title: Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer.
abstract: Cancer stem cells are suggested to contribute to the extremely poor prognosis of pancreatic ductal adenocarcinoma and dysregulation of symmetric and asymmetric stem cell division may be involved. Anticancer benefits of phytochemicals like the polyphenol quercetin, present in many fruits, nuts and vegetables, could be expedited by microRNAs, which orchestrate cell-fate decisions and tissue homeostasis. The mechanisms regulating the division mode of cancer stem cells in relation to phytochemical-induced microRNAs are poorly understood.
  
  
  
  Patient-derived pancreas tissue and 3 established pancreatic cancer cell lines were examined by immunofluorescence and time-lapse microscopy, microRNA microarray analysis, bioinformatics and computational analysis, qRT-PCR, Western blot analysis, self-renewal and differentiation assays.
  
  
  
  We show that symmetric and asymmetric division occurred in patient tissues and in vitro, whereas symmetric divisions were more extensive. By microarray analysis, bioinformatics prediction and qRT-PCR, we identified and validated quercetin-induced microRNAs involved in Notch signaling/cell-fate determination. Further computational analysis distinguished miR-200b-3p as strong candidate for cell-fate determinant. Mechanistically, miR-200b-3p switched symmetric to asymmetric cell division by reversing the Notch/Numb ratio, inhibition of the self-renewal and activation of the potential to differentiate to adipocytes, osteocytes and chondrocytes. Low miR-200b-3p levels fostered Notch signaling and promoted daughter cells to become symmetric while high miR-200b-3p levels lessened Notch signaling and promoted daughter cells to become asymmetric.
  
  
  
  Our findings provide a better understanding of the cross talk between phytochemicals, microRNAs and Notch signaling in the regulation of self-renewing cancer stem cell divisions.
authors.affiliation: Department of General, Molecular OncoSurgery, Section Surgical Research, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany.
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Nwaeburu
authors.affiliation: Department of General, Molecular OncoSurgery, Section Surgical Research, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany.
authors.forename: Alia
authors.initials: A
authors.lastname: Abukiwan
authors.affiliation: Department of General, Molecular OncoSurgery, Section Surgical Research, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany.
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of General, Molecular OncoSurgery, Section Surgical Research, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany. i.herr@uni-heidelberg.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011794:Quercetin / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011794:Quercetin