RESUMO
MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.
Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/metabolismo , Mieloma Múltiplo/metabolismo , Apoptose/genética , Proteínas Argonautas , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Análise por Conglomerados , Fator de Iniciação 2 em Eucariotos/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Inativação Gênica , Estudo de Associação Genômica Ampla , Humanos , MicroRNAs/genética , Mieloma Múltiplo/genética , Análise de Sequência com Séries de Oligonucleotídeos , Oligonucleotídeos/genética , Medição de Risco , Sindecana-1/metabolismoRESUMO
Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1alpha (Hif-1alpha) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1alpha and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1alpha-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1alpha as a novel molecular target in MM and add another facet to anti-MM drug activity.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mieloma Múltiplo/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Western Blotting , Linhagem Celular Tumoral , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Humanos , Hidroquinonas/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Nus , Mieloma Múltiplo/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
The clinical significance of cytogenetic abnormalities (CA) present in randomly sampled (RS) or focal lesion (FL) bone marrow sites was examined in 419 untreated myeloma patients. Among 290 patients with gene expression profiling (GEP) data generated from RS sites, GEP-defined high-risk was present in 52% of the RS+/FL+ group but in only 9% of the remainder (P < 0.001). The RS+/FL+ constellation (18%) was an independent predictor of poor survival, also after adjusting for GEP-derived risk and TP53 status (Hazard ratio = 2.42, P = 0.004). The prevalence of high-risk myeloma in the RS+/FL+ group may reflect a dissemination-prone condition not shared by the other three groups.