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-2 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 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-2 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.-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.

We previously reported that syndecan‐2 expression is increased on the colonic epithelium during chronic inflammation. Here, we report that syndecan‐2 exhibits a different pattern of site‐specific colonic expression during acute inflammation. Syndecan‐2 expression was up‐regulated predominantly in the proximal colon of dextran sulfate sodium‐induced colitis mice. The colitis‐associated up‐regulation of syndecan‐2 was barely detected in Rag‐1−/− (recombination activating gene 1 knockout) mice under colitis‐inducing conditions. Increased syndecan‐2 expression correlated with increased levels of infiltrated CD4+IL‐17A+ T cells in the proximal colon. Serum levels of IL‐17A were increased during the acute inflammatory response in normal mice but not Rag‐1−/− mice. IL‐17A directly induced IL‐17 receptor (IL‐17RA) and syndecan‐2 expression in ex vivo‐cultured proximal colon tissues and adenoma cell lines from proximal colon. IL‐17RA knockdown reduced the IL‐17A‐mediated syndecan‐2 expression in SNU1235 cells. No elevation of syndecan‐2 or IL‐17RA was observed in colonic tissues from IL‐17A−/− mice during colitis induction. Finally, increased expression of syndecan‐2 and IL‐17RA was observed in the proximal colons of cecal ligation and puncture‐induced sepsis mice and infectious pan colitis patients. Together, these data suggest that acute inflammation induces syndecan‐2 expression predominantly in the proximal colon via IL‐17A‐IL‐17RA signaling during the early stage of the inflammatory response and that proximal colonic syndecan‐2 might be a biomarker for acute inflammation.—Hong, H., Song, H.‐K., Hwang, E. S., Lee, A. R., Han, D. S., Kim, S.‐E., Oh, E.‐S. Up‐regulation of syndecan‐2 in proximal colon correlates with acute inflammation. FASEB J. 33, 11381–11395 (2019). http://www.fasebj.org

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Introduction Syndecan-2 expression is elevated during chronic inflammation and cancer development, and its shedding is observed in cancer patients. However, it remained unknown whether inflammation triggers syndecan-2 shedding. Methods The colitis model was produced in C57BL/6 mice by oral administration of 2–3% dextran sulfate sodium (DSS) in the drinking water. Syndecan-2 and MMP-7 expression levels in tissues and cells were detected by real-time PCR, Western blotting, and immunohistochemistry. Shed syndecan-2 levels were detected by slot blotting. For tissue culture, colon tissues were divided into proximal, transverse, and distal parts, and incubated in culture media. Results In C57BL/6 mice with DSS-induced colitis, syndecan-2 shedding began to increase after week 12 of chronic inflammation and continued to increase at week 15. The level of shed syndecan-2 correlated with the colocalization of syndecan-2 and MMP-7 in distal colon tissues. The mRNA expression of IL-6 was increased specifically in trans-distal colon tissues from weeks 9 to 15. IL-6 induced syndecan-2 expression and shedding and MMP-7 expression in ex vivo-cultured distal colon tissues and adenoma cell lines derived from the distal colon. IL-6 treatment induced STAT3 phosphorylation and MMP-7 expression in DLD-1 cells. The application of MMP-7 to ex vivo-cultured colon tissues increased the shedding of syndecan-2 to the culture medium. Conclusion Our findings suggest that chronic inflammation induces syndecan-2 shedding via the site-specific colocalization of syndecan-2 with MMP-7 in the distal colon.