Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression
Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression
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DOI：
10.1038/onc.2015.127
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发表时间：
2016-02-04
期刊：
影响因子：
8
通讯作者：
Ben-Ze'ev, A.
中科院分区：
文献类型：
--
作者：
Shvab, A.;Haase, G.;Ben-Ze'ev, A.
Wnt-β-连环蛋白信号传导过度激活，包括 β-连环蛋白-TCF 靶基因表达，是结直肠癌 (CRC) 发展的标志。我们将细胞粘附受体成员 L1 的免疫球蛋白家族鉴定为 β-连环蛋白-TCF 靶基因，优先在人类 CRC 组织的侵袭边缘表达。当 L1 在 CRC 细胞中表达时，可以增强运动性和肝转移能力。 L1 介导的转移能力是通过涉及 ezrin 和 NF-κ B 靶基因激活的机制发挥的。在这项研究中，我们确定了分泌型模块化钙结合基质细胞蛋白 2 (SMOC-2) 是由 L1-ezrin-NF-kappa B 信号传导激活的基因。 SMOC-2 也被称为小鼠肠道干细胞特征基因，在肠隐窝底部的细胞中表达 Lgr5。在表达 L1 的 CRC 细胞中诱导 SMOC-2 表达对于 L1 赋予的细胞运动、应激下增殖和肝转移的增加是必要的。 SMOC-2 表达通过涉及整合素连接激酶 (ILK) 的信号传导，诱导 CRC 细胞中更像间充质的表型、E-钙粘蛋白的减少和 Snail 的增加。 SMOC-2 位于正常人结肠隐窝的底部，在 CRC 组织中表达水平升高，并优先在肿瘤的侵袭区域表达。我们发现过表达 L1、p65 或 SMOC-2 的 CRC 细胞中 Lgr5 水平升高，表明 L1 介导的 CRC 进展涉及干细胞样表型的获得，并且 SMOC-2 升高对于 L1 介导的更具侵袭性/侵袭性 CRC 特性的诱导是必要的。
Overactivation of Wnt-beta-catenin signaling, including beta-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 beta-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-kappa B 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-kappa B 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.