Premium
Loss of dual‐specificity phosphatase‐2 promotes angiogenesis and metastasis via up‐regulation of interleukin‐8 in colon cancer
Author(s) -
Lin ShihChieh,
Hsiao KueiYang,
Chang Ning,
Hou PeiChi,
Tsai ShawJenq
Publication year - 2017
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4868
Subject(s) - gene knockdown , angiogenesis , medicine , cancer research , metastasis , cancer , chemistry , biochemistry , gene
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.