Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo

S. Winsel, Jenni Mäki-Jouppila, Mahesh Tambe, M.R. Aure, Sofia-Maria Pruikkonen, Anna Salmela, T. Halonen, Suvi Leivonen, Lila Kallio, A.-L. Børresen-Dale, M.J. Kallio (Corresponding Author)

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Abstract

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.
Original languageEnglish
Pages (from-to)2142-2151
JournalBritish Journal of Cancer
Volume111
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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Winsel, S., Mäki-Jouppila, J., Tambe, M., Aure, M. R., Pruikkonen, S-M., Salmela, A., Halonen, T., Leivonen, S., Kallio, L., Børresen-Dale, A-L., & Kallio, M. J. (2014). Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo. British Journal of Cancer, 111, 2142-2151. https://doi.org/10.1038/bjc.2014.524