MicroRNAs Transfer from Human Macrophages to Hepato-Carcinoma Cells and Inhibit Proliferation

Aucher, Anne; Rudnicka, Dominika; Davis, Daniel M.

doi:10.4049/jimmunol.1301728

Cited by 215 publications

(212 citation statements)

References 61 publications

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“…In particular, as the role of gap junctions in mediating miRNA transfer has been suggested, 33,34 we tested whether they played a role also in this model. Treating cells with oleic acid or heptanol-2 well-known gap junction uncoupler agents-was not accompanied by miRNA transfer inhibition (Online Figure IIID).…”

Section: Transfer Of Mir-143/145 From Smcs To Ecsmentioning

confidence: 99%

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

Climent

Quintavalle

Miragoli

et al. 2015

Circulation Research

187

142

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Rationale: The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring endothelial cells (ECs) is still unknown. Objective: To determine whether SMCs control EC functions through passage of miR-143 and miR-145. Methods and Results: We used cocultures of SMCs and ECs under different conditions, as well as intact vessels to assess the transfer of miR-143 and miR-145 from one cell type to another. Imaging of cocultured cells transduced with fluorescent miRNAs suggested that miRNA transfer involves membrane protrusions known as tunneling nanotubes. Furthermore, we show that miRNA passage is modulated by the transforming growth factor (TGF) β pathway because both a specific transforming growth factor-β (TGFβ) inhibitor (SB431542) and an shRNA against TGFβRII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and miR-145 modulated angiogenesis by reducing the proliferation index of ECs and their capacity to form vessel-like structures when cultured on matrigel. We also identified hexokinase II ( HKII ) and integrin β 8 ( ITGβ8 )—2 genes essential for the angiogenic potential of ECs—as targets of miR-143 and miR-145, respectively. The inhibition of these genes modulated EC phenotype, similarly to miR-143 and miR-145 overexpression in ECs. These findings were confirmed by ex vivo and in vivo approaches, in which it was shown that TGFβ and vessel stress, respectively, triggered miR-143/145 transfer from SMCs to ECs. Conclusions: Our results demonstrate that miR-143 and miR-145 act as communication molecules between SMCs and ECs to modulate the angiogenic and vessel stabilization properties of ECs.

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Section: Transfer Of Mir-143/145 From Smcs To Ecsmentioning

confidence: 99%

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

Climent

Quintavalle

Miragoli

et al. 2015

Circulation Research

187

142

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“…9 Although miR-223 is commonly repressed in hepatocellular carcinoma, 10 miR-223 transfer from human macrophages was found to inhibit hepatocellular cancer cell proliferation. 11 In addition, elevated serum levels of miR-223 are found in patients with hepatocellular carcinoma or chronic hepatitis B virus and have the potential to serve as a biomarker for liver injury. 12 These findings suggest a potential role of miR-223 in liver pathobiology, although detailed biological functions and molecular mechanisms of miR-223 action in liver cells and liver diseases remain to be further defined.…”

mentioning

confidence: 99%

miR-223 Deficiency Protects against Fas-Induced Hepatocyte Apoptosis and Liver Injury through Targeting Insulin-Like Growth Factor 1 Receptor

Qadir

Chen

Chang

et al. 2015

The American Journal of Pathology

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The biological functions and molecular mechanisms of miR-223 action in liver cells and liver diseases remain unclear. We therefore determined the effect and mechanism of action of miR-233 in Fas-induced hepatocyte apoptosis and liver injury. Wild-type (WT) and miR-223 knockout (KO) mice were treated i.p. with 0.5 mg/g body weight anti-Fas antibody Jo2, and the animals were monitored for survival and the extent of liver injury. Although WT mice died 4 to 6 hours after Jo2 injection (n Z 6), all of the miR-223 KO mice (n Z 6) survived. In comparison to WT mice, the miR-223 KO mice showed resistance to Fas-induced liver injury, as indicated by less tissue damage under histopathological examination, fewer apoptotic hepatocytes under caspase-3 immunostaining, and less elevation of serum transaminases. miR-223 KO livers showed less caspase-3, caspase-8, and caspase-9 activation and less poly (ADP-ribose) polymerase cleavage compared with WT livers (P < 0.05). Furthermore, tail vein injection of miR-223 lentiviral vector to miR-223 KO mice restored Jo2-induced liver injury. Transfection of miR-223 KO hepatocytes with miR-223 mimic enhanced Jo2-induced activation of caspase-3, caspase-8, and caspase-9, whereas transfection of WT hepatocytes with the miR-223 inhibitor attenuated Jo2-induced apoptosis. These findings demonstrate that miR-223 deficiency protects against Fas-induced hepatocyte apoptosis and liver injury. Further in vitro and in vivo data indicate that miR-223 regulates Fas-induced hepatocyte apoptosis and liver injury by targeting the insulin-like growth factor 1 receptor. (Am J Pathol 2015, 185: 3141e3151; http://dx

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“…Macrophage-derived MVs have been demonstrated to carry functionally active miR-223 that subsequently induces macrophage differentiation and is an important contributor to the innate immune response (35). Another example of transferring functionally active miRNAs was provided by an observation where human macrophages, via gap junctions, transferred miR-142 and miR-223 to hepatocarcinoma cells (HCCs) (1). Such transfer of miRNAs resulted in PTGS of target proteins, that is, stathmin-1 and insulin-like growth factor-1 receptor in HCC, suggesting that such transfer is not just a passive process, rather it actively regulates functions in the acceptor cell.…”

Section: Roymentioning

confidence: 99%

miRNA in Macrophage Development and Function

Roy

2016

Antioxidants & Redox Signaling

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Significance: MicroRNAs (miRNAs) control cellular gene expression via primarily binding to 3¢ or 5¢ untranslated region of the target transcript leading to translational repression or mRNA degradation. In most cases, miRNAs have been observed to fine-tune the cellular responses and, therefore, act as a rheostat rather than an on/off switch. Transcription factor PU.1 is a master switch that controls monocyte/macrophage development from hematopoietic stem cells. Recent Advances: PU.1 induces a specific set of miRNAs while suppressing the miR17-92 cluster to regulate monocyte/macrophage development. In addition to development, miRNAs tightly control the macrophage polarization continuum from proinflammatory M1 or proreparative M2 by regulating expression of key transcription factors involved in the process of polarization. Critical Issues: miRNAs are intricately involved with fine-tuning fundamental macrophage functions such as phagocytosis, efferocytosis, inflammation, tissue repair, and tumor promotion. Macrophages are secretory cells that participate in intercellular communication by releasing regulatory molecules and microvesicles (MVs). MVs are bilayered lipid membranes packaging a hydrophilic cargo, including proteins and nucleic acids. Macrophage-derived MVs carry functionally active miRNAs that suppress gene expression in target cells via post-transcriptional gene silencing, thus regulating cell function. In summary, miRNAs fine-tune several major facets of macrophage development and function. Such fine-tuning is critical in preventing exaggerated macrophage response to endogenous or exogenous stimuli. Future Directions: A critical role of miRNAs in the regulation of innate immune response and macrophage biology, including development, differentiation, and activation, has emerged. A clear understanding of such regulation on macrophage function remains to be elucidated. Antioxid. Redox Signal. 25, 795-804.

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MicroRNAs Transfer from Human Macrophages to Hepato-Carcinoma Cells and Inhibit Proliferation

Cited by 215 publications

References 61 publications

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

miR-223 Deficiency Protects against Fas-Induced Hepatocyte Apoptosis and Liver Injury through Targeting Insulin-Like Growth Factor 1 Receptor

miRNA in Macrophage Development and Function

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