Open AccessMicroRNA let‐7b regulates genomic balance by targeting Aurora B kinase
Author(s) -
Mäki-Jouppila Jenni Heidi Eveliina,
Pruikkonen Sofia,
Tambe Mahesh Balasaheb,
Aure Miriam Ragle,
Halonen Tuuli,
Salmela Anna-Leena,
Laine Leena,
Børresen-Dale Anne-Lise,
Kallio Marko Johannes
Publication year - 2015
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2015.01.005
Subject(s) - aurora b kinase , biology , carcinogenesis , mitosis , microrna , cancer research , kinase , aurora inhibitor , spindle checkpoint , cancer cell , microbiology and biotechnology , spindle apparatus , cancer , cell cycle , cell , cell division , genetics , gene
The let‐7 microRNA (miRNA) family has been implicated in the regulation of diverse cellular processes and disease pathogenesis. In cancer, loss‐of‐function of let‐7 miRNAs has been linked to tumorigenesis via increased expression of target oncogenes. Excessive proliferation rate of tumor cells is often associated with deregulation of mitotic proteins. Here, we show that let‐7b contributes to the maintenance of genomic balance via targeting Aurora B kinase, a key regulator of the spindle assembly checkpoint (SAC). Our results indicate that let‐7b binds to Aurora B kinase 3′UTR reducing mRNA and protein expression of the kinase. In cells, excess let‐7b induced mitotic defects characteristic to Aurora B perturbation including increased rate of polyploidy and multipolarity, and premature SAC inactivation that leads to forced exit from chemically induced mitotic arrest. Moreover, the frequency of aneuploid HCT‐116 cells was significantly increased upon let‐7b overexpression compared to controls. Interestingly, together with a chemical Aurora B inhibitor, let‐7b had an additive effect on polyploidy induction in HeLa cells. In breast cancer patients, reduced let‐7b expression was found to be associated with increased Aurora B expression in grade 3 tumors. Furthermore, let‐7b was found downregulated in the most aggressive forms of breast cancer determined by clinicopathological parameters. Together, our findings suggest that let‐7b contributes to the fidelity of cell division via regulation of Aurora B. Moreover, the loss of let‐7b in aggressive tumors may drive tumorigenesis by up‐regulation of Aurora B and other targets of the miRNA, which further supports the role of let‐7b in tumor suppression.