Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells
Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells
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DOI：
10.1016/j.bbagen.2009.07.015
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发表时间：
2009-10-01
影响因子：
3
通讯作者：
Sutton, Angela
中科院分区：
文献类型：
--
作者：
Charni, Faten;Friand, Veronique;Sutton, Angela
背景：我们之前已经证明cc趋化因子RANTES /CCL5通过其G蛋白偶联受体CCR1对人肝癌Huh7细胞发挥促瘤作用。糖胺聚糖在这些生物事件中起着重要作用。方法:在本研究中，我们探索了1 /通过使用特定的药物抑制剂，RANTES/CCL5介导的肝癌细胞迁移或侵袭的信号通路；2/通过使用二聚体RANTES/CCL5， RANTES/CCL5寡聚化在这些作用中的作用；3/两种膜硫酸肝素蛋白聚糖的可能参与；RANTES/ ccl5中的syndecan-1 （SDC-1）和syndecan-4 （SDC-4）通过特异性抗体预孵育细胞或通过RNA干扰降低SDC-1或-4的表达，诱导细胞趋化和扩散。结果和结论：目前的数据表明，局灶黏附激酶磷酸化、磷酸肌苷激酶3-、丝裂原活化蛋白激酶-和Rho激酶活化参与了RANTES/CCL5对Huh7细胞的促瘤作用。干扰趋化因子的寡聚化降低了RANTES/ ccl5介导的细胞趋化性。本研究还提示，趋化因子诱导HepG2、Hep3B和Huh7人肝癌细胞迁移、侵袭或扩散可能需要SDC-1和-4。这些结果也进一步证明了糖胺聚糖的参与，因为糖胺聚糖结合缺陷的RANTES/CCL5变体，其中精氨酸47被赖氨酸取代，没有效果。一般意义：通过趋化因子-syndecan相互作用调节RANTES/ ccl5介导的细胞效应可能是肝癌治疗的新途径。(C) 2009 Elsevier B.V.版权所有
Background: We previously demonstrated that the CC-chemokine Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES)/CCL5 exerts pro-tumoral effects on human hepatoma Huh7 cells through its G protein-coupled receptor, CCR1. Glycosaminoglycans play major roles in these biological events.Methods: In the present study, we explored 1 / the signalling pathways underlying RANTES/CCL5-mediated hepatoma cell migration or invasion by the use of specific pharmacological inhibitors, 2/ the role of RANTES/CCL5 oligomerization in these effects by using a dimeric RANTES/CCL5, 3/ the possible involvement of two membrane heparan sulfate proteoglycans, syndecan-1 (SDC-1) and syndecan-4 (SDC-4) in RANTES/CCL5-induced cell chemotaxis and spreading by pre-incubating cells with specific antibodies or by reducing SDC-1 or -4 expression by RNA interference.Results and conclusion: The present data suggest that focal adhesion kinase phosphorylation, phosphoinositide 3-kinase-, mitogen-activated protein kinase- and Rho kinase activations are involved in RANTES/CCL5 pro-tumoral effects on Huh7 cells. Interference with oligomerization of the chemokine reduced RANTES/CCL5-mediated cell chemotaxis. This study also indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. These results also further demonstrate the involvement of glycosaminoglycans as the glycosaminoglycan-binding deficient RANTES/CCL5 variant, in which arginine 47 was replaced by lysine, was devoid of effect.General significance: The modulation of RANTES/CCL5-mediated cellular effects by targeting the chemokine-syndecan interaction could represent a new therapeutic approach for hepatocellular carcinoma. (C) 2009 Elsevier B.V. All rights reserved.