Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling

Abstract

Specific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in 60 newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared with normal PC. It is interesting to note that miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated with changes in specific miRNAs.

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

“…When we assessed the effect of miR-214 on protein haematologica | 2013; 98(4) To further validate these results on primary MM samples, we evaluated PSMD10 and ASF1B expression in myeloma cell samples obtained from eight MM patients who, according to previous miRNA profiling analysis, had low miR-214 levels. 6 The expression values of PSMD10 and ASF1B were significantly higher in MM cases than in normal plasma cells: median value of 0.042 (range, 0.029-0.074) versus median, 0.009 (range, 0.006-0.025) for PSMD10 (P=0.004), and median value of 0.019 (range, 0.009-0.033) versus median, 0.009 (range, 0.002-0.013) for ASF1B (P=0.048) (Online Supplementary Figure S6). …”

“…To assess whether the decrease of cell growth was the result of apoptosis induction, annexin V-positive cells were quantified as well as DiOC 6 (4) 643 at 72 h at significant levels in H929 and JJN3 cell lines (P<0.01) ( Figure 2C). In addition, using DiOC 6 (3), a decrease in mitochondrial membrane potential was observed after miR-214 transfection ( Figure 2D).…”

“…6 The integrity of the RNA was verified with an Agilent 2100 Bioanalyzer. Full microarray data are available at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=xjcdlmem-keeemps&acc=GSE35948).…”

“…5 We have previously reported the down-regulation of 11 miRNA (miR-375, miR-650, miR-214, miR-135b, miR-196a, miR-155, miR-203, miR-95, miR-486, miR-10a and miR-196b) in MM samples compared to in normal plasma cells. 6 Interestingly, only miR-214 and miR-375 were significantly under-expressed in all the different cytogenetic subgroups (including IGH translocations, RB deletions and normal fluorescence in situ hybridization). miR-214 deregulation has been observed in different types of cancer.…”

Prediction of disease-related microRNAs by incorporating functional similarity and common association information

“…Experimental methods, such as qRT-PCR and microarray profiling, can successfully identify disease-related miRNAs (Barad et al, 2004;Lu et al, 2005;Gaur et al, 2007;Chen et al, 2009;Gutierrez et al, 2010). They can certainly highlight potential new miRNA-disease associations, which then need to be followed up by in vitro manipulation.…”