A1 Journal article – refereed
Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells' sensitivity to paclitaxel




List of Authors: Mahesh Tambe, Sofia Pruikkonen, Jenni Mäki-Jouppila, Ping Chen,
Bente Vilming Elgaaen, Anne Hege Straume, Kaisa Huhtinen, Olli Cárpen, Per
Eystein Lønning, Ben Davidson, Sampsa Hautaniemi, Marko J. Kallio

Publisher: IMPACT JOURNALS LLC
Publication year: 2016
Journal: Oncotarget
Journal name in source: ONCOTARGET
Journal acronym: ONCOTARGET
Volume number: 7
Issue number: 11
Number of pages: 19
ISSN: 1949-2553
eISSN: 1949-2553

Abstract
The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3' UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy.

Last updated on 2019-29-01 at 21:24