RESUMEN
BACKGROUND: MicroRNA (miRNA, miR)-18a is a member of the miR-17-92 cluster, an important locus that is markedly overexpressed in several cancers and associated with cancer development and progression. However, the mechanism of action of the miR-17-92 cluster and its individual miRNAs are largely unknown. METHODS AND RESULTS: In this study, we investigated the expression of the miR-17-92 cluster by in situ hybridisation (ISH) assay and copy-number analysis in gastric tissue microarray (TMA) specimens. We determined that miR-18a was present at higher levels than the other five miRNAs in the cluster. In addition, we identified Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 3 (PIAS3) as a direct target of miR-18a in gastric cancer. miR-18a level was positively correlated with levels of Survivin, Bcl-xL, and c-Myc, which are downstream transcriptional targets of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3-induced transcription can be negatively regulated by PIAS3; consistent with this, PIAS3 level was negatively correlated with levels of Survivin, Bcl-xL, and c-Myc. CONCLUSION: Our findings indicate that miR-18a acts as an oncogene and plays a role in gastric adenocarcinogenesis, at least in part by negatively regulating PIAS3 and thereby modulating expression of STAT3 target genes.
Asunto(s)
Adenocarcinoma/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Chaperonas Moleculares/metabolismo , Proteínas Inhibidoras de STAT Activados/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Femenino , Mucosa Gástrica/metabolismo , Humanos , Técnicas para Inmunoenzimas , Hibridación in Situ , Masculino , Chaperonas Moleculares/genética , Estadificación de Neoplasias , Pronóstico , Proteínas Inhibidoras de STAT Activados/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Estómago/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Análisis de Matrices Tisulares , Células Tumorales CultivadasRESUMEN
Thyroid activity was tested in two substrains of SHR. Plasma level and pituitary content of TSH increased significantly in both substrains of SHR. As a result, the thyroid weight and thyroidal radioiodine uptake increased significantly. Plasma T3 concentration was decreased in Kyoto substrain but was normal in NN substrain, while plasma T4 concentration decreased significantly in both substrains. Since the pituitary content and plasma level of TSH were significantly higher in spite of the normal concentration of plasma T3, it is concluded that the pituitary "hormostat" is set at a higher level at least in the NN substrain of SHR.
