Nuclear factor-κB signaling and ezrin are essential for L1-mediated metastasis of colon cancer cells
Nuclear factor-κB signaling and ezrin are essential for L1-mediated metastasis of colon cancer cells
复制标题
DOI：
10.1242/jcs.069542
复制
发表时间：
2010-06-15
影响因子：
4
通讯作者：
Ben-Ze'ev, Avri
中科院分区：
文献类型：
--
作者：
Gavert, Nancy;Ben-Shmuel, Amir;Ben-Ze'ev, Avri
β-连环蛋白-T细胞因子（TCF）调节的基因转录的过度活化是结直肠癌（CRC）的标志。细胞-神经粘附分子L1 CAM（以下简称L1）是β-连环蛋白-TCF的靶点，仅在人类CRC侵袭前沿表达。L1在CRC细胞中的过表达增加细胞生长和运动，并促进肝转移。由L1诱导的基因也在人CRC组织中表达，但L1赋予转移的机制仍然未知。我们发现核因子κ B（NF-κ B）的信号传导是必不可少的，因为κ B超阻遏物（I κ B-SR）抑制信号传导阻断了L1介导的转移。NF-κ B p65亚单位的过表达足以增加CRC细胞的增殖、运动和转移。L1细胞结构域与埃兹蛋白（一种细胞骨架交联蛋白）的结合对于转移是必要的，因为当与L1的结合被中断或埃兹蛋白基因表达被特异性shRNA抑制时，转移不会发生。L1和ezrin结合并介导I κ B的磷酸化。我们还观察到一个复合物包含I κ B，L1和ezrin在大肠癌细胞的质膜区域。此外，我们发现L1、ezrin和磷酸化p65在人CRC组织中的浸润前沿共表达，表明L1介导的涉及ezrin的NF-κ B信号传导的激活是CRC进展的主要途径。
Hyperactivation of beta-catenin-T-cell-factor (TCF)-regulated gene transcription is a hallmark of colorectal cancer (CRC). The cell-neural adhesion molecule L1CAM (hereafter referred to as L1) is a target of beta-catenin-TCF, exclusively expressed at the CRC invasive front in humans. L1 overexpression in CRC cells increases cell growth and motility, and promotes liver metastasis. Genes induced by L1 are also expressed in human CRC tissue but the mechanisms by which L1 confers metastasis are still unknown. We found that signaling by the nuclear factor kappa B (NF-kappa B) is essential, because inhibition of signaling by the inhibitor of kB super repressor (I kappa B-SR) blocked L1-mediated metastasis. Overexpression of the NF-kappa B p65 subunit was sufficient to increase CRC cell proliferation, motility and metastasis. Binding of the L1 cytodomain to ezrin - a cytoskeleton-crosslinking protein - is necessary for metastasis because when binding to L1 was interrupted or ezrin gene expression was suppressed with specific shRNA, metastasis did not occur. L1 and ezrin bound to and mediated the phosphorylation of I kappa B. We also observed a complex containing I kappa B, L1 and ezrin in the juxtamembrane region of CRC cells. Furthermore, we found that L1, ezrin and phosphorylated p65 are co-expressed at the invasive front in human CRC tissue, indicating that L1-mediated activation of NF-kappa B signaling involving ezrin is a major route of CRC progression.