MicroRNAs 130a/b are regulated by BCR-ABL and downregulate expression of CCN3 in CML
- 3 June 2011
- journal article
- Published by Wiley in Journal of Cell Communication and Signaling
- Vol. 5 (3), 183-191
- https://doi.org/10.1007/s12079-011-0139-x
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.Keywords
This publication has 31 references indexed in Scilit:
- MicroRNAs, cancer and cancer stem cellsCancer Letters, 2011
- TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAsNature, 2010
- MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic outputProceedings of the National Academy of Sciences of the United States of America, 2010
- Defining normal and abnormal fetal growth: promises and challengesAmerican Journal of Obstetrics and Gynecology, 2010
- MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancerEuropean Journal Of Cancer, 2010
- miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic BlastsCell, 2010
- CCN3: a key growth regulator in Chronic Myeloid LeukaemiaJournal of Cell Communication and Signaling, 2009
- MicroRNA Signature of Primary Pigmented Nodular Adrenocortical Disease: Clinical Correlations and Regulation of Wnt SignalingCancer Research, 2009
- Roles for MicroRNAs, miR-93 and miR-130b, and Tumor Protein 53–Induced Nuclear Protein 1 Tumor Suppressor in Cell Growth Dysregulation by Human T-Cell Lymphotrophic Virus 1Cancer Research, 2008
- Genetic and Epigenetic Silencing of MicroRNA-203 Enhances ABL1 and BCR-ABL1 Oncogene ExpressionCancer Cell, 2008