DUSP2 Regulates Extracellular Vesicle-VEGF-C Secretion and Pancreatic Cancer Early Dissemination

Overview

Journal J Extracell Vesicles

Publisher Wiley

Date 2020 Apr 29

PMID 32341770

Citations 24

Authors

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

Affiliations

Soon will be listed here.

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 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. DUSP2: dual-specificity phosphatase-2; VEGF-C: vascular endothelial growth factor-C; EV: extracellular vesicles; PDAC: pancreatic ductal adenocarcinoma; KD: knockdown.

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