Loss of dual-specificity phosphatase-2 promotes angiogenesis and metastasis via up-regulation of interleukin-8 in colon cancer

被引:29
作者
Lin, Shih-Chieh [1 ]
Hsiao, Kuei-Yang [1 ]
Chang, Ning [1 ]
Hou, Pei-Chi [2 ]
Tsai, Shaw-Jenq [1 ,2 ]
机构
[1] Natl Cheng Kung Univ, Dept Physiol, Coll Med, 1 Univ Rd, Tainan 701, Taiwan
[2] Natl Cheng Kung Univ, Inst Basic Med Sci, Coll Med, Tainan, Taiwan
关键词
DUSP2; IL-8; hypoxia; angiogenesis; metastasis; HUMAN COLORECTAL-CARCINOMA; BREAST-CANCER; TUMOR-GROWTH; IN-VIVO; CELLS; HYPOXIA; EXPRESSION; PROGRESSION; VEGF; INFLAMMATION;
D O I
10.1002/path.4868
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/EBP-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 (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:638 / 648
页数:11
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