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

J Pathol. 2017 Apr;241(5):638-648. doi: 10.1002/path.4868.

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.

Keywords: DUSP2; IL-8; angiogenesis; hypoxia; metastasis.

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Colon / enzymology
  • Colon / pathology
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Down-Regulation
  • Dual Specificity Phosphatase 2 / genetics*
  • Dual Specificity Phosphatase 2 / metabolism
  • Heterografts
  • Humans
  • Interleukin-8 / genetics*
  • Interleukin-8 / metabolism
  • Male
  • Mice
  • Mice, SCID
  • Microvessels / enzymology
  • Microvessels / pathology
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction
  • Up-Regulation

Substances

  • CXCL8 protein, human
  • Interleukin-8
  • DUSP2 protein, human
  • Dual Specificity Phosphatase 2
  • Dusp2 protein, mouse