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UBC Theses and Dissertations

Zinc depletion-induced apoptosis is associated with altered microRNA expression in human breast cancer MDA-MB-231 cells Bakker, Melinda


Zinc is an essential trace element required for many physiological functions, including growth. At the cellular level, zinc is required for structural and catalytic roles in thousands of proteins, and adequate labile zinc is an important determinant of cellular viability. However, abnormal zinc accumulation in breast tissue is associated with breast cancer, suggesting that zinc status plays a role in breast cancer pathogenesis. Chelationinduced depletion of labile intracellular zinc promotes apoptosis, or programmed cell death, in multiple breast cancer cell lines. The mechanisms whereby zinc regulates apoptosis remain unclear. In particular, little is known about the role of microRNAs (miRs), a novel class of short non-coding RNA, involved in the regulation of gene expression. Zinc status can influence miR expression, and possibly the processing and stability of miRs. The hypothesis of my thesis research is that miRs are involved in zinc depletion-induced apoptosis in human breast cancer cells. The overall objective of this study was to determine the involvement of miRs in zinc depletion-induced apoptosis in breast cancer MDA-MB-231 cells. Zinc depletion for 24, 48 and 72 h induced apoptosis in 4.5, 24.4 and 28.0 % of the cells, respectively, indicating a time-dependent increase in zinc depletion-induced apoptosis. Expression of 8, 90, and 94 miRs were significantly altered during the early stages of zinc depletion-induced apoptosis, at 3, 12, and 24 h of zinc depletion, respectively. Overall, expression of 285 unique miRs was significantly affected by zinc depletion, duration of zinc depletion, and their interactions. qRT-PCR analysis confirmed that zinc depletion resulted in an increased abundance of miR-132-3p, miR-1246, miR-1273, miR-4484 and miR-4787-5p and a decreased abundance of miR-4521 in a time-dependent manner. MiR-132-3p and miR 1246 have previously been shown to play a role in mediating apoptosis in prostate cancer PC-3 and lung cancer A549 cells, respectively. In conclusion, abundance of numerous miRs was altered during the early stages of zinc depletion-induced apoptosis, indicating possible involvement of these miRs in mediating zinc depletion-induced apoptosis. The role and targets of these miRs in zinc depletion-induced apoptosis requires validation in further research.

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