RESUMEN
MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumor-suppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5'aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.
Asunto(s)
MicroARNs/genética , Animales , Ciclo Celular , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cisplatino/farmacología , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Ácidos Hidroxámicos/farmacología , Masculino , Ratones , Ratones Desnudos , MicroARNs/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción de Dominio TEA , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The p53 tumor suppressor serves as a crucial barrier against cancer development. In tumor cells and their progenitors, p53 suppresses cancer in a cell-autonomous manner. However, p53 also possesses non-cell-autonomous activities. For example, p53 of stromal fibroblasts can modulate the spectrum of proteins secreted by these cells, rendering their microenvironment less supportive of the survival and spread of adjacent tumor cells. We now report that epithelial tumor cells can suppress p53 induction in neighboring fibroblasts, an effect reproducible by tumor cell-conditioned medium. The ability to suppress fibroblast p53 activation is acquired by epithelial cells in the course of neoplastic transformation. Specifically, stable transduction of immortalized epithelial cells by mutant H-Ras and p53-specific short inhibitory RNA endows them with the ability to quench fibroblast p53 induction. Importantly, human cancer-associated fibroblasts are more susceptible to this suppression than normal fibroblasts. These findings underscore a mechanism whereby epithelial cancer cells may overcome the non-cell-autonomous tumor suppressor function of p53 in stromal fibroblasts.
Asunto(s)
Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular , Transformación Celular Neoplásica , Medios de Cultivo Condicionados/farmacología , Células Epiteliales/metabolismo , Genes Supresores de Tumor , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Ratones , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Spontaneous coronary dissection is a rare event occurring particularly in women during the peripartum and postpartum period. Two cases related to the early postpartum period with a successful outcome are described, together with a comprehensive review of all the previously published cases. Diagnostic and therapeutic considerations of this unique clinical entity are discussed and reviewed.