DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination

Chu An Wang, I. Heng Chang, Pei Chi Hou, Yu Jing Tai, Wan Ning Li, Pei Ling Hsu, Shang Rung Wu, Wen Tai Chiu, Chien Feng Li, Yan Shen Shan, Shaw Jenq Tsai

研究成果: Article

摘要

Early dissemination is a unique characteristic and a detrimental process of pancreatic ductal adenocarcinoma (PDAC); however, the underlying mechanism remains largely unknown. Here, we investigate the role of dual-specificity phosphatase-2 (DUSP2)-vascular endothelial growth factor-C (VEGF-C) axis in mediating PDAC lymphangiogenesis and lymphovascular invasion. Expression of DUSP2 is greatly suppressed in PDAC, which results in increased aberrant expression of extracellular vesicle (EV)-associated VEGF-C secretion. EV-VEGF-C exerts paracrine effects on lymphatic endothelial cells and autocrine effects on cancer cells, resulting in the lymphovascular invasion of cancer cells. Tissue-specific knockout of Dusp2 in mouse pancreas recapitulates PDAC phenotype and lymphovascular invasion. Mechanistically, loss-of-DUSP2 enhances proprotein convertase activity and vesicle trafficking to promote the release of the mature form of EV-VEGF-C. Collectively, these findings represent a conceptual advance in understanding pancreatic cancer lymphovascular invasion and suggest that loss-of-DUSP2-mediated VEGF-C processing may play important roles in early dissemination of pancreatic cancer. Abbreviations: DUSP2: dual-specificity phosphatase-2; VEGF-C: vascular endothelial growth factor-C; EV: extracellular vesicles; PDAC: pancreatic ductal adenocarcinoma; KD: knockdown.

原文English
文章編號1746529
期刊Journal of Extracellular Vesicles
9
發行號1
DOIs
出版狀態Published - 2020 一月 1

All Science Journal Classification (ASJC) codes

  • Histology
  • Cell Biology

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