Pseudopodial Actin Dynamics Control Epithelial-Mesenchymal Transition in Metastatic Cancer Cells
Pseudopodial Actin Dynamics Control Epithelial-Mesenchymal Transition in Metastatic Cancer Cells
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DOI：
10.1158/0008-5472.can-09-4439
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Nabi, Ivan R.
中科院分区：
文献类型：
--
作者：
Shankar, Jay;Messenberg, Anat;Nabi, Ivan R.
在许多癌症中，与侵袭性或转移性程序相关的关键细胞过程是上皮细胞向间充质状态的转化，该过程称为上皮向间充质转化或EMT。细胞伪足的肌动蛋白依赖性突起是间充质细胞迁移的关键因素，因此是癌症转移的关键因素。然而，EMT是否发生在人类癌症中，特别是它是否是肿瘤细胞侵袭和转移的先决条件，仍然是一个争论的主题。微阵列和蛋白质组学分析肌动蛋白丰富的伪足从6个转移性人类肿瘤细胞系确定了384个mRNA和64种蛋白质共同的伪足的6个转移性人类肿瘤细胞系的各种癌症的起源，导致19个常见的伪足特异性蛋白质的表征。其中四种（AHNAK，septin-9，eIF 4 E和S100 A11）被证明是伪足突出和肿瘤细胞迁移和侵袭所必需的。在转移性细胞中敲低这些蛋白质中的每一种导致肌动蛋白细胞骨架动力学降低和间质-上皮转变（MET）的诱导，这可以通过稳定肌动蛋白细胞骨架来防止。因此，肌动蛋白依赖性伪足突出和肿瘤细胞迁移是EMT的决定因素。伪足肌动蛋白动力学的蛋白质调节剂可能是诱导MET的独特分子靶点，从而抑制肿瘤细胞的转移潜能。Cancer Res; 70（9）; 3780-90. (C)2010年AACR。
A key cellular process associated with the invasive or metastatic program in many cancers is the transformation of epithelial cells toward a mesenchymal state, a process called epithelial to mesenchymal transition or EMT. Actin-dependent protrusion of cell pseudopodia is a critical element of mesenchymal cell migration and therefore of cancer metastasis. However, whether EMT occurs in human cancers and, in particular, whether it is a prerequisite for tumor cell invasion and metastasis, remains a subject of debate. Microarray and proteomic analysis of actin-rich pseudopodia from six metastatic human tumor cell lines identified 384 mRNAs and 64 proteins common to the pseudopodia of six metastatic human tumor cell lines of various cancer origins leading to the characterization of 19 common pseudopod-specific proteins. Four of these (AHNAK, septin-9, eIF4E, and S100A11) are shown to be essential for pseudopod protrusion and tumor cell migration and invasion. Knockdown of each of these proteins in metastatic cells resulted in reduced actin cytoskeleton dynamics and induction of mesenchymal-epithelial transition (MET) that could be prevented by the stabilization of the actin cytoskeleton. Actin-dependent pseudopodial protrusion and tumor cell migration are therefore determinants of EMT. Protein regulators of pseudopodial actin dynamics may represent unique molecular targets to induce MET and thereby inhibit the metastatic potential of tumor cells. Cancer Res; 70(9); 3780-90. (C) 2010 AACR.