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Human umbilical vein endothelial cells-derived microRNA-203-containing extracellular vesicles alleviate non-small-cell lung cancer progression through modulating the DTL/p21 axis

Cancer Gene Therapy volume 29, pages 87–100 (2022)Cite this article

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Abstract

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and is characterized by extensive metastasis and poor prognosis. Extracellular vesicles (EVs) derived from endothelial cells carrying microRNAs (miRNAs/miRs) have diagnostic and therapeutic potential for NSCLC. We herein investigate the potential of EVs derived from human umbilical vein endothelial cells (HUVECs) to transfer miR-203 to affect the progression of NSCLC. miR-203 and p21 were poorly expressed while DTL was highly expressed both in NSCLC tissues and cell lines. We employed CCK-8 proliferation, colony formation, and Transwell migration and invasion assays to evaluate the effects of miR-203 on NSCLC cell behaviors using loss- and gain-function approaches. EVs were isolated from HUVECs and then co-cultured with the A549 cells transfected with mimic-NC or miR-203 inhibitor. miR-203 targeted DTL and downregulated its expression, subsequently leading to increased stability of p21 which is a tumor suppressor. EV-enriched miR-203 from HUVECs suppressed malignant phenotypes of NSCLC cells and delayed tumor growth. In conclusion, miR-203 from HUVEC-derived EVs exerts inhibitory effects on the progression of NSCLC by targeting DTL and promoting p21 protein stability.

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Fig. 1: miR-203 may be involved in the NSCLC development.
Fig. 2: Elevation of miR-203 correlates with better prognosis and inhibits the proliferation of human NSCLC cells.
Fig. 3: Upregulated miR-203 retards NSCLC tumor growth in vivo.
Fig. 4: miR-203 induces stability of p21 protein by targeting DTL.
Fig. 5: miR-203-targeted inhibition of DTL restrains human NSCLC cell proliferation, migration, and invasion.
Fig. 6: HUVEC-derived EVs deliver miR-203 to NSCLC cells.
Fig. 7: HUVEC-derived EVs transferring miR-203 delays A549 cell proliferation, migration, and invasion.
Fig. 8: miR-203 delivered from HUVEC-derived EVs prevents tumor growth in vivo.
Fig. 9: The figure abstract implicating the molecular mechanism by which HUVEC-derived EV regulates the pathogenesis of NSCLC.

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Acknowledgements

The authors would like to acknowledge the helpful comments on this paper received from the reviewers.

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, the 2nd Hospital of Jilin University, Changchun, 130021, P.R. China

    Tiangang Ma & Qinghua Zhang

  2. Department of Ultrasound, the 2nd Hospital of Jilin University, Changchun, 130021, P.R. China

    Yanbing Hu

  3. Department of Clinical Laboratory, the 2nd Hospital of Jilin University, Changchun, 130021, P.R. China

    Yinxue Guo

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  1. Tiangang Ma
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Tiangang Ma wrote the paper and conceived and designed the experiments; Yanbing Hu analyzed the data; Yinxue Guo and Qinghua Zhang collected and provided the sample for this study. All authors have read and approved the final submitted manuscript.

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Correspondence to Qinghua Zhang.

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Ma, T., Hu, Y., Guo, Y. et al. Human umbilical vein endothelial cells-derived microRNA-203-containing extracellular vesicles alleviate non-small-cell lung cancer progression through modulating the DTL/p21 axis. Cancer Gene Ther 29, 87–100 (2022). https://doi.org/10.1038/s41417-020-00292-3

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