Inflammatory hypoxia induces syndecan-2 expression through IL-1β-mediated FOXO3a activation in colonic epithelia

Sojoong Choi, Heesung Chung, Heejeong Hong, So Yeon Kim, Seong Eun Kim, Ju Young Seoh, Chang Mo Moon, Eun Gyeong Yang, Eok Soo Oh

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27 Scopus citations

Abstract

Chronic inflammation is known to be a key causative factor in tumor progression, but we do not yet fully understand the molecular mechanism through which inflammation leads to cancer. Here, we report that the dextran sulfate sodium (DSS)-induced mouse model of chronic colitis is associated with increases in the serum level of IL-1β and the colonic epithelial expression of the cell-surface heparan sulfate proteoglycan, syndecan-2. We further show that IL-11β stimulated the transcription of syndecan-2 via NF-κB-dependent FOXO3a activation in CCD841CoN normal colonic epithelial cells and early-stage HT29 colon cancer cells. Inflammatory hypoxia was observed in the colonic epithelia of mice with chronic colitis, suggesting that hypoxic stress is involved in the regulation of syndecan-2 expression. Consistently, experimental inflammatory hypoxia induced hypoxia inducible factor-1α-dependent FOXO3a expression and the p38MAPKmediated nuclear localization of FOXO3a. FOXO3a directly mediated syndecan-2 expression in both cell lines and the colonic epithelia of mice with DSS-induced colitis. Moreover, syndecan-2 expression was detected in azoxymethane/DSS-induced colon tumors. Together, these data demonstrate that inflammatory hypoxia upregulates syndecan-2 via the IL-1β-NF-κB-FOXO3a pathway. These findings provide new mechanistic insights into inflammatory hypoxia-mediated syndecan-2 expression to connect chronic inflammation and the development of colon cancer.

Original languageEnglish
Pages (from-to)1516-1530
Number of pages15
JournalFASEB Journal
Volume31
Issue number4
DOIs
StatePublished - Apr 2017

Bibliographical note

Funding Information:
The authors thank the National Research Foundation of Korea for Grants 2012R1A5A1048236 and 2014K1A3A7A03075056 (to E.-S.O.), and Grant 2012M3A9B9028156 (to E.G.Y.), Korean Ministry of Science, Information and Communications Technology (ICT) and Future Planning Grant NRF2012M3A9C4048761 (to E.-S.O.), and a Korea Institute of Science and Technology grant. The construct of dominant negative p38 was kindly provided by Dr. Y. J. Oh (Yonsei University, Seoul, South Korea). The syndecan-2 promoter constructs, wild p3.62kb-LUC, and mutant p3.62kb-LUC (in which FOXO3a binding was abolished) were kindly provided by Dr. D. Modrowski (Laboratory of Osteoblast Biology and Pathology, INSERM U606, Paris, France). The authors declare no competing financial interests.

Publisher Copyright:
© 2017 FASEB.

Keywords

  • Colon cancer
  • FOXO3a
  • IL-1β

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