MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase

Jenni Heidi Eveliina Mäki-Jouppila, Sofia Pruikkonen, Mahesh Balasaheb Tambe, Miriam Ragle Aure, Tuuli Halonen, Anna-Leena Salmela, Leena Laine, Anne-Lise Børresen-Dale, Marko Johannes Kallio

Research output: Contribution to journalArticleScientificpeer-review

10 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1056-1070
JournalMolecular Oncology
Volume9
Issue number6
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

Fingerprint

Aurora Kinase B
MicroRNAs
M Phase Cell Cycle Checkpoints
Polyploidy
Neoplasms
Carcinogenesis
Breast Neoplasms
HCT116 Cells
3' Untranslated Regions
Aneuploidy
HeLa Cells
Oncogenes
Cell Division
Protein Kinases
Up-Regulation
Down-Regulation
Maintenance
Messenger RNA
Proteins

Keywords

  • let-7b
  • mitosis
  • microRNA
  • Aurora B
  • aneuploidy

Cite this

Mäki-Jouppila, J. H. E., Pruikkonen, S., Tambe, M. B., Aure, M. R., Halonen, T., Salmela, A-L., ... Kallio, M. J. (2015). MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase. Molecular Oncology, 9(6), 1056-1070. https://doi.org/10.1016/j.molonc.2015.01.005
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. / MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase. In: Molecular Oncology. 2015 ; Vol. 9, No. 6. pp. 1056-1070.
@article{13f18f07dd6249af851b940d7ebcad6e,
title = "MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase",
abstract = "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.",
keywords = "let-7b, mitosis, microRNA, Aurora B, aneuploidy",
author = "M{\"a}ki-Jouppila, {Jenni Heidi Eveliina} and Sofia Pruikkonen and Tambe, {Mahesh Balasaheb} and Aure, {Miriam Ragle} and Tuuli Halonen and Anna-Leena Salmela and Leena Laine and Anne-Lise B{\o}rresen-Dale and Kallio, {Marko Johannes}",
year = "2015",
doi = "10.1016/j.molonc.2015.01.005",
language = "English",
volume = "9",
pages = "1056--1070",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "6",

}

Mäki-Jouppila, JHE, Pruikkonen, S, Tambe, MB, Aure, MR, Halonen, T, Salmela, A-L, Laine, L, Børresen-Dale, A-L & Kallio, MJ 2015, 'MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase', Molecular Oncology, vol. 9, no. 6, pp. 1056-1070. https://doi.org/10.1016/j.molonc.2015.01.005

MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase. / 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.

In: Molecular Oncology, Vol. 9, No. 6, 2015, p. 1056-1070.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase

AU - Mäki-Jouppila, Jenni Heidi Eveliina

AU - Pruikkonen, Sofia

AU - Tambe, Mahesh Balasaheb

AU - Aure, Miriam Ragle

AU - Halonen, Tuuli

AU - Salmela, Anna-Leena

AU - Laine, Leena

AU - Børresen-Dale, Anne-Lise

AU - Kallio, Marko Johannes

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - let-7b

KW - mitosis

KW - microRNA

KW - Aurora B

KW - aneuploidy

U2 - 10.1016/j.molonc.2015.01.005

DO - 10.1016/j.molonc.2015.01.005

M3 - Article

VL - 9

SP - 1056

EP - 1070

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 6

ER -

Mäki-Jouppila JHE, Pruikkonen S, Tambe MB, Aure MR, Halonen T, Salmela A-L et al. MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase. Molecular Oncology. 2015;9(6):1056-1070. https://doi.org/10.1016/j.molonc.2015.01.005