Cancer Letters, 2011, 307(1):26-36.

Notch-1 induces Epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells

Bin Bao, Zhiwei Wang, Shadan Ali, et al

Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; et al

Activation of Notch-1 is known to be associated with the development and progression of human malignancies including pancreatic cancer. Emerging evidence suggest that the acquisition of epithelial–mesenchymal transition (EMT) phenotype and induction of cancer stem cell (CSC) or cancer stem-like cell phenotype are interrelated and contributes to tumor recurrence and drug resistance. The molecular mechanism(s) by which Notch-1 contributes to the acquisition of EMT phenotype and CSC self-renewal capacity has not been fully elucidated. Here we show that forced over-expression of Notch-1 leads to increased cell growth, clonogenicity, migration and invasion of AsPC-1 cells. Moreover, over-expression of Notch-1 led to the induction of EMT phenotype by activation of mesenchymal cell markers such as ZEB1, CD44, EpCAM, and Hes-1. Here we also report, for the first time, that over-expression of Notch-1 leads to increased expression of miR-21, and decreased expression of miR-200b, miR-200c, let-7a, let-7b, and let-7c. Re-expression of miR-200b led to decreased expression of ZEB1, and vimentin, and increased expression of E-cadherin. Over-expression of Notch-1 also increased the formation of pancreatospheres consistent with expression of CSC surface markers CD44 and EpCAM. Finally, we found that genistein, a known natural anti-tumor agent inhibited cell growth, clonogenicity, migration, invasion, EMT phenotype, formation of pancreatospheres and expression of CD44 and EpCAM. These results suggest that the activation of Notch-1 signaling contributes to the acquisition of EMT phenotype, which is in part mediated through the regulation of miR-200b and CSC self-renewal capacity, and these processes could be attenuated by genistein treatment.

爱尔兰《癌症快讯》，2011年8月

在胰腺癌细胞中Notch-1 诱导上皮-间充质细胞转型为癌症干细胞表型

包斌，王志伟，亚丹 阿里等

美国韦恩州立大学卡马诺斯癌症研究所病理学部等

已知Notch-1的激活与包括胰腺癌在内的人体恶性肿瘤相关。最新证据表明表型上皮-间充质细胞转换 (EMT) 表型的收集和诱导的肿瘤干细胞 (CSC) 或癌症干细胞表型相互关联，有利于肿瘤复发和耐药性。Notch-1 有助于获得 EMT 表型与 CSC 自我更新能力的分子机制尚未完全阐明。这里我们展示Notch-1 被强迫的过表达可以促进细胞生长、 单克隆、AsPC 1的 细胞迁移和侵袭。此外， Notch-1的过度表达会导致EMT 表型的诱导通过活化骨髓间充质细胞标记如 ZEB1、 CD44、 EpCAM和Hes-1。这里我们也报告了，第一次，Notch-1 过表达导致了 miR-21表达的增加，和 miR-200b 、miR-200 c、 let-7a、 let-7b 和let-7c表达的降低。miR-200b 的重新表达导致了ZEB1 和波形蛋白表达的降低和 E-钙粘蛋白表达增加。Notch-1 的过度表达也增加了符合 CSC 表面标志物 CD44 和 EpCAM 的集落形成的表达。最后，我们发现金雀异黄素，已知的一种天然抗肿瘤剂，可以抑制细胞生长，单克隆、 迁移、 入侵、 EMT 表型，集落的形成和 CD44 与 EpCAM 的表达。