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1.
Int J Cancer ; 144(12): 3056-3069, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30536754

RESUMO

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.


Assuntos
Neoplasias Gástricas/metabolismo , Superóxido Dismutase/metabolismo , Receptor 2 Toll-Like/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Reprogramação Celular/fisiologia , Metabolismo Energético , Indução Enzimática , Glicólise , Humanos , Imuno-Histoquímica , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Regulação para Cima
2.
Sci Transl Med ; 3(77): 77ra30, 2011 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-21471434

RESUMO

Fusion genes are chimeric genes formed in cancers through genomic aberrations such as translocations, amplifications, and rearrangements. To identify fusion genes in gastric cancer, we analyzed regions of chromosomal imbalance in a cohort of 106 primary gastric cancers and 27 cell lines derived from gastric cancers. Multiple samples exhibited genomic breakpoints in the 5' region of SLC1A2/EAAT2, a gene encoding a glutamate transporter. Analysis of a breakpoint-positive SNU16 cell line revealed expression of a CD44-SLC1A2 fusion transcript caused by a paracentric chromosomal inversion, which was predicted to produce a truncated but functional SLC1A2 protein. In primary tumors, CD44-SLC1A2 gene fusions were detected in 1 to 2% of gastric cancers, but not in adjacent matched normal gastric tissues. When we specifically silenced CD44-SLC1A2, cellular proliferation, invasion, and anchorage-independent growth were significantly reduced. Conversely, CD44-SLC1A2 overexpression in gastric cells stimulated these pro-oncogenic traits. CD44-SLC1A2 silencing caused significant reductions in intracellular glutamate concentrations and sensitized SNU16 cells to cisplatin, a commonly used chemotherapeutic agent in gastric cancer. We conclude that fusion of the SLC1A2 gene coding region to CD44 regulatory elements likely causes SLC1A2 transcriptional dysregulation, because tumors expressing high SLC1A2 levels also tended to be CD44-SLC1A2-positive. CD44-SLC1A2 may represent a class of gene fusions in cancers that establish a pro-oncogenic metabolic milieu favoring tumor growth and survival.


Assuntos
Fusão Gênica/genética , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Receptores de Hialuronatos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Transportador 2 de Aminoácido Excitatório , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
3.
Clin Cancer Res ; 17(9): 2657-67, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21415212

RESUMO

PURPOSE: MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC). EXPERIMENTAL DESIGN: Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors. RESULTS: Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified hsa-miR-486 (miR-486) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of miR-486 expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting miR-486 expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the miR-486 locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting miR-486, consistent with miR-486 playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein OLFM4 as a potential miR-486 target. Restoring miR-486 expression in GC cells decreased endogenous OLFM4 transcript and protein levels, and also inhibited expression of luciferase reporters containing an OLFM4 3' untranslated region with predicted miR-486 binding sites. Supporting the biological relevance of OLFM4 as a miR-486 target, proliferation in GC cells was also significantly reduced by OLFM4 silencing. CONCLUSIONS: miR-486 may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of OLFM4.


Assuntos
Carcinoma/genética , Deleção de Genes , Fator Estimulador de Colônias de Granulócitos/genética , MicroRNAs/fisiologia , Neoplasias Gástricas/genética , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Instabilidade Genômica/genética , Instabilidade Genômica/fisiologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , MicroRNAs/genética , Análise em Microsséries , Neoplasias/genética , Neoplasias/patologia , Neoplasias Gástricas/patologia
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