title: Loss of dual-specificity phosphatase-2 promotes angiogenesis and metastasis via up-regulation of interleukin-8 in colon cancer.
abstract: Dual-specificity phosphatase 2 (DUSP2) is a negative regulator of mitogen-activated protein kinases. Our previous study showed that DUSP2 expression is down-regulated in many human cancers and loss of DUSP2 promotes cancer progression; however, the underlying mechanism remains largely uncharacterized. Herein, we found that loss of DUSP2 induces angiogenesis, while forced expression of DUSP2 inhibits microvessel formation in xenografted mouse tumours. Genome-wide screening of expression profiles, and meta-analysis of clinical data, identified that the level of interleukin-8 (IL-8) correlated negatively with that of DUSP2, suggesting that it may be a downstream target of DUSP2. Molecular characterization revealed that DUSP2 inversely regulates IL-8 expression, mediated by ERK1/2 and C/EBPα-dependent transcriptional regulation. Further study showed that hypoxia-induced IL-8 expression in cancer cells is also mediated via down-regulation of DUSP2. Treatment with the IL-8 receptor inhibitor reparixin or knockdown of IL-8 in cancer cells abolished angiogenesis induced by loss of DUSP2. Functionally, knockdown of DUSP2 enhanced tumour growth and metastasis, which were abolished by treatment with reparixin or knockdown of IL-8 in an orthotopic mouse model. Taken together, our results demonstrate that hypoxia inhibits DUSP2 expression in colon cancer, leading to up-regulation of IL-8, which facilitates angiogenesis and tumour metastasis. Our findings suggest that blocking hypoxia-DUSP2-IL-8 signalling may be a plausible approach for therapeutic intervention in cancer. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Kuei-Yang
authors.identifier: 0000-0002-1648-974X
authors.initials: KY
authors.lastname: Hsiao
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ning
authors.identifier: 0000-0003-2842-7658
authors.initials: N
authors.lastname: Chang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Hou
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shaw-Jenq
authors.initials: SJ
authors.lastname: Tsai
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D054641:Dual Specificity Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D055806:Microvessels / Q000201:enzymology / Q000473:pathology; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; C517033:Dusp2 protein, mouse
keywords: DUSP2; IL-8; angiogenesis; hypoxia; metastasis