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

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.

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet‐derived growth factor BB

“…Inhibition of tumor angiogenesis has been speculated to be one of the most promising strategies to inhibit tumor growth and metastasis. However, traditional anti‐angiogenesis treatments sometimes lead to accelerated tumor growth by inducing hypoxia and metastasis . To use anti‐angiogenesis therapies effectively in CRC, it is essential to identify the molecular mechanisms that activate angiogenesis in CRC.…”

Down‐regulation of exosomal miR‐106b‐5p derived from cholesteatoma perimatrix fibroblasts promotes angiogenesis in endothelial cells by overexpression of Angiopoietin 2

“…Several studies have demonstrated that exosomal miRNA can modulate angiogenesis through targeting different mRNAs (van Balkom et al, ; Kang et al, ; Liang et al, ; Ramakrishnan et al, ). Exosomal miR‐126‐3p from CD34 + stem cells (Mathiyalagan et al, ), exosomal miR‐125a from adipose‐derived MSCs (Liang et al, ), exosomal miR‐23a from hypoxic lung cells (Hsu et al, ), exosomal miR‐17‐92 cluster and miR‐21 from leukaemia cells (Umezu et al, ), and exosomal miR‐21 from glioma stem cell (Sun et al, ) promote endothelial cell viability, proliferation, migration, or tube formation. Here, we showed that miR‐106b‐5p is down‐regulated in hCPFs‐Exo and this down‐regulation enhances endothelial cell angiogenesis.…”

Horizontal transfer of miR‐23a from hypoxic tumor cell colonies can induce angiogenesis

“…Another report specified the role of miR‐27a/b from breast cancer cells with anti‐angiogenic properties (Hannafon et al, ) and another member from the cluster miR‐23a in Exosomes has been reported to act as a biomarker in colon cancer development (Ogata‐Kawata et al, ). Recently in 2017, Hsu et al () provided the evidence for the exosomal transfer of miR‐23a from hypoxic Lung cancer cells leading to increased angiogenesis by targeting prolyl hydroxylase and the tight junction protein ZO‐1. With convincing data on the role of horizontally transferred miR‐23a in the process of angiogenesis, we next tried to find the mechanism that may be responsible for miR‐23a mediated effect in angiogenic process.…”