title: Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells.
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.
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Hematology/Oncology Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA.
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.affiliation: University of Mississippi Cancer Institute, Jackson, MS, USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA. Electronic address: fsarkar@med.wayne.edu.
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D014945:Wound Healing
chemical_list: D016588:Anticarcinogenic Agents; D000951:Antigens, Neoplasm; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D019833:Genistein