Syndecan-1 modulates β-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation
Syndecan-1 modulates β-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation
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DOI：
10.1111/febs.12111
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发表时间：
2013-05-01
期刊：
影响因子：
5.4
通讯作者：
Goette, Martin
中科院分区：
文献类型：
--
作者：
Hassan, Hebatallah;Greve, Burkhard;Goette, Martin
Syndecan-1是一种细胞表面硫酸乙酰肝素蛋白多糖，具有多种与肿瘤进展和炎症相关的生物学功能，包括细胞黏附、细胞基质相互作用以及驱动细胞增殖和运动的细胞因子信号转导。Syndecan-1是乳腺癌的预后因子，对新辅助化疗有预测价值。Syndecan-1如何在肿瘤微环境中整合基质依赖和细胞因子依赖的信号过程仍然知之甚少。在这里，我们评估了Syndecan-1在白介素6存在的情况下调节依赖基质的乳腺癌细胞迁移的潜在作用，以及它在体外辐射抵抗中的潜在参与。将Syndecan-1小干扰RNA或对照试剂瞬时导入乳腺癌细胞MDA-MB-231，再用IL-6刺激或照射。通过黏附、迁移和集落形成试验以及细胞信号分析来监测细胞反应。Syndecan-1的缺失增加了细胞与纤维连接蛋白的黏附。IL-6可显著抑制纤维粘连蛋白的迁移增加，GRGDSP多肽对黏附和迁移均有抑制作用。在Syndecan-1缺陷细胞中，IL-6诱导的粘着斑激酶的激活和组成性核因子kappaB信号的减少均减少。Syndecan-1缺失细胞中粘着斑激酶的过度激活与辐射敏感性显著降低有关。我们得出结论，Syndecan-1的缺失导致1-整合素和粘着斑激酶的激活增强，从而增加了乳腺癌细胞的黏附、迁移和对辐射的抵抗力。Syndecan-1缺乏也减弱了炎性微环境成分IL-6对癌细胞迁移的调节作用。
Syndecan-1 is a cell surface heparan sulfate proteoglycan with various biological functions relevant to tumor progression and inflammation, including cellcell adhesion, cellmatrix interaction, and cytokine signaling driving cell proliferation and motility. Syndecan-1 is a prognostic factor in breast cancer, and has a predicitive value for neodadjuvant chemotherapy. It is still poorly understood how syndecan-1 integrates matrix-dependent and cytokine-dependent signaling processes in the tumor microenvironment. Here, we evaluated the potential role of syndecan-1 in modulating matrix-dependent breast cancer cell migration in the presence of interleukin-6, and its potential involvement in resistance to irradiation invitro. MDA-MB-231 breast cancer cells were transiently transfected with syndecan-1 small interfering RNA or control reagents, and this was followed by stimulation with interleukin-6 or irradiation. Cellular responses were monitored by adhesion, migration and colony formation assays, as well as analysis of cell signaling. Syndecan-1 depletion increased cell adhesion to fibronectin. Increased migration on fibronectin was significantly suppressed by interleukin-6, and GRGDSP peptides inhibited both adhesion and migration. Interleukin-6-induced activation of focal adhesion kinase and reduction of constitutive nuclear factor kappaB signaling were decreased in syndecan-1-deficient cells. Focal adhesion kinase hyperactivation in syndecan-1-depleted cells was associated with dramatically reduced radiation sensitivity. We conclude that loss of syndecan-1 leads to enhanced activation of 1-integrins and focal adhesion kinase, thus increasing breast cancer cell adhesion, migration, and resistance to irradiation. Syndecan-1 deficiency also attenuates the modulatory effect of the inflammatory microenvironment constituent interleukin-6 on cancer cell migration.