RESUMEN
Recent studies have shown that Beclin 1, a key regulator of autophagic process, is frequently downregulated and may serve as an independent prognostic biomarker for nonsmall cell lung cancer. However, the molecular mechanisms underlying its downregulation remain poorly understood. The signal transducer and activator of transcription 3 (Stat3) is a transcription factor which plays a crucial role for multiple tumor growth and progression. Here, we demonstrate that Beclin 1 is a direct transcriptional target of Stat3 in lung cancer cells. Interleukin-6 (IL-6) treatment or transfection of a constitutively activated Stat3 in AGS and NCI-H1650 cells inhibited Beclin 1 expression. At the molecular level, we further revealed that Stat3 could directly bind to the promoter region of Beclin 1 and repressed its transcription through recruiting histone deacetylase 3 (HDAC3). Collectively, our results suggest that the activated Stat3 may represent an important mechanism for Beclin 1 downregulation in nonsmall cell lung cancer development.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Histona Desacetilasas/metabolismo , Proteínas de la Membrana/biosíntesis , Factor de Transcripción STAT3/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Beclina-1 , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/genética , Humanos , Interleucina-6/administración & dosificación , Interleucina-6/genética , Proteínas de la Membrana/genética , Regiones Promotoras Genéticas , Factor de Transcripción STAT3/genética , Transducción de SeñalRESUMEN
MicroRNAs (miRNA) play an important role in tumorigenesis, proliferation, and differentiation. Altered miRNA expression in cancer indicates that miRNAs can function as tumor suppressors or oncogenes. MiR-449c downregulation in non-small cell lung cancer (NSCLC) compared with normal lung tissues was investigated in this study. NSCLC cell proliferation and invasion assays indicate that transfection of miR-449c expression plasmid inhibits the proliferation and invasion ability of NCI-H23 and NCI-H838 cells. In addition, miR-449c overexpression could suppress tumor growth in vivo. Morever, c-Myc was identified as a direct target gene of miR-449c. These findings clearly suggest that miR-449c downregulation and c-Myc amplification may be involved in the development of NSCLC.
