Gap junction-mediated transfer of miR-145-5p from microvascular endothelial cells to colon cancer cells inhibits angiogenesis

Thüringer, Dominique; Jégo, Gaëtan; Berthenet, Kevin; Hammann, Arlette; Solary, Éric

doi:10.18632/oncotarget.8583

Cited by 72 publications

(70 citation statements)

References 43 publications

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“…More recently the long noncoding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) was found to regulate the expression of miR‐145‐5p, which in turn targeted AKAP12 . While these findings were made using prostate cancer cells, MALAT1, and miR‐145 are both known to affect endothelial cell migration and angiogenesis, especially in cells exposed to hypoxia and in the tumour microenvironment.…”

Section: Discussionmentioning

confidence: 99%

AKAP12 deficiency impairs VEGF‐induced endothelial cell migration and sprouting

et al. 2019

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Aim Protein kinase (PK) A anchoring protein (AKAP) 12 is a scaffolding protein that anchors PKA to compartmentalize cyclic AMP signalling. This study assessed the consequences of the downregulation or deletion of AKAP12 on endothelial cell migration and angiogenesis. Methods The consequences of siRNA‐mediated downregulation AKAP12 were studied in primary cultures of human endothelial cells as well as in endothelial cells and retinas from wild‐type versus AKAP12−/− mice. Molecular interactions were investigated using a combination of immunoprecipitation and mass spectrometry. Results AKAP12 was expressed at low levels in confluent endothelial cells but its expression was increased in actively migrating cells, where it localized to lamellipodia. In the postnatal retina, AKAP12 was expressed by actively migrating tip cells at the angiogenic front, and its deletion resulted in defective extension of the vascular plexus. In migrating endothelial cells, AKAP12 was co‐localized with the PKA type II‐α regulatory subunit as well as multiple key regulators of actin dynamics and actin filament‐based movement; including components of the Arp2/3 complex and the vasodilator‐stimulated phosphoprotein (VASP). Fitting with the evidence of a physical VASP/AKAP12/PKA complex, it was possible to demonstrate that the VEGF‐stimulated and PKA‐dependent phosphorylation of VASP was dependent on AKAP12. Indeed, AKAP12 colocalized with phospho‐Ser157 VASP at the leading edge of migrating endothelial cells. Conclusion The results suggest that compartmentalized AKAP12/PKA signalling mediates VASP phosphorylation at the leading edge of migrating endothelial cells to translate angiogenic stimuli into altered actin dynamics and cell movement.

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Section: Discussionmentioning

confidence: 99%

AKAP12 deficiency impairs VEGF‐induced endothelial cell migration and sprouting

et al. 2019

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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

Traffic

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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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“…Previous studies demonstrated that miR‐145 functions as a tumor suppressor via inhibition of tumor angiogenesis in various cancers, including colon cancer, pancreatic cancer, and breast cancer . VEGF was an established downstream target of miR‐145 during regulation of tumor angiogenesis .…”

Section: Discussionmentioning

confidence: 99%

LncRNA DANCR promotes tumor growth and angiogenesis in ovarian cancer through direct targeting of miR‐145

Lin

Yang

et al. 2019

Molecular Carcinogenesis

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Differentiation antagonizing non‐protein coding RNA (DANCR) is a newly identified oncogenic long noncoding RNA found in various cancers. However, the functional role of DANCR in tumor angiogenesis and the underlying mechanisms are still unclear. The expression of DANCR was determined in ovarian malignant tissues and cell lines. The functional role of DANCR in tumor angiogenesis was revealed by the following methods: CD31 staining of ovarian tumor tissues, matrigel‐plug assay tissues, HUVEC‐related tube formation assay, and invasion assay. Enzyme‐linked immunosorbent assay, Western blotting, luciferase assay, and rescue experiments were used to investigate the underlying mechanisms of DANCR‐regulating angiogenesis. DANCR was upregulated in ovarian malignant tissues and ovarian cancer cells. Knockdown of DANCR efficiently impaired ovarian tumor growth through inhibition of tumor angiogenesis. Furthermore, the conditional culture medium from DANCR‐knockdown ovarian cells significantly inhibited tube formation and invasion of HUVEC in vitro. Mechanistic investigation indicated that vascular endothelial growth factor A (VEGF‐A, VEGF) plays a crucial role during DANCR inhibition of tumor angiogenesis in ovarian cancer. Further results demonstrated that miR‐145 is the direct binding target of DANCR during regulation of VEGF expression and tumor angiogenesis in ovarian cancer cells. Collectively, DANCR plays a promotional role in tumor angiogenesis in ovarian cancer through regulation of miR‐145/VEGF axis. Therefore, DANCR may be a novel therapy target for ovarian cancer.

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Gap junction-mediated transfer of miR-145-5p from microvascular endothelial cells to colon cancer cells inhibits angiogenesis

Cited by 72 publications

References 43 publications

AKAP12 deficiency impairs VEGF‐induced endothelial cell migration and sprouting

AKAP12 deficiency impairs VEGF‐induced endothelial cell migration and sprouting

Potential mechanisms of microRNA mobility

LncRNA DANCR promotes tumor growth and angiogenesis in ovarian cancer through direct targeting of miR‐145

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