Abstract
BackgroundMicroRNAs (miR, miRNAs) play pivotal roles in numerous physiological and pathophysiological contexts. We investigated whether miR-362-5p act as an oncogene in chronic myeloid leukaemia (CML) and aimed to understand its potential underlying mechanisms.MethodsWe compared the miR-362-5p expression levels between CML and non-CML cell lines, and between fresh blood samples from CML patients and normal healthy controls using quantitative real-time PCR (qPCR). Cell counting kit-8 (CCK-8) and Annexin V-FITC/PI analyses were used to measure the effects of miR-362-5p on proliferation and apoptosis, and Transwell assays were used to evaluate migration and invasion. A xenograft model was used to examine in vivo tumourigenicity. The potential target of miR-362-5p was confirmed by a luciferase reporter assay, qPCR and western blotting. Involvement of the JNK1/2 and P38 pathways was investigated by western blotting.ResultsmiR-362-5p was up-regulated in CML cell lines and fresh blood samples from CML patients, and was associated with Growth arrest and DNA damage-inducible (GADD)45α down-regulation. Inhibition of miR-362-5p simultaneously repressed tumour growth and up-regulated GADD45α expression in a xenograft model. Consistently, the knockdown of GADD45α expression partially neutralized the effects of miR-362-5p inhibition. Furthermore study suggested that GADD45α mediated downstream the effects of miR-362-5p, which might indirectly regulates the activation of the JNK1/2 and P38 signalling pathways.ConclusionmiR-362-5p acts as an oncomiR that down-regulates GADD45α, which consequently activates the JNK1/2 and P38 signalling. This finding provides novel insights into CML leukaemogenesis and may help identify new diagnostic and therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0465-3) contains supplementary material, which is available to authorized users.
Highlights
MicroRNAs play pivotal roles in numerous physiological and pathophysiological contexts
Results miR-362-5p is highly expressed in both leukaemia cell lines and fresh chronic myeloid leukaemia (CML) samples To test the expression and significance of miR-362-5p in leukaemia, quantitative real-time PCR was used to measure the expression levels of miR-362-5p in several leukaemia cell lines
We found that miR362-5p was highly expressed in leukaemia cell lines, such as BV173, K562, Ball-1 and Jurkat, but it not in nonleukemia 293 T cells and normal CD34+ cells (Fig. 1a); and the highest level of miR-362-5p expression was found in CML cell lines (BV173 and K562, Fig. 1a)
Summary
MicroRNAs (miR, miRNAs) play pivotal roles in numerous physiological and pathophysiological contexts. We investigated whether miR-362-5p act as an oncogene in chronic myeloid leukaemia (CML) and aimed to understand its potential underlying mechanisms. CML accounts for approximately 15 % of leukaemia case in adults [1, 2], and it is consistently associated with a reciprocal translocation of 9q34 with 22q11, which generates the Breakpoint cluster region/ Abelson. MiRNAs play key roles in numerous biological processes, including cell growth, cell cycle progression, apoptosis, migration and invasion [13]. Dysregulated miRNAs may act as oncogenes or tumour suppressors, depending on the biological function of their targets [14, 15]. The biological role and underlying mechanisms of miR-362-5p in CML have not been investigated
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