Journal
BRITISH JOURNAL OF CANCER
Volume 111, Issue 11, Pages 2142-2151Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2014.524
Keywords
miR-378a-5p; mitosis; chromosome instability; Aurora B; ERK1/2
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Funding
- Academy of Finland [138204, 137468]
- Finnish Cancer Organizations, the Finnish Cultural Foundation
- K.G. Jebsen Centre for Breast Cancer Research, South-Eastern Norway Regional Health Authority [2011042]
- Norwegian Cancer Society [138296-PR-2008-0108]
- Academy of Finland (AKA) [138204, 138204, 137468, 137468] Funding Source: Academy of Finland (AKA)
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Background: Optimal expression and proper function of key mitotic proteins facilitate control and repair processes that aim to prevent loss or gain of chromosomes, a hallmark of cancer. Altered expression of small regulatory microRNAs is associated with tumourigenesis and metastasis but the impact on mitotic signalling has remained unclear. Methods: Cell-based high-throughput screen identified miR-378a-5p as a mitosis perturbing microRNA. Transient transfections, immunofluorescence, western blotting, time-lapse microscopy, FISH and reporter assays were used to characterise the mitotic anomalies by excess miR-378a-5p. Analysis of microRNA profiles in breast tumours was performed. Results: Overexpression of miR-378a-5p induced numerical chromosome changes in cells and abrogated taxol-induced mitotic block via premature inactivation of the spindle assembly checkpoint. Moreover, excess miR-378a-5p triggered receptor tyrosine kinase-MAP kinase pathway signalling, and was associated with suppression of Aurora B kinase. In breast cancer in vivo, we found that high miR-378a-5p levels correlate with the most aggressive, poorly differentiated forms of cancer. Interpretation: Downregulation of Aurora B by excess miR-378a-5p can explain the observed microtubule drug resistance and increased chromosomal imbalance in the microRNA-overexpressing cells. The results suggest that breast tumours may deploy high miR-378a-5p levels to gain growth advantage and antagonise taxane therapy.
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