Integrative High-resolution Microarray Analysis of Human Myeloma Cell Lines Reveals Deregulated miRNA Expression Associated with Allelic Imbalances and Gene Expression Profiles

Department of Medical Sciences, Leukemia Study Centre, University of Milan, Hematology 1-CTMO, Foundation IRCCS Policlinico, Milan, Italy.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 06/2009; 48(6):521-31. DOI: 10.1002/gcc.20660
Source: PubMed


It is thought that altered microRNA (miRNA) expression due to various mechanisms plays a critical role in the pathogenesis of most human cancers. Notably, about half of the known miRNAs are intragenic and frequently coexpressed with their host genes. To date there is little evidence concerning miRNA expression in multiple myeloma (MM). In an attempt to provide insights into miRNA deregulation in MM, we profiled global miRNA expression in a panel of molecularly well-characterized human myeloma cell lines (HMCLs) using high-resolution microarrays, and then used integrative analyses to identify altered patterns correlated with DNA copy number (CN) or gene expression profiles. We identified 16 miRNAs mapped to chromosomal regions frequently involved in numerical imbalances in MM, whose expression significantly correlated with the CN of the corresponding miRNA genes; among these, miR-22 expression was also affected by chromosome arm 17p loss in a representative panel of primary MM tumors. The expression of 32 intronic miRNAs significantly correlated with that of their host transcripts, some of which were highly deregulated in MM patients. The expression of some of the miRNAs was validated by quantitative RT-PCR. Finally, a number of the identified miRNAs have previously been reported to play important roles in tumorigenesis. Overall, our data highlight that genomic alterations may significantly affect miRNA expression in HMCLs and demonstrate a frequent coexpression of intronic miRNAs with their host genes that may have a pathogenetic relevance in plasma cell transformation.

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Available from: Luca Agnelli
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    • "Aberrant miRNA expression or function in cancer can be attributed to various mechanisms involving both genomic and epigenetic aberrations. It has been observed in MM that miRNA expression could be disrupted by deregulation of miRNA host genes, copy number (CN) at miRNA-containing genomic locus [86, 89, 108, 109], abnormalities in miRNA biogenesis pathways [87], and abnormal activity of transcription factors [110]. However, it seems that the most important mechanism behind aberrant miRNA deregulation is epigenetic alterations, including abnormal DNA methylation and histone modifications [111–114]. "
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    ABSTRACT: Recent studies have revealed a pivotal role played by a class of small, noncoding RNAs, microRNA (miRNA), in multiple myeloma (MM), a plasma cell (PC) malignancy causing significant morbidity and mortality. Deregulated miRNA expression in patient's PCs and plasma has been associated with tumor progression, molecular subtypes, clinical staging, prognosis, and drug response in MM. A number of important oncogenic and tumor suppressor miRNAs have been discovered to regulate important genes and pathways such as p53 and IL6-JAK-STAT signaling. miRNAs may also form complex regulatory circuitry with genetic and epigenetic machineries, the deregulation of which could lead to malignant transformation and progression. The translational potential of miRNAs in the clinic is being increasingly recognized that they could represent novel biomarkers and therapeutic targets. This review comprehensively summarizes current progress in delineating the roles of miRNAs in MM pathobiology and management.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "At the molecular level, miR-15a/16-1 have been shown to inhibit cyclin-D1, cyclin-D2, and CDC25A, key regulators of cell cycle progression [77], as well as protein kinase B (AKT) and nuclear factor-kappa B (NF-κB) pathways involved in oncogenesis [80]. Most cases of multiple myeloma demonstrate deregulation of one or more cyclin-D genes [82], which in this case might be explained by reduced miR-15a/16-1 levels. Combined with the role of these miRNAs in lymphomas and leukaemia, miR-15a/16-1 provide evidence that a single miRNA can have multiple and complex effects in cell biology [77]. "
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    ABSTRACT: Currently, there are over 1,800 annotated human miRNAs, many of which have tissue-specific expression. Numerous studies have highlighted their role in haematopoietic differentiation and proliferation, acting as master regulators of haematopoietic stem cell function. Aberrant expression of miRNAs has been observed in haematological cancers, exhibiting unique expression signatures in comparison to normal counterparts. Functional and target analyses as well as animal models have attempted to annotate how different miRNA may contribute to the pathophysiology of these malignancies from modulating cancer associated genes, functioning directly as oncogenes or tumour suppressor genes or acting as bystanders or regulators of the epigenetic mechanisms in cancer. miRNAs have also been shown to play a role in modulating drug resistance and determining prognosis between the various subtypes of blood cancers. This review discusses the important role that miRNAs play in haematological malignancies by exploring associations that exist between the two and trying to examine evidence of causality to support the tantalising possibility that miRNAs might serve as therapeutic targets in blood cancers.
    Full-text · Article · Dec 2013
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    • "Recent studies revealed a high frequency in copy number abnormality of miRNA processing genes, such as Dicer1 and Argonature2, in breast and ovarian cancers [28,29]. Although copy number alterations of miRNAs and their regulatory genes were frequently investigated in oncogenesis [28-30], the evolutionary and functional impact of CNV-miRNAs on the human genome has not been studied extensively. "
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    ABSTRACT: Background microRNAs (miRNAs) represent a class of small (typically 22 nucleotides in length) non-coding RNAs that can degrade their target mRNAs or block their translation. Recent research showed that copy number alterations of miRNAs and their target genes are highly prevalent in cancers; however, the evolutionary and biological functions of naturally existing copy number variable miRNAs (CNV-miRNAs) among individuals have not been studied extensively throughout the genome. Results In this study, we comprehensively analyzed the properties of genes regulated by CNV-miRNAs, and found that CNV-miRNAs tend to target a higher average number of genes and prefer to synergistically regulate the same genes; further, the targets of CNV-miRNAs tend to have higher variability of expression within and between populations. Finally, we found the targets of CNV-miRNAs are more likely to be differentially expressed among tissues and developmental stages, and participate in a wide range of cellular responses. Conclusions Our analyses of CNV-miRNAs provide new insights into the impact of copy number variations on miRNA-mediated post-transcriptional networks. The deeper interpretation of patterns of gene expression variation and the functional characterization of CNV-miRNAs will help to broaden the current understanding of the molecular basis of human phenotypic diversity.
    Full-text · Article · Dec 2012 · BMC Genomics
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