Role of CXCR4/SDF-1α in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the transforming growth factor-β
Role of CXCR4/SDF-1α in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the transforming growth factor-β
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DOI：
10.1016/j.cellsig.2009.06.006
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发表时间：
2009-11-01
影响因子：
4.8
通讯作者：
Fabregat, Isabel
中科院分区：
文献类型：
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作者：
Bertran, Esther;Caja, Laia;Fabregat, Isabel
用TGF-β处理FaO大鼠肝癌细胞选择存活至其凋亡效应并经历上皮-间充质转化（EMT）的细胞。我们已经建立了一种细胞系（T β T-FaO，来自TGF-β处理的FaO），该细胞系在TGF-β存在下显示出间充质、去分化的表型，并且对其抑制作用不敏感。在缺乏这种细胞因子的情况下，细胞在3 - 4周内恢复上皮表型并恢复对TGF-β的应答。T β T-FaO显示出比在亲本FaO细胞中观察到的更高的迁移能力。我们发现FaO细胞表达低水平的CXCR4，并且对SDF-1 α没有反应。然而，TGF-β通过NF κ B依赖性机制上调CXCR4，并且T β T-FaO细胞显示CXCR4水平升高，其位于假定的迁移前沿。一种特异性CXCR4拮抗剂（AMD 3100）可减弱T β T-FaO细胞在胶原凝胶上的迁移能力。细胞外SDF-1 α激活T β T-FaO中的ERK通路，但不激活FaO细胞中的ERK通路，增加细胞分散并保护细胞免受血清剥夺诱导的细胞凋亡。用特异性siRNA靶向敲低CXCR4阻断T β T-FaO对SDF-1 α的应答。因此，SDF-1/CXCR4轴可能在介导肝癌细胞中TGF-β诱导的EMT后的细胞迁移和存活中起重要作用。(C)2009 Elsevier Inc. All rights reserved.
Treatment of FaO rat hepatoma cells with TGF-beta selects cells that survive to its apoptotic effect and undergo epithelial-mesenchymal transitions (EMT). We have established a cell line (T beta T-FaO, from TGF-beta-treated FaO) that shows a mesenchymal, de-differentiated, phenotype in the presence of TGF-beta and is refractory to its suppressor effects. In the absence of this cytokine, cells revert to an epithelial phenotype in 3-4 weeks and recover the response to TGF-beta. T beta T-FaO show higher capacity to migrate than that observed in the parental FaO cells. We found that FaO cells express low levels of CXCR4 and do not respond to SDF-1 alpha. However, TGF-beta up-regulates CXCR4, through a NFkappaB-dependent mechanism, and T beta T-FaO cells show elevated levels of CXCR4, which is located in the presumptive migration front. A specific CXCR4 antagonist (AMD3100) attenuates the migratory capacity of T beta T-FaO cells on collagen gels. Extracellular SDF-1 alpha activates the ERKs pathway in T beta T-FaO, but not in FaO cells, increasing cell scattering and protecting cells from apoptosis induced by serum deprivation. Targeted knock-down of CXCR4 with specific siRNA blocks the T beta T-FaO response to SDF-1 alpha. Thus, the SDF-1/CXCR4 axis might play an important role in mediating cell migration and survival after a TGF-beta-induced EMT in hepatoma cells. (C) 2009 Elsevier Inc. All rights reserved.