@article{fb51e64f7b8f46348da0e2bbdad05dfb,
title = "DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination",
abstract = "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.",
author = "Wang, {Chu An} and Chang, {I. Heng} and Hou, {Pei Chi} and Tai, {Yu Jing} and Li, {Wan Ning} and Hsu, {Pei Ling} and Wu, {Shang Rung} and Chiu, {Wen Tai} and Li, {Chien Feng} and Shan, {Yan Shen} and Tsai, {Shaw Jenq}",
note = "Funding Information: This work was supported by the Ministry of Science and Technology, Taiwan [103-2321-B-006-020-MY3]; Ministry of Science and Technology, Taiwan [106-2321-B-006 −022-MY3]; National Health Research Institutes, Taiwan [NHRI-EX106-10516BI]. We thank Dr. Jonathan Jou (University of Illinois) for critical reading and editing of the manuscript. Human lymphatic endothelial cell line (LECs) was kindly provided by Dr. Wen-Chun Hung, National Health Research Institutes and human umbilical vein endothelial cells (HUVECs) was a kind gift from Dr. Chia-Ching Wu{\textquoteright}s laboratory in Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University. We like to thank Yi-Shan Ya, Shu-Chen Hung, Yi-Chen Tang, Yi-Jou Chung and Yen-Yu Lai for the technical support in immunohistochemistry staining, animal experiments, and bioinformatics analysis. We thank Taiwan Bioinformatics Institute Core Facility for the assistance on using Oncomine (National Core Facility Program for Biotechnology (MOST 105-2319-B-400-002). We thank the technical services provided by the “Bioimaging Core Facility of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan”. We thank the Center for Genomic Medicine and Center for Micro/Nano Science and Technology for Bioinformatic analysis and NTA analysis, respectively. Publisher Copyright: {\textcopyright} 2020, {\textcopyright} 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.",
year = "2020",
month = jan,
day = "1",
doi = "10.1080/20013078.2020.1746529",
language = "English",
volume = "9",
journal = "Journal of Extracellular Vesicles",
issn = "2001-3078",
publisher = "Taylor and Francis Ltd.",
number = "1",
}