Epithelial Cell Adhesion Molecule Regulates Tumor Initiation and Tumorigenesis via Activating Reprogramming Factors and Epithelial-Mesenchymal Transition Gene Expression in Colon Cancer
Epithelial Cell Adhesion Molecule Regulates Tumor Initiation and Tumorigenesis via Activating Reprogramming Factors and Epithelial-Mesenchymal Transition Gene Expression in Colon Cancer
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DOI：
10.1074/jbc.m112.386235
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发表时间：
2012-11-16
影响因子：
4.8
通讯作者：
Wu, Han-Chung
中科院分区：
文献类型：
--
作者：
Lin, Cheng-Wei;Liao, Mei-Yin;Wu, Han-Chung
上皮细胞粘附分子（Epithelial cell adhesion molecule, EpCAM）在上皮转化瘤变和肿瘤启动细胞（tumor-initiated cells, TICs）中高度表达，但EpCAM在TICs的干性特性中所起的作用尚不清楚。在这里，我们发现EpCAM和重编程因子（c-Myc, Oct4， Nanog和Sox2）在tic中同时升高，这被证明具有优越的自我更新，侵袭性和肿瘤启动能力。EpCAM的升高促进了肿瘤球的形成和肿瘤的发生。EpCAM的敲除抑制重编程因子和上皮-间质转化基因的表达，从而抑制肿瘤的发生、自我更新和侵袭性。此外，EpCAM，特别是EpCAM的胞内结构域（epd）与重编程因子的启动子结合并激活。用γ -分泌酶抑制剂（DAPT）治疗可阻断重编程因子和上皮-间质转化基因的表达，并伴有肿瘤自我更新和侵袭的减少。此外，EpEX释放的增加增加了epd的产生，并调节了重编程因子的表达。综上所述，这些发现表明EpCAM在调节结肠癌tic的癌症启动能力方面起着重要作用。这一发现可用于开发癌症治疗的新策略。
Epithelial cell adhesion molecule (EpCAM) is highly expressed in epithelial-transformed neoplasia and tumor-initiated cells (TICs), but the role that EpCAM plays in the stemness properties of TICs is still unclear. Here we show that EpCAM and reprogramming factors (c-Myc, Oct4, Nanog, and Sox2) were concomitantly elevated in TICs, which were shown to have superior self-renewal, invasiveness, and tumor-initiating abilities. Elevation of EpCAM enhanced tumorsphere formation and tumor initiation. Knock-down of EpCAM inhibited the expressions of reprogramming factors and epithelial-mesenchymal transition genes, thereby suppressing tumor initiation, self-renewal, and invasiveness. In addition, EpCAM, especially intracellular domain of EpCAM (EpICD), bound to and activated the promoter of reprogramming factors. Treatment with the inhibitor of gamma-secretase (DAPT) led to the blockage of the expressions of reprogramming factors and epithelial-mesenchymal transition genes, which was accompanied by the reduction of tumor self-renewal and invasion. Furthermore, the increased release of EpEX enhanced production of EpICD and regulated the expression of reprogramming factors. Together, these findings suggest that EpCAM plays an important role in regulating cancer-initiating abilities in TICs of colon cancer. This discovery can be used in the development of new strategies for cancer therapy.