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

BACKGROUND: 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,...

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Autores principales: Nwaeburu, Clifford C., Abukiwan, Alia, Zhao, Zhefu, Herr, Ingrid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282715/
https://www.ncbi.nlm.nih.gov/pubmed/28137273
http://dx.doi.org/10.1186/s12943-017-0589-8
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author Nwaeburu, Clifford C.
Abukiwan, Alia
Zhao, Zhefu
Herr, Ingrid
author_facet Nwaeburu, Clifford C.
Abukiwan, Alia
Zhao, Zhefu
Herr, Ingrid
author_sort Nwaeburu, Clifford C.
collection PubMed
description BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0589-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-52827152017-02-03 Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer Nwaeburu, Clifford C. Abukiwan, Alia Zhao, Zhefu Herr, Ingrid Mol Cancer Research BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0589-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-01-31 /pmc/articles/PMC5282715/ /pubmed/28137273 http://dx.doi.org/10.1186/s12943-017-0589-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Nwaeburu, Clifford C.
Abukiwan, Alia
Zhao, Zhefu
Herr, Ingrid
Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
title Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
title_full Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
title_fullStr Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
title_full_unstemmed Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
title_short Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
title_sort quercetin-induced mir-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282715/
https://www.ncbi.nlm.nih.gov/pubmed/28137273
http://dx.doi.org/10.1186/s12943-017-0589-8
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