G5 Doctoral dissertation (article)
MicroRNA-mediated regulation of mitosis and taxane sensitivity in breast and ovarian cancer




List of Authors: Aakko. Sofia
Publisher: University of Turku
Place: Turku
Publication year: 2017
ISBN: 978-951-29-7001-8
eISBN: 978-951-29-7002-5

Abstract

Taxanes are microtubule targeting chemotherapeutics that block cell division (mitosis) and induce cell death. Taxanes are commonly used in the neoadjuvant chemotherapy for breast and ovarian cancer. However, the patient responses are hindered by the compounds’ cytotoxicity and the commonly observed drug resistance. One route for an improved therapy outcome would be to determine the tumor cells’ sensitivity to taxanes before starting the therapy. MicroRNAs (miRNAs) are central components of the post-transcriptional gene regulation. They are also potential biomarker molecules as their expression is known to differ between malignant and normal tissue. The aim of this thesis work was to identify mitosis-regulating miRNAs, characterize their cellular functions, and evaluate their potency in the prediction of tumor cells’ taxane sensitivity. Two miRNAs, miR-493-3p and let-7b, were discovered to regulate the mitotic checkpoint and the sensitivity of cancer cells to a taxane (paclitaxel) in vitro by controlling the expression of MAD2 and AURKB, respectively. Moreover, the expression of the miRNAs was found to be significantly altered in aggressive breast and ovarian tumors, which also correlated with reduced patient survival. A third mitosis-regulating miRNA, miR-193a-3p, was found to control cytokinesis via targeting the tumor suppressor RASSF1A. Excess of miR-193a-3p induced polyploidization and multipolarity in the next M-phase. Finally, a fourth miRNA, miR-203b-3p, was identified that sensitized breast and ovarian cancer cells to clinically relevant doses of paclitaxel through suppression of the anti-apoptotic protein Bcl-xL. Interestingly, this miRNA is a possible mediator of the previously reported c-Myc-induced sensitization to taxane therapy. Overall, the results presented here provide new information on the role of mitosisregulating miRNAs in tumorigenesis and the drug sensitivity of breast and ovarian cancers. Profiling the expression of these miRNAs from tumors may advance cancer diagnostics and help to stratify the patients that would benefit most from taxane therapy.


Last updated on 2019-20-07 at 12:07