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

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 miR130b 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.

Comprehensive analysis of human small RNA sequencing data provides insights into expression profiles and miRNA editing

“…[34][35][36][37] These 2 miRNAs were also reported to be regulated by BCR-ABL, an oncoprotein in chronic myeloid leukemia. 38 These evidences suggest these common miRNAs may play an important role in cancer progress across several cancer types. Editing sites in miRNA sequences may influence miRNA functions by changing their target bindings, which confirmed by our target prediction and enrichment analysis.…”

Identification of radiation-induced microRNA transcriptome by next-generation massively parallel sequencing

“…miR-20b modulates vascular endothelial growth factor (VEGF) expression by targeting hypoxia inducible factor 1 (HIF-1) alpha as well as signal transducer and activator of transcription 3 (STAT3) in MCF-7 breast cancer cells [47]. miR-130b is regulated by BCR-ABL [48]. …”

Role of Epigenetics in Chronic Myeloid Leukemia

“…The inhibitory effect on growth of K562 through c-MYC silencing was partially reverted by the overexpression of ectopic construct encoding miR-17-19b. Altogether, the data support the existence of the BCR-ABL / c-MYC / miR-17-92 pathway in CML pathogenesis. MiR - 130a is mediated by BCR-ABL in K562 cells [59]. After the BCR-ABL silencing in K562, the levels of miR-130a and miR-130b significantly decreased, whereas the expression of their putative target, the growth negative regulator CCN3 , significantly increased.…”

“…MiR - 130a is mediated by BCR-ABL in K562 cells [59]. After the BCR-ABL silencing in K562, the levels of miR-130a and miR-130b significantly decreased, whereas the expression of their putative target, the growth negative regulator CCN3 , significantly increased.…”