Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway

• Published in: The EMBO journal Vol. 31; no. 17; pp. 3513 - 3523
• Main Authors: Zhuang, Guanglei, Wu, Xiumin, Jiang, Zhaoshi, Kasman, Ian, Yao, Jenny, Guan, Yinghui, Oeh, Jason, Modrusan, Zora, Bais, Carlos, Sampath, Deepak, Ferrara, Napoleone
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 29.08.2012; Nature Publishing Group UK; Springer Nature B.V; Nature Publishing Group
• Subjects: Angiogenesis; Animals; Cell Line; Cell Line, Tumor; Cell Movement; Cercopithecus aethiops; COS Cells; EMBO24; EMBO36; Endothelial Cells - physiology; endothelium; Growth factors; Humans; JAK-STAT; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - metabolism; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Mice; Mice, Inbred BALB C; microRNA; MicroRNAs - biosynthesis; Molecular biology; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Protein Kinase Inhibitors - therapeutic use; Ribonucleic acid; RNA; Signal Transduction; STAT1 Transcription Factor - antagonists & inhibitors; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling Proteins - metabolism; Tumors; tumour; Up-Regulation; Vascular endothelial growth factor; Xenograft Model Antitumor Assays; JAK‐STAT; endothelium; microRNA; angiogenesis; tumour
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2012.183

Angiogenesis plays a crucial role during tumorigenesis and much progress has been recently made in elucidating the role of VEGF and other growth factors in the regulation of angiogenesis. Recently, microRNAs (miRNAs) have been shown to modulate a variety of physiogical and pathological processes. We identified a set of differentially expressed miRNAs in microvascular endothelial cells co‐cultured with tumour cells. Unexpectedly, most miRNAs were derived from tumour cells, packaged into microvesicles (MVs), and then directly delivered to endothelial cells. Among these miRNAs, we focused on miR‐9 due to the strong morphological changes induced in cultured endothelial cells. We found that exogenous miR‐9 effectively reduced SOCS5 levels, leading to activated JAK‐STAT pathway. This signalling cascade promoted endothelial cell migration and tumour angiogenesis. Remarkably, administration of anti‐miR‐9 or JAK inhibitors suppressed MV‐induced cell migration in vitro and decreased tumour burden in vivo . Collectively, these observations suggest that tumour‐secreted miRNAs participate in intercellular communication and function as a novel pro‐angiogenic mechanism. Secreted miRNAs are increasingly recognized in multiple biological processes. Here, miR‐9 is shown to be secreted from cancer cells to enhance endothelial recruitment. This contribution to tumour angiogenesis could be amenable for therapeutic intervention.