Choi Sojoong, Chung Heesung, Hong Heejeong, Kim So Yeon, Kim Seong-Eun, Seoh Ju-Young, Moon Chang Mo, Yang Eun Gyeong, Oh Eok-Soo
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
Department of Life Sciences, Ewha Womans University, Seoul, South Korea;
FASEB J. 2017 Apr;31(4):1516-1530. doi: 10.1096/fj.201601098R. Epub 2016 Dec 28.
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.
已知慢性炎症是肿瘤进展的关键致病因素，但我们尚未完全了解炎症导致癌症的分子机制。在此，我们报告硫酸葡聚糖钠（DSS）诱导的慢性结肠炎小鼠模型与血清白细胞介素-1β水平升高以及细胞表面硫酸乙酰肝素蛋白聚糖syndecan-2的结肠上皮表达增加有关。我们进一步表明，白细胞介素-1β刺激了CCD841CoN正常结肠上皮细胞和早期HT29结肠癌细胞中syndecan-2的转录 NF-κB依赖的FOXO3a激活。在慢性结肠炎小鼠的结肠上皮中观察到炎症性缺氧，提示缺氧应激参与了syndecan-2表达的调节。一致地，实验性炎症性缺氧诱导缺氧诱导因子-1α依赖的FOXO3a表达以及p38丝裂原活化蛋白激酶介导的FOXO3a核定位。FOXO3a直接介导了两种细胞系以及DSS诱导的结肠炎小鼠结肠上皮中的syndecan-2表达。此外，在氧化偶氮甲烷/DSS诱导的结肠肿瘤中检测到syndecan-2表达。总之，这些数据表明炎症性缺氧通过IL-1β-NF-κB-FOXO3a途径上调syndecan-2。这些发现为炎症性缺氧介导的syndecan-2表达提供了新的机制见解，以连接慢性炎症与结肠癌的发展。-崔，S.，郑，H.，洪，H.，金，S.Y.，金，S.-E.，徐，J.-Y.，文，C.M.，杨，E.G.，吴，E.-S. 炎症性缺氧通过IL-1β介导的结肠上皮FOXO3a激活诱导syndecan-2表达
