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

Shih Chieh Lin, Kuei Yang Hsiao, Ning Chang, Pei Chi Hou, Shaw Jenq Tsai

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)638-648
Number of pages11
JournalJournal of Pathology
Volume241
Issue number5
DOIs
Publication statusPublished - 2017 Apr 1

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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