Gavert Nancy, Sheffer Michal, Raveh Shani, Spaderna Simone, Shtutman Michael, Brabletz Thomas, Barany Francis, Paty Phillip, Notterman Daniel, Domany Eytan, Ben-Ze'ev Avri
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Cancer Res. 2007 Aug 15;67(16):7703-12. doi: 10.1158/0008-5472.CAN-07-0991.
L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of beta-catenin-T-cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of beta-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy.
L1细胞粘附分子（L1-CAM）是一种神经元细胞粘附受体，也在多种癌细胞中表达。最近的研究确定L1-CAM是在人类结肠癌组织侵袭前沿表达的β-连环蛋白-T细胞因子（TCF）信号的靶基因。我们发现，在缺乏L1-CAM的结肠癌细胞中L1-CAM的表达赋予了转移能力，将此类细胞注射到小鼠脾脏中会形成肝转移。我们确定金属蛋白酶ADAM10是β-连环蛋白-TCF信号的一个新靶基因，它可切割L1-CAM的细胞外结构域。在显示内源性L1-CAM的结肠癌细胞中ADAM10的过表达增强了L1-CAM的切割并诱导肝转移，ADAM10也增强了稳定转染L1-CAM的结肠癌细胞的转移。对结肠癌细胞中由L1-CAM诱导的基因进行的DNA微阵列分析确定了一组在大量人类结肠癌组织样本中也上调的基因。这些基因在正常结肠上皮中的表达较低。这些结果表明，在结肠癌细胞中有一个由L1-CAM诱导的基因程序，该程序也存在于结直肠癌组织中，并提示L1-CAM可作为结肠癌治疗的靶点。
