Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency

Wanying Zhang, Jie Liao, Haonan Li, Hua Dong, Han Bai, Allison Yang, Bruce D. Hammock, Guang Yu Yang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Soluble epoxide hydrolase (sEH) quickly inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) by converting them to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has shown effects against inflammation, but little is studied about the role of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study, the effect of sEH gene deficiency on the development of IBD-induced tumor development was determined in IL-10 knockout mice combined with sEH gene deficiency. Tumor development in the bowel was examined at the age of 25wk for male mice and 35wk for female mice. Compared to IL-10(-/-) mice, sEH (-/-)/IL-10(-/-) mice exhibited a significant decrease of tumor multiplicity (2±0.9tumors/mouse vs. 1±0.3tumors/mouse) and tumor size (344.55±71.73mm3 vs. 126.94±23.18mm3), as well as a marked decrease of precancerous dysplasia. The significantly lower inflammatory scores were further observed in the bowel in sEH(-/-)/IL-10(-/-) mice as compared to IL-10(-/-) mice, including parameters of inflammation-involved area (0.70±0.16 vs. 1.4±0.18), inflammation cell infiltration (1.55±0.35 vs. 2.15±0.18), and epithelial hyperplasia (0.95±0.21 vs. 1.45±0.18), as well as larger ulcer formation. qPCR and Western blotting assays demonstrated a significant downregulation of cytokines/chemokines (TNF-α, MCP-1, and IL-12, 17, and 23) and NF-κB signals. Eicosanoid acid metabolic profiling revealed a significant increase of ratios of EETs to DHETs and EpOMEs to DiOMEs. These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD.

Original languageEnglish (US)
Pages (from-to)726-738
Number of pages13
JournalMolecular Carcinogenesis
Volume52
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • Carcinogenesis
  • Eicosanoid acid metabolic profiling
  • IL-10
  • Inflammatory bowel disease
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

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