Transfer of functional microRNAs between glioblastoma and microvascular endothelial cells through gap junctions

Thüringer, Dominique; Boucher, Jonathan; Jégo, Gaëtan; Pernet, Nicolas; Cronier, Laurent; Hammann, Arlette; Solary, Éric; Garrido, Carmen

doi:10.18632/oncotarget.12136

Cited by 44 publications

(53 citation statements)

References 32 publications

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“…These channels directly couple adjacent cells and allow passage of small molecules (<1 kD), 25,26 such as ATP, NAD + , IP 3 , prostaglandins and cyclic nucleotides and, interestingly, even miRNA. 27 Each channel consists of two corresponding hemichannnels, also called connexons, which are located in the membrane of adjacent cells. Connexons consist of 6 connexins which are either of the same (homomeric) or of different types (heteromeric) 10 (Figure 1B).…”

Section: Structure and Compositionmentioning

confidence: 99%

Connexins in the control of vasomotor function

Pogoda

Kameritsch

Mannell³

et al. 2018

Acta Physiologica

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Vascular endothelial cells, as well as smooth muscle cells, show heterogeneity with regard to their receptor expression and reactivity. For the vascular wall to act as a functional unit, the various cells' responses require integration. Such an integration is not only required for a homogeneous response of the vascular wall, but also for the vasomotor behaviour of consecutive segments of the microvascular arteriolar tree. As flow resistances of individual sections are connected in series, sections require synchronization and coordination to allow effective changes of conductivity and blood flow. A prerequisite for the local coordination of individual vascular cells and different sections of an arteriolar tree is intercellular communication. Connexins are involved in a dual manner in this coordination. (i) By forming gap junctions between cells, they allow an intercellular exchange of signalling molecules and electrical currents. In particular, the spread of electrical currents allows for coordination of cell responses over longer distances. (ii) Connexins are able to interact with other proteins to form signalling complexes. In this way, they can modulate and integrate individual cells' responses also in a channel-independent manner. This review outlines mechanisms allowing the vascular connexins to exert their coordinating function and to regulate the vasomotor reactions of blood vessels both locally, and in vascular networks. Wherever possible, we focus on the vasomotor behaviour of small vessels and arterioles which are the main vessels determining vascular resistance, blood pressure and local blood flow.

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Section: Structure and Compositionmentioning

confidence: 99%

Connexins in the control of vasomotor function

Pogoda

Kameritsch

Mannell³

et al. 2018

Acta Physiologica

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“…For example, astrocytes deliver miRNAs (eg, miR‐16, miR‐709) to cancer cells via a GJ‐dependent mechanism to suppress tumor cell growth . Similarly, the exchange of miR‐145 and miR‐5096 was found between endothelial cells and glioblastoma cells . Upon co‐culture with macrophages, the proliferative activity of hepato‐carcinoma cells was decreased, mediated by the delivery of miR‐142 and miR‐223 via GJs .…”

Section: Gap Junctional Shuttling Of Mirnamentioning

confidence: 99%

Potential mechanisms of microRNA mobility

Lemcke

Dávid

2018

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microRNAs (miRNAs) are important epigenetic modulators of gene expression that control cellular physiology as well as tissue homeostasis, and development. In addition to the temporal aspects of miRNA-mediated gene regulation, the intracellular localization of miRNA is crucial for its silencing activity. Recent studies indicated that miRNA is even translocated between cells via gap junctional cell-cell contacts, allowing spatiotemporal modulation of gene expression within multicellular systems. Although non coding RNA remains a focus of intense research, studies regarding the intra-and intercellular mobility of small RNAs are still largely missing. Emerging data from experimental and computational work suggest the involvement of transport mechanisms governing proper localization of miRNA in single cells and cellular syncytia. Based on these data, we discuss a model of miRNA translocation that could help to address the spatial aspects of miRNA function and the impact of miRNA molecules on the intercellular signaling network.

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“…Accumulated evidence indicates that gap junctions mediate the delivery of miRNA from human macrophages to hepatocellular carcinoma cells, from bone marrow stroma to breast cancer cells, and between human microvascular endothelial cells and glioma U87 cells . However, it remains unknown what length of miRNA can pass through a gap junction.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulated evidence indicates that gap junctions mediate the delivery of miRNA from human macrophages to hepatocellular carcinoma cells, 29 from bone marrow stroma to breast cancer cells, 30 and between human microvascular endothelial cells and glioma U87 cells. 31 To date, 21 isoforms of Cx have been identified in humans, and the permeability of gap junctions composed of various Cx was shown to differ. 33,34 However, it remains unknown which type of Cx make up the gap junctions that transfer miRNA.…”

Section: Discussionmentioning

confidence: 99%

Pattern of cell‐to‐cell transfer of microRNA by gap junction and its effect on the proliferation of glioma cells

et al. 2019

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Micro RNA is expected to be a novel therapeutic tool for tumors. Gap junctions facilitate the transfer of micro RNA , which exerts biological effects on tumor cells. However, the length of micro RNA that can pass through certain gap junctions composed of specific connexin remains unknown. To address this question, the present study investigated the permeability of gap junctions composed of various connexins, including connexin 43, connexin 32 or connexin 37, to micro RNA s consisting of 18‐27 nucleotides in glioma cells and cervical cancer cells. Results indicated that all of the micro RNA s were able to be transferred from donor glioma cells to neighboring cells through the connexin 43 composed gap junction, but not the gap junctions composed of connexin 32 or connexin 37, in cervical cancer cells. Downregulation of the function of gap junctions comprising connexin 43 by pharmacological inhibition and sh RNA significantly decreased the transfer of these micro RNA s. In contrast, gap junction enhancers and overexpression of connexin 43 effectively increased these transfers. In glioma cells, cell proliferation was inhibited by micro RNA ‐34a. Additionally, these effects of micro RNA ‐34a were significantly enhanced by overexpression of connexin 43 in U251 cells, indicating that gap junctions play an important role in the antitumor effect of micro RNA by transfer of micro RNA to neighboring cells. Our data are the first to clarify the pattern of micro RNA transmission through gap junctions and provide novel insights to show that antitumor micro RNA s should be combined with connexin 43 or a connexin 43 enhancer, not connexin 32 or connexin 37, in order to improve the therapeutic effect.

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Transfer of functional microRNAs between glioblastoma and microvascular endothelial cells through gap junctions

Cited by 44 publications

References 32 publications

Connexins in the control of vasomotor function

Connexins in the control of vasomotor function

Potential mechanisms of microRNA mobility

Pattern of cell‐to‐cell transfer of microRNA by gap junction and its effect on the proliferation of glioma cells

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