Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer

Molecular Cancer

Research

Zhefu Zhao¹  Ingrid Herr¹  Alia Abukiwan¹  Clifford C. Nwaeburu¹ 

[1] Department of General, Molecular OncoSurgery, Section Surgical Research, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany;

关键词: Quercetin;    Cancer Stem Cell;    Notch Signaling;    Pancreatic Ductal Adenocarcinoma;    Notch Signaling Pathway;   

DOI  :  10.1186/s12943-017-0589-8

 received in 2016-09-01, accepted in 2017-01-17,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCancer 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.MethodsPatient-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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© The Author(s). 2017