Park Haein, Han Innoc, Kwon Ho Jeong, Oh Eok-Soo
Department of Life Science, Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea.
Cancer Res. 2005 Nov 1;65(21):9899-905. doi: 10.1158/0008-5472.CAN-05-1386.
Expression of syndecan-2, a transmembrane heparan sulfate proteoglycan, is crucial for the tumorigenic activity in colon carcinoma cells. However, despite the high-level expression of syndecan-2 in mesenchymal cells, few studies have addressed the function of syndecan-2 in sarcoma cells. In HT1080 fibrosarcoma cells, we found that syndecan-2 regulated migration, invasion into Matrigel, and anchorage-independent growth but not cell-extracellular matrix adhesion or proliferation, suggesting that syndecan-2 plays different functional roles in fibrosarcoma and colon carcinoma cells. Consistent with the increased cell migration/invasion of syndecan-2-overexpressing HT1080 cells, syndecan-2 overexpression increased phosphorylation and interaction of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K), membrane localization of T-lymphoma invasion and metastasis gene-1 (Tiam-1), and activation of Rac. Syndecan-2-mediated cell migration/invasion of HT1080 cells was diminished when (a) cells were cotransfected with nonphosphorylatable mutant FAK Y397F or with other FAK mutants lacking PI3K interactions, (b) cells were treated with a specific PI3K inhibitor, or (c) levels of Tiam-1 were knocked down with small interfering RNAs. Furthermore, expression of several FAK mutants inhibited syndecan-2-mediated enhancement of anchorage-independent growth in HT1080 cells. Taken together, these data suggest that syndecan-2 regulates the tumorigenic activities of HT1080 fibrosarcoma cells and that FAK is a key regulator of syndecan-2-mediated tumorigenic activities.
Syndecan-2是一种跨膜硫酸乙酰肝素蛋白聚糖，其表达对于结肠癌细胞的致瘤活性至关重要。然而，尽管syndecan-2在间充质细胞中高表达，但很少有研究探讨syndecan-2在肉瘤细胞中的功能。在HT1080纤维肉瘤细胞中，我们发现syndecan-2调节细胞迁移、侵袭进入基质胶以及非锚定依赖生长，但不调节细胞与细胞外基质的黏附或增殖，这表明syndecan-2在纤维肉瘤和结肠癌细胞中发挥不同的功能作用。与syndecan-2过表达的HT1080细胞的细胞迁移/侵袭增加一致，syndecan-2过表达增加了黏着斑激酶（FAK）和磷脂酰肌醇3激酶（PI3K）的磷酸化及相互作用、T淋巴瘤侵袭与转移基因-1（Tiam-1）的膜定位以及Rac的激活。当（a）细胞与非磷酸化突变体FAK Y397F或其他缺乏PI3K相互作用的FAK突变体共转染时，（b）细胞用特异性PI3K抑制剂处理时，或（c）用小干扰RNA敲低Tiam-1水平时，syndecan-2介导的HT1080细胞迁移/侵袭会减弱。此外，几种FAK突变体的表达抑制了syndecan-2介导的HT1080细胞非锚定依赖生长的增强。综上所述，这些数据表明syndecan-2调节HT1080纤维肉瘤细胞的致瘤活性，并且FAK是syndecan-2介导的致瘤活性的关键调节因子。
