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Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1

Oncogene volume 36, pages 4929–4942 (2017)Cite this article

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Abstract

Hypoxia plays a critical role during the evolution of malignant cells and tumour microenvironment (TME).Tumour-derived exosomes contain informative microRNAs involved in the interaction of cancer and stromal cells, thus contributing to tissue remodelling of tumour microenvironment. This study aims to clarify how hypoxia affects tumour angiogenesis through exosomes shed from lung cancer cells. Lung cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. miR-23a was significantly upregulated in exosomes from lung cancer under hypoxic conditions. Exosomal miR-23a directly suppressed its target prolyl hydroxylase 1 and 2 (PHD1 and 2), leading to the accumulation of hypoxia-inducible factor-1 α (HIF-1 α) in endothelial cells. Consequently, hypoxic lung cancer cells enhanced angiogenesis by exosomes derived from hypoxic cancer under both normoxic and hypoxic conditions. In addition, exosomal miR-23a also inhibits tight junction protein ZO-1, thereby increasing vascular permeability and cancer transendothelial migration. Inhibition of miR-23a by inhibitor administration decreased angiogenesis and tumour growth in a mouse model. Furthermore, elevated levels of circulating miR-23a are found in the sera of lung cancer patients, and miR-23a levels are positively correlated with proangiogenic activities. Taken together, our study reveals the clinical relevance and prognostic value of cancer-derived exosomal miR-23a under hypoxic conditions, and investigates a unique intercellular communication, mediated by cancer-derived exosomes, which modulates tumour vasculature.

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Acknowledgements

This study was supported by grants from the Ministry of Science and Technology (MOST 104-2314-B-037-053-MY4; MOST 104-2320-B-037-014-MY3; MOST 103-2320-B-037-006-MY3), and the Kaohsiung Medical University ‘Aim for the Top Journals Grant’ (Grant No. KMU-DT106005).

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Authors and Affiliations

  1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Y-L Hsu

  2. Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    J-Y Hung & W-A Chang

  3. School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    J-Y Hung

  4. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    W-A Chang, Y-S Lin, Y-C Pan, P-H Tsai, C-Y Wu & P-L Kuo

  5. Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan

    P-L Kuo

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Hsu, YL., Hung, JY., Chang, WA. et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene 36, 4929–4942 (2017). https://doi.org/10.1038/onc.2017.105

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