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MicroRNAs 130a/b are regulated by BCR-ABL and downregulate expression of CCN3 in CML

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Chronic Myeloid Leukaemia (CML) is a myeloproliferative disorder characterized by the expression of the oncoprotein, Bcr-Abl kinase. CCN3 normally functions as a negative growth regulator, but it is downregulated in CML, the mechanism of which is not known. MicroRNAs (miRNAs) are small non-coding RNAs, which negatively regulate protein translation by binding to the complimentary sequences of the 3′ UTR of messenger RNAs. Deregulated miRNA expression has emerged as a hallmark of cancer. In CML, BCR-ABL upregulates oncogenic miRNAs and downregulates tumour suppressor miRNAs favouring leukaemic transformation. We report here that the downregulation of CCN3 in CML is mediated by BCR-ABL dependent miRNAs. Using the CML cell line K562, we profiled miRNAs, which are BCR-ABL dependent by transfecting K562 cells with anti-BCR-ABL siRNA. MiRNA expression levels were quantified using the Taqman Low Density miRNA array platform. From the miRNA target prediction databases we identified miRNAs that could potentially bind to CCN3 mRNA and reduce expression. Of these, miR-130a, miR-130b, miR-148a, miR-212 and miR-425-5p were significantly reduced on BCR-ABL knockdown, with both miR-130a and miR-130b decreasing the most within 24 h of siRNA treatment. Transfection of mature sequences of miR-130a and miR-130b individually into BCR-ABL negative HL60 cells resulted in a decrease of both CCN3 mRNA and protein. The reduction in CCN3 was greatest with overexpression of miR-130a whereas miR-130b overexpression resulted only in marginal repression of CCN3. This study shows that miRNAs modulate CCN3 expression. Deregulated miRNA expression initiated by BCR-ABL may be one mechanism of downregulating CCN3 whereby leukaemic cells evade negative growth regulation.

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Abbreviations

CML:

Chronic Myeloid Leukaemia

MiRNA:

MicroRNA

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Acknowledgements

This work has been supported by Cancer Research UK graduate studentship.

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Authors and Affiliations

  1. Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Lisburn Road, Belfast, BT9 7BL, UK

    Sukanya Suresh, Wanhua Lu & Alexandra E. Irvine

  2. Blood Sciences, School of Biomedical and Biological Sciences, University of Plymouth, Drake Circus, Plymouth, PL4 8AA, UK

    Lynn McCallum

  3. Universite Paris 7D Diderot, Paris, 75005, France

    Noureddine Lazar

  4. L’Oreal R & D, Clark, NJ, 07066, USA

    Bernard Perbal

Authors
  1. Sukanya Suresh
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  2. Lynn McCallum
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  3. Wanhua Lu
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  4. Noureddine Lazar
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  5. Bernard Perbal
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  6. Alexandra E. Irvine
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Correspondence to Alexandra E. Irvine.

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Suresh, S., McCallum, L., Lu, W. et al. MicroRNAs 130a/b are regulated by BCR-ABL and downregulate expression of CCN3 in CML. J. Cell Commun. Signal. 5, 183–191 (2011). https://doi.org/10.1007/s12079-011-0139-x

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  • DOI: https://doi.org/10.1007/s12079-011-0139-x

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