title: Inflammatory hypoxia induces syndecan-2 expression through IL-1β-mediated FOXO3a activation in colonic epithelia.
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-1β stimulated the transcription of syndecan-2viaNF-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 p38 MAPK-mediated 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 up-regulates syndecan-2viathe 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.-Choi, S., Chung, H., Hong, H., Kim, S. Y., Kim, S.-E., Seoh, J.-Y., Moon, C. M., Yang, E. G., Oh, E.-S. Inflammatory hypoxia induces syndecan-2 expression through IL-1β-mediated FOXO3a activation in colonic epithelia.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
authors.forename: Sojoong
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul, South Korea; eunyang@kist.re.kr.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, South Korea.
authors.forename: Heesung
authors.initials: H
authors.lastname: Chung
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul, South Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, South Korea.
authors.forename: Heejeong
authors.initials: H
authors.lastname: Hong
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea; and.
authors.forename: Seong-Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Ewha Womans University, Seoul, South Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Seoh
authors.affiliation: Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea; and.
authors.forename: Chang Mo
authors.initials: CM
authors.lastname: Moon
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea; eunyang@kist.re.kr.
authors.forename: Eun Gyeong
authors.initials: EG
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, Ewha Womans University, Seoul, South Korea; ohes@ewha.ac.kr.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, South Korea.
authors.forename: Eok-Soo
authors.initials: ES
authors.lastname: Oh
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D053669:Syndecan-2 / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D053583:Interleukin-1beta; D016328:NF-kappa B; D053669:Syndecan-2; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen
keywords: FOXO3a; IL-1β; colon cancer