c-Kit Is Suppressed in Human Colon Cancer Tissue and Contributes to L1-Mediated Metastasis
c-Kit Is Suppressed in Human Colon Cancer Tissue and Contributes to L1-Mediated Metastasis
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DOI：
10.1158/0008-5472.can-13-0576
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发表时间：
2013-09-15
期刊：
影响因子：
11.2
通讯作者：
Ben-Ze'ev, Avri
中科院分区：
文献类型：
--
作者：
Gavert, Nancy;Shvab, Anna;Ben-Ze'ev, Avri
跨膜型神经细胞黏附受体L1是Wnt/β-catenin的靶基因，表达于多种肿瘤类型。在人类结直肠癌中，L1优先定位于肿瘤的侵袭前沿，当在结直肠癌细胞中过表达时，它促进了肿瘤向肝脏的转移。在这项研究中，我们研究了在人类结直肠癌中受调控的基因，以及与肝转移有关的L1-NF-kappa B通路。C-Kit基因是结直肠癌组织和L1-NF-kB通路中抑制程度最高的基因。由L1介导的信号转导导致的c-Kit抑制依赖于核因子-kappa B，它直接抑制c-Kit基因启动子的主要激活因子SP1的转录。重组c-Kit在L1细胞中的表达，阻断了L1过表达在驱动运动和肝转移方面的生物学效应。我们发现，c-Kit在结直肠癌细胞中的表达与更明显的上皮形态有关，伴随着E-钙粘蛋白表达的增加和slug的表达减少。虽然c-Kit过表达抑制了表达L1的结直肠癌细胞的运动和转移，但它促进了结直肠癌细胞的增殖和肿瘤的发生，认为c-Kit通过不同的途径介导了肿瘤的发生和转移。我们的发现为结直肠癌如何转移到肝脏提供了洞察力，肝脏是这种癌症最常见的扩散部位。(C)2013年AACR。
The transmembrane neural cell adhesion receptor L1 is a Wnt/beta-catenin target gene expressed in many tumor types. In human colorectal cancer, L1 localizes preferentially to the invasive front of tumors and when overexpressed in colorectal cancer cells, it facilitates their metastasis to the liver. In this study, we investigated genes that are regulated in human colorectal cancer and by the L1-NF-kappa B pathway that has been implicated in liver metastasis. c-Kit was the most highly suppressed gene in both colorectal cancer tissue and the L1-NF-kB pathway. c-Kit suppression that resulted from L1-mediated signaling relied upon NF-kappa B, which directly inhibited the transcription of SP1, a major activator of the c-Kit gene promoter. Reconstituting c-Kit expression in L1-transfected cells blocked the biological effects conferred by L1 overexpression in driving motility and liver metastasis. We found that c-Kit expression in colorectal cancer cells is associated with a more pronounced epithelial morphology, along with increased expression of E-cadherin and decreased expression of Slug. Although c-Kit overexpression inhibited the motility and metastasis of L1-expressing colorectal cancer cells, it enhanced colorectal cancer cell proliferation and tumorigenesis, arguing that separate pathways mediate tumorigenicity and metastasis by c-Kit. Our findings provide insights into how colorectal cancer metastasizes to the liver, the most common site of dissemination in this cancer. (C) 2013 AACR.