribution of endothelial-derived cells to the neo-intima in vivo [17]. Recently, HOPPER et al [11] have provided insights into the mechanism by which TGF-β can induce EndMT.…”

Section: Endothelial-to-mesenchymal Transitionmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Hemnes

Humbert

2017

Eur Respir Rev

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The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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Transforming Growth Factor-β–Induced Endothelial-to-Mesenchymal Transition Is Partly Mediated by MicroRNA-21

Cited by 260 publications

References 67 publications

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

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