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The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a.

ABSTRACT: Angiogenesis is an important factor contributing to the radioresistance of lung cancer. However, the associated mechanisms underlying radiotherapy-induced pro-angiogenesis are unclear. Here, we demonstrated that Extracellular vesicles (EVs) derived from cultured cells in vitro enhanced HUVEC proliferation and migration, and the enhancement effect became more obvious when HUVECs were treated with EV derived from A549 or H1299, two lung cancer cell lines. Additionally, the pro-angiogenesis effect induced by EV could be strengthened when the lung cancer cells were exposed to X-ray irradiation. Furthermore, we verified that the downregulation of PTEN plays a vital role in this process. By evaluating the changes in the levels of microRNAs(miRNAs) targeting PTEN in EV, we found that miR-23a was significantly upregulated and mediated a decrease in PTEN. A luciferase reporter gene transfer experiment demonstrated that PTEN was the direct target of miR-23a, and the kinetics of PTEN expression were opposite to those of miR-23a. Our results show that the miR-23a/PTEN pathway plays an important role in EV-induced angiogenesis. These findings implicate the miR-23a/PTEN axis as a novel therapeutic target for lung cancer radiotherapy.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC5572936 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a.

Zheng Yongfa Y Liu Liang L Chen Cong C Ming Pingpo P Huang Qin Q Li Changhu C Cao Dedong D Xu Ximing X Ge Wei W

PeerJ 20170825

Angiogenesis is an important factor contributing to the radioresistance of lung cancer. However, the associated mechanisms underlying radiotherapy-induced pro-angiogenesis are unclear. Here, we demonstrated that Extracellular vesicles (EVs) derived from cultured cells in vitro enhanced HUVEC proliferation and migration, and the enhancement effect became more obvious when HUVECs were treated with EV derived from A549 or H1299, two lung cancer cell lines. Additionally, the pro-angiogenesis effect ...[more]

PMID: 28852584

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Project description:Rationale: White matter repair is critical for the cognitive and neurological functional recovery after ischemic stroke. M2 microglia are well-documented to enhance remyelination and their extracellular vesicles (EVs) mediate cellular function after brain injury. However, whether M2 microglia-derived EVs could promote white matter repair after cerebral ischemia and its underlying mechanism are largely unknown. Methods: EVs were isolated from IL-4 treated microglia (M2-EVs) and untreated microglia (M0-EVs). Adult ICR mice subjected to 90-minute transient middle cerebral artery occlusion received intravenous EVs treatment for seven consecutive days. Brain atrophy volume, neurobehavioral tests were examined within 28 days following ischemia. Immunohistochemistry, myelin transmission electron microscope and compound action potential measurement were performed to assess white matter structural remodeling, functional repair and oligodendrogenesis. The effects of M2-EVs on oligodendrocyte precursor cells (OPCs) were also examined in vitro. EVs' miRNA sequencing, specific miR-23a-5p knockdown in M2-EVs and luciferase reporter assay were used to explore the underlying mechanism. Results: M2-EVs reduced brain atrophy volume, promoted functional recovery, oligodendrogenesis and white matter repair in vivo, increased OPC proliferation, survival and differentiation in vitro. miR-23a-5p was enriched in M2-EVs and could promote OPC proliferation, survival and maturation, while knocking down miR-23a-5p in M2-EVs reversed the beneficial effects of M2-EVs both in vitro and in vivo. Luciferase reporter assay showed that miR-23a-5p directly targeted Olig3. Conclusion: Our results demonstrated that M2 microglia could communicate to OPCs through M2-EVs and promote white matter repair via miR-23a-5p possibly by directly targeting Olig3 after ischemic stroke, suggesting M2-EVs is a novel and promising therapeutic strategy for white matter repair in stroke and demyelinating disease.

Dataset Information

The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a.

Publications

The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a.

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