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1.
Cancers (Basel) ; 13(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572851

RESUMO

Multiple myeloma (MM) is a genetically heterogeneous disease characterized by genomic chaos making it difficult to distinguish driver from passenger mutations. In this study, we integrated data from whole genome gene expression profiling (GEP) microarrays and CytoScan HD high-resolution genomic arrays to integrate GEP with copy number variations (CNV) to more precisely define molecular alterations in MM important for disease initiation, progression and poor clinical outcome. We utilized gene expression arrays from 351 MM samples and CytoScan HD arrays from 97 MM samples to identify eight CNV events that represent possible MM drivers. By integrating GEP and CNV data we divided the MM into eight unique subgroups and demonstrated that patients within one of the eight distinct subgroups exhibited common and unique protein network signatures that can be utilized to identify new therapeutic interventions based on pathway dysregulation. Data also point to the central role of 1q gains and the upregulated expression of ANP32E, DTL, IFI16, UBE2Q1, and UBE2T as potential drivers of MM aggressiveness. The data presented here utilized a novel approach to identify potential driver CNV events in MM, the creation of an improved definition of the molecular basis of MM and the identification of potential new points of therapeutic intervention.

2.
Oncotarget ; 6(38): 40496-506, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26415231

RESUMO

Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/ß-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/patologia , Células-Tronco Neoplásicas/patologia , Animais , Humanos , Mieloma Múltiplo/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos
3.
Innate Immun ; 18(6): 846-55, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22522429

RESUMO

Recognition of microbial products by members of the Toll-like receptor (TLR) family initiates intracellular signaling cascades that result in NF-κB activation and subsequent production of inflammatory cytokines. We explored the potential roles of microRNAs (miRNAs) in regulating TLR pathways. A target analysis approach to the TLR4 pathway adaptor molecules identified several putative targets of miR-200a, miR-200b and miR-200c. miRNA mimics were co-transfected with a NF-κB activity reporter plasmid into HEK293 cells stably expressing TLR4 (HEK293-TLR4). Mimics of both miR-200b and miR-200c, but not miR-200a, decreased NF-κB reporter activity in either untreated cells or in cells treated with endotoxin:MD2 as a TLR4 agonist. Transfection of HEK293-TLR4 cells with miR-200b or miR-200c significantly decreased expression of MyD88, whereas TLR4, IRAK-1 and TRAF-6 mRNAs were unaffected. When miR-200b or miR-200c mimics were transfected into the differentiated monocytic THP-1 cell line, the abundance of MyD88 transcripts, as well as LPS-induced expression of the pro-inflammatory molecules IL-6, CXCL9 and TNF-α were diminished. These data define miRNAs miR-200b and miR-200c as factors that modify the efficiency of TLR4 signaling through the MyD88-dependent pathway and can thus affect host innate defenses against microbial pathogens.


Assuntos
MicroRNAs/metabolismo , Monócitos/imunologia , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Regulação para Baixo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , MicroRNAs/genética , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Ativação Transcricional/genética , Transgenes/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Lab Invest ; 90(12): 1727-36, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20625373

RESUMO

MicroRNAs (miRNAs) are small RNAs that regulate gene expression pathways. Previous studies have shown interactions between hepatitis C virus (HCV) and host miRNAs. We measured miR-122 and miR-21 levels in HCV-infected human liver biopsies relative to uninfected human livers and correlated these with clinical patient data. miR-122 is required for HCV replication in vitro, and miR-21 is involved in cellular proliferation and tumorigenesis. We found that miR-21 expression correlated with viral load, fibrosis and serum liver transaminase levels. miR-122 expression inversely correlated with fibrosis, liver transaminase levels and patient age. miR-21 was induced ∼twofold, and miR-122 was downregulated on infection of cultured cells with the HCV J6/JFH infectious clone, thus establishing a link to HCV. To further examine the relationship between fibrosis and the levels of miR-21 and miR-122, we measured their expression levels in a mouse carbon tetrachloride fibrosis model. As in the HCV-infected patient samples, fibrotic stage positively correlated with miR-21 and negatively correlated with miR-122 levels. Transforming growth factor ß (TGF-ß) is a critical mediator of fibrogenesis. We identified SMAD7 as a novel miR-21 target. SMAD7 is a negative regulator of TGF-ß signaling, and its expression is induced by TGF-ß. To confirm the relationship between miR-21 and the TGF-ß signaling pathway, we measured the effect of miR-21 on a TGF-ß-responsive reporter. We found that miR-21 enhanced TGF-ß signaling, further supporting a relationship between miR-21 and fibrosis. We suggest a model in which miR-21 targeting of SMAD7 could increase TGF-ß signaling, leading to increased fibrogenesis.


Assuntos
Hepatite C Crônica/complicações , Hepatite C Crônica/genética , MicroRNAs/metabolismo , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biópsia , Linhagem Celular , Células Cultivadas , Células Clonais , Regulação para Baixo , Feminino , Fibrose/patologia , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C Crônica/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Transdução de Sinais/genética , Estatísticas não Paramétricas , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Carga Viral
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