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Cancer Lett. 2011 Aug 1;307(1):26-36. doi: 10.1016/j.canlet.2011.03.012. Epub 2011 Apr 3.

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

Author information

1
Department of Pathology, Wayne State University, Detroit, MI, USA.
2
Division of Hematology/Oncology Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
3
University of Mississippi Cancer Institute, Jackson, MS, USA.
4
Department of Pathology, Wayne State University, Detroit, MI, USA. Electronic address: fsarkar@med.wayne.edu.

Abstract

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.

PMID:
21463919
PMCID:
PMC3104092
DOI:
10.1016/j.canlet.2011.03.012
[Indexed for MEDLINE]
Free PMC Article

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