Abstract
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.
Highlights
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
Symmetric Cell Division (SCD) mostly occurs in Pancreatic Ductal Adenocarcinoma (PDA) cells It is an established fact that cancer stem cells (CSCs) divide by both symmetric and asymmetric cell divisions [5] with asymmetric division maintaining suitable numbers of cell offspring [6] and symmetric division, imperative for growth and regenerative competences [7]
Notch and Numb genes are crucial to self-renewing divisions as markers for symmetric and asymmetric division markers respectively [5] (Fig. 1a)
Summary
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. CSC self-renewing division gives rise to symmetric or asymmetric cell division. The former, resulting to two identical daughter cells and the later to Studies have shown different regulators of the CSCs mode of divisions [8]. Notch is an essential gene encoding a signaling receptor, which has a major contribution to proper development, cell fate decision, cell proliferation and survival [13, 14]. Notch inhibitor [17], Numb, is a cell fate determinant [18] and implicated as a tumor suppressor [19] and marker for asymmetric cell division [20]
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