RESUMO
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.
Assuntos
MicroRNAs/genética , Animais , Ciclo Celular , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/genética , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição de Domínio TEA , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Transformação Celular Neoplásica , Meios de Cultivo Condicionados/farmacologia , Células Epiteliais/metabolismo , Genes Supressores de Tumor , Proteínas de Fluorescência Verde/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
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.