Fender Alexander W, Nutter Jennifer M, Fitzgerald Timothy L, Bertrand Fred E, Sigounas George
Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
J Cell Biochem. 2015 Nov;116(11):2517-27. doi: 10.1002/jcb.25196.
Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, resulting in an average of 50,000 deaths per year. Surgery and combination chemotherapy comprise current treatment strategies. However, curative options are limited if surgery and chemotherapy are unsuccessful. Several studies have indicated that CRC aggressiveness and potential for metastatic spread are associated with the acquisition of stem cell like properties. The Notch-1 receptor and its cognate signaling pathway is well known for controlling cell fate decisions and stem-cell phenotypes. Alterations in Notch receptors and Notch signaling has been reported for some colon cancers. Herein, we examine a potential role for Notch-1 signaling in CRC. In CRC patient samples, Notch-1 expression was increased in colon tumor tissue as compared with normal colon tissue. Retroviral transduction of constitutively active Notch-1 (ICN1) into the colon tumor cell line HCT-116 resulted in increased expression of the EMT/stemness associated proteins CD44, Slug, Smad-3, and induction of Jagged-1 expression. These changes in ICN1 expressing cells were accompanied by increased migration and increased anchorage independent growth by 2.5-fold and 23%, respectively. Experiments with the pan-Notch inhibitor DAPT, and soluble Jagged-1-Fc protein provided evidence that Notch-1 signaling activates CD44, Slug, and Smad-3 via a cascade of other Notch-receptors through induction of Jagged-1 expression. These data indicate a key role for Notch signaling in the phenotype of CRC and suggest that targeting of Notch signaling may be of therapeutic value in colon cancers.
结直肠癌（CRC）是美国癌症死亡的第三大主要原因，平均每年导致50000人死亡。手术和联合化疗是目前的治疗策略。然而，如果手术和化疗不成功，治愈选择就很有限。几项研究表明，CRC的侵袭性和转移扩散潜力与获得干细胞样特性有关。Notch-1受体及其同源信号通路以控制细胞命运决定和干细胞表型而闻名。在一些结肠癌中已报道了Notch受体和Notch信号的改变。在此，我们研究了Notch-1信号在CRC中的潜在作用。在CRC患者样本中，与正常结肠组织相比，结肠肿瘤组织中Notch-1表达增加。将组成型激活的Notch-1（ICN1）逆转录病毒转导至结肠肿瘤细胞系HCT-116中，导致上皮-间质转化/干性相关蛋白CD44、Slug、Smad-3的表达增加，并诱导Jagged-1表达。ICN1表达细胞中的这些变化分别伴随着迁移增加和非锚定依赖性生长增加2.5倍和23%。使用泛Notch抑制剂DAPT和可溶性Jagged-1-Fc蛋白进行的实验提供了证据，表明Notch-1信号通过诱导Jagged-1表达，经由一系列其他Notch受体激活CD44、Slug和Smad-3。这些数据表明Notch信号在CRC表型中起关键作用，并表明靶向Notch信号可能对结肠癌具有治疗价值。
