Journal of Cellular Biochemistry, 2011, 112(9):2296-306.

Over-expression of FoxM1 leads to epithelial-mesenchymal transition and 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 48201, USA; et al

FoxM1 is known to play important role in the development and progression of many malignancies including pancreatic cancer. Studies have shown that the acquisition of epithelial-to-mesenchymal transition (EMT) phenotype and induction of cancer stem cell (CSC) or cancer stem-like cell phenotypes are highly inter-related, and contributes to drug resistance, tumor recurrence, and metastasis. The molecular mechanism(s) by which FoxM1 contributes to the acquisition of EMT phenotype and induction of CSC self-renewal capacity is poorly understood. Therefore, we established FoxM1 over-expressing pancreatic cancer (AsPC-1) cells, which showed increased cell growth, clonogenicity, and cell migration. Moreover, over-expression of FoxM1 led to the acquisition of EMT phenotype by activation of mesenchymal cell markers, ZEB1, ZEB2, Snail2, E-cadherin, and vimentin, which is consistent with increased sphere-forming (pancreatospheres) capacity and expression of CSC surface markers (CD44 and EpCAM). We also found that over-expression of FoxM1 led to decreased expression of miRNAs (let-7a, let-7b, let-7c, miR-200b, and miR-200c); however, re-expression of miR-200b inhibited the expression of ZEB1, ZEB2, vimentin as well as FoxM1, and induced the expression of E-cadherin, leading to the reversal of EMT phenotype. Finally, we found that genistein, a natural chemo-preventive agent, inhibited cell growth, clonogenicity, cell migration and invasion, EMT phenotype, and formation of pancreatospheres consistent with reduced expression of CD44 and EpCAM. These results suggest, for the first time, that FoxM1 over-expression is responsible for the acquisition of EMT and CSC phenotype, which is in part mediated through the regulation of miR-200b and these processes, could be easily attenuated by genistein.

美国《细胞生物化学杂志》，2011年9月

在胰腺癌细胞中FoxM1 的过表达会导致上皮-间充质细胞转型和癌症干细胞表型

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

众所周知，FoxM1 在许多肿瘤包括胰腺癌的生成与发展中发挥了重要作用。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，有利于耐药、 肿瘤复发和转移。其中对 FoxM1 有助于 EMT 表型的收集和诱导 CSC 自我更新能力的分子机制了解甚少。因此，我们建立 了FoxM1 过度表达的胰腺癌 (AsPC-1) 细胞，表现出细胞生长增加、 单克隆和细胞迁移。此外， FoxM1的过度表达导致通过间充质细胞标志物 ZEB1、 ZEB2、 Snail2、 E-钙粘蛋白和波形蛋白等活化收集EMT 表型，与提高成群落 (pancreatospheres) 能力和 CSC 表面标志物 （CD44 和 EpCAM） 的表达相符。我们还发现 FoxM1的过表达导致miRNAs的 表达降低（let-7a、 let-7b、 let-7c、miR-200b 和 miR-200c）；然而，miR-200b的再表达抑制了 ZEB1、 ZEB2、 波形蛋白以及 FoxM1的表达，并诱导E-钙粘蛋白表达，从而导致 EMT 表型的逆转。最后，我们发现金雀异黄素，一种天然的化学预防试剂，可以抑制细胞的生长， 单克隆，细胞迁移和入侵，EMT 表型和适合 CD44 和 EpCAM表达减少的菌群的形成。这些结果表明，第一次，FoxM1 的过度表达会影响EMT 和 CSC 表型的获得，部分会通过miR-200b的调节，并且这些过程可以被染料木黄酮轻松地减弱。