Shvab A, Haase G, Ben-Shmuel A, Gavert N, Brabletz T, Dedhar S, Ben-Ze'ev A
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Department of Experimental Medicine 1, University of Erlangen-Nuernberg, Erlangen, Germany.
Oncogene. 2016 Feb 4;35(5):549-57. doi: 10.1038/onc.2015.127. Epub 2015 Apr 27.
Overactivation of Wnt-β-catenin signaling, including β-catenin-TCF target gene expression, is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin family of cell-adhesion receptors member L1 as a β-catenin-TCF target gene preferentially expressed at the invasive edge of human CRC tissue. L1 can confer enhanced motility and liver metastasis when expressed in CRC cells. This ability of L1-mediated metastasis is exerted by a mechanism involving ezrin and the activation of NF-κB target genes. In this study, we identified the secreted modular calcium-binding matricellular protein-2 (SMOC-2) as a gene activated by L1-ezrin-NF-κB signaling. SMOC-2 is also known as an intestinal stem cell signature gene in mice expressing Lgr5 in cells at the bottom of intestinal crypts. The induction of SMOC-2 expression in L1-expressing CRC cells was necessary for the increase in cell motility, proliferation under stress and liver metastasis conferred by L1. SMOC-2 expression induced a more mesenchymal like phenotype in CRC cells, a decrease in E-cadherin and an increase in Snail by signaling that involves integrin-linked kinase (ILK). SMOC-2 was localized at the bottom of normal human colonic crypts and at increased levels in CRC tissue with preferential expression in invasive areas of the tumor. We found an increase in Lgr5 levels in CRC cells overexpressing L1, p65 or SMOC-2, suggesting that L1-mediated CRC progression involves the acquisition of a stem cell-like phenotype, and that SMOC-2 elevation is necessary for L1-mediated induction of more aggressive/invasive CRC properties.
Wnt-β-连环蛋白信号通路的过度激活，包括β-连环蛋白-TCF靶基因的表达，是结直肠癌（CRC）发生发展的一个标志。我们将细胞黏附受体L1鉴定为免疫球蛋白家族成员，它作为β-连环蛋白-TCF靶基因，在人类CRC组织的侵袭边缘优先表达。当在CRC细胞中表达时，L1可增强细胞运动性并促进肝转移。L1介导的转移能力是通过一种涉及埃兹蛋白和NF-κB靶基因激活的机制发挥作用的。在本研究中，我们将分泌型模块化钙结合基质细胞蛋白-2（SMOC-2）鉴定为一种由L1-埃兹蛋白-NF-κB信号通路激活的基因。在小鼠中，位于肠隐窝底部表达Lgr5的细胞中，SMOC-2也被认为是一种肠干细胞特征基因。在表达L1的CRC细胞中诱导SMOC-2表达，对于L1所赋予的细胞运动性增加、应激状态下的增殖以及肝转移是必要的。SMOC-2表达通过涉及整合素连接激酶（ILK）的信号传导，在CRC细胞中诱导出更具间充质样的表型，E-钙黏蛋白减少，Snail增加。SMOC-2定位于正常人类结肠隐窝的底部，在CRC组织中的水平升高，在肿瘤的侵袭区域优先表达。我们发现，过表达L1、p65或SMOC-2的CRC细胞中Lgr5水平升高，这表明L1介导的CRC进展涉及获得干细胞样表型，并且SMOC-2升高对于L1介导的诱导更具侵袭性/转移性的CRC特性是必要的。
