MicroRNAs: a developing story

MicroRNAs (miRNAs) are short noncoding RNAs regulating gene expression that play roles in human diseases, including cancer. Each miRNA is predicted to regulate hundreds of transcripts, but only few have experimental validation. In chronic lymphocytic leukemia (CLL), the most common adult human leukemia, miR-15a and miR-16-1 are lost or down-regulated in the majority of cases. After our previous work indicating a tumor suppressor function of miR-15a/16-1 by targeting the BCL2 oncogene, here, we produced a high-throughput profiling of genes modulated by miR-15a/16-1 in a leukemic cell line model (MEG-01) and in primary CLL samples. By combining experimental and bioinformatics data, we identified a miR-15a/16-1-gene signature in leukemic cells. Among the components of the miR-15a/ 16-1 signature, we observed a statistically significant enrichment in AU-rich elements (AREs). By examining the Gene Ontology (GO) database, a significant enrichment in cancer genes (such as MCL1, BCL2, ETS1, or JUN) that directly or indirectly affect apoptosis and cell cycle was found. (5), PicTar (6), and Diana microT (7) have been developed to identify miRNA targets, but only few of these predictions have been experimentally validated, supporting the rationale for a combination of bioinformatics and biological strategies to this aim. Two independent studies predicted that 20-30% of human genes could be controlled by miRNAs (8, 9). Deviations from normal miRNA expression patterns play roles in human diseases, including cancer (for reviews see refs. 10-15).The miR-15a/16-1 cluster resides at chromosome 13q14.3, a genomic region frequently deleted in B cell chronic lymphocytic leukemias (CLLs), and the two members of the cluster are cotranscribed and down-regulated in the majority of CLL patients (16). CLL is a disease with a frequent association in families (10-20% of patients have at least one first-degree relative with CLL) (17). Previously, we identified germ-line or somatic mutations in several miRNAs (including miR-16-1) in Ϸ15% of CLL patients, with the majority of the patients having a known personal or family history of CLL or other hematopoietic and solid tumors (18). These findings, together with the identification of an abnormal miR-15a/ 16-1 locus in the NZB strain of mice that naturally develop CLL (19), suggest that this cluster might play also a role in familial CLL.Among the targets of miR-15a and miR-16, we identified the antiapoptotic protein Bcl2, which is overexpressed in the malignant, mostly nondividing B cells of CLL (20), and in many solid and hematologic malignancies (21). Restoration of miR-15-a/16-1 induces apoptosis in MEG-01, a cell line derived from acute megakaryocytic leukemia (22). These data support a role for miR-15a and miR-16-1 as tumor-suppressor genes (TSGs) in CLLs and perhaps in other malignancies in which these genes are lost or down-regulated.Here, to investigate the mechanism of action of miR-15a and miR-16-1 as tumor suppressors in leukemias, we analyzed the effects of miR-15a and miR-16-1 on...

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“…Deviations from normal miRNA expression patterns play roles in human diseases, including cancer (for reviews see refs. [10][11][12][13][14][15].…”

Section: Icrornas (Mirnas) Are Short Noncoding Rnas Of ϸ19-24mentioning

confidence: 99%

MiR-15a and miR-16-1 cluster functions in human leukemia

Calin

Cimmino

Fabbri

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

703

540

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“…[1][2][3] This occurs through imperfect complementarity to the 3′ untranslated region (3′UTR) of target mRNAs; this partial homology recognition results in mRNAs translational inhibition and/or degradation, 4,5 finally leading to a reduction in protein expression level. 1 To date more than 1000 human microRNAs have been discovered (http://www.mirbase.…”

Section: Introductionmentioning

confidence: 99%

The locus of microRNA-10b

et al. 2013

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“…MicroRNAs (miRNAs) represent a previously uncharacterized class of gene products that are believed to function as negative regulators of gene expression (12)(13)(14)(15)(16). Recently, miRNA genes have been implicated in several cancers (14,(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

mentioning

confidence: 99%