Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells.
Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells.
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DOI：
10.1002/jcb.23150
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发表时间：
2011-09
影响因子：
4
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Bao, Bin;Wang, Zhiwei;Ali, Shadan;Kong, Dejuan;Banerjee, Sanjeev;Ahmad, Aamir;Li, Yiwei;Azmi, Asfar S.;Miele, Lucio;Sarkar, Fazlul H.
FoxM1在包括胰腺癌在内的许多恶性肿瘤的发生和发展中发挥着重要作用。研究表明，上皮-间充质转化（Epithelial-to-mesenchymal transition， EMT）表型的获得与癌症干细胞（cancer stem cell， CSC）或癌症干细胞样细胞表型的诱导是高度相关的，并有助于耐药、肿瘤复发和转移。FoxM1参与获得EMT表型和诱导CSC自我更新能力的分子机制尚不清楚。因此，我们建立了FoxM1过表达的胰腺癌（AsPC-1）细胞，其细胞生长、克隆原性和细胞迁移均有所增加。此外，FoxM1的过表达通过激活间充质细胞标记物ZEB1、ZEB2、Snail2、E-cadherin和vimentin获得了EMT表型，这与CSC表面标记物CD44和EpCAM的表达和增球能力（胰球）一致。我们还发现FoxM1的过表达导致mirna （let-7a, let-7b, let-7c， miR-200b和miR-200c）的表达降低；然而，miR-200b的重新表达抑制了ZEB1、ZEB2、vimentin和FoxM1的表达，并诱导了E-cadherin的表达，导致EMT表型逆转。最后，我们发现染料木黄酮，一种天然的化学预防剂，抑制细胞生长、克隆性、细胞迁移和侵袭、EMT表型和胰球形成，与CD44和EpCAM的表达降低一致。这些结果首次表明FoxM1过表达负责EMT和CSC表型的获得，这在一定程度上是通过miR-200b的调控介导的，这些过程可以很容易地被染料木素减弱。
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.
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影响因子：
3.7
作者：
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通讯作者：
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影响因子：
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通讯作者：
Sarkar, Fazlul H.
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