Department of Life Sciences, Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul 120-725, Republic of Korea.
Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2014 Apr 4;446(2):487-92. doi: 10.1016/j.bbrc.2014.02.142. Epub 2014 Mar 12.
The cell surface heparan sulfate proteoglycan, syndecan-2, is known to play an important role in the tumorigenic activity of colon cancer cells. In addition, the extracellular domain of syndecan-2 is cleaved by matrix metalloproteinase-7 (MMP-7) in various colon cancer cells, but factors involved in regulating this process remain unknown. Here, we demonstrate a role for interleukin-1α (IL-1α) in syndecan-2 shedding in colon cancer cells. Treatment of low metastatic (HT-29) and highly metastatic (HCT-116) colon cancer cells with various soluble growth factors and cytokines revealed that IL-1α specifically increased extracellular shedding of syndecan-2 in a concentration- and time-dependent manner. IL-1α did not affect the expression of syndecan-2, but did significantly reduce its cell surface levels. Notably, IL-1α increased the mRNA expression and subsequent secreted levels of MMP-7 protein and enhanced the phosphorylation of p38 and ERK mitogen-activated protein kinases. Furthermore, increased syndecan-2 shedding was dependent on the mitogen-activated protein kinase-mediated MMP-7 expression. Taken together, these data suggest that IL-1α regulates extracellular domain shedding of syndecan-2 through regulation of the MAP kinase-mediated MMP-7 expression in colon cancer cells.
细胞表面硫酸乙酰肝素蛋白聚糖，即黏附素-2，已知在结肠癌细胞的致瘤活性中发挥重要作用。此外，黏附素-2 的细胞外结构域在各种结肠癌细胞中被基质金属蛋白酶-7（MMP-7）切割，但调节这一过程的因素尚不清楚。在这里，我们证明白细胞介素-1α（IL-1α）在结肠癌细胞中黏附素-2脱落过程中发挥作用。用各种可溶性生长因子和细胞因子处理低转移性（HT-29）和高转移性（HCT-116）结肠癌细胞后发现，IL-1α 特异性地以浓度和时间依赖的方式增加了黏附素-2 的细胞外脱落。IL-1α 不影响黏附素-2 的表达，但显著降低其细胞表面水平。值得注意的是，IL-1α 增加了 MMP-7 蛋白的 mRNA 表达和随后的分泌水平，并增强了 p38 和 ERK 丝裂原活化蛋白激酶的磷酸化。此外，黏附素-2 的脱落增加依赖于丝裂原活化蛋白激酶介导的 MMP-7 表达。综上所述，这些数据表明，IL-1α 通过调节 MAP 激酶介导的 MMP-7 表达来调节结肠癌细胞中黏附素-2 的细胞外结构域脱落。
