RESUMEN
The deregulation of microRNAs (miRNAs) is often implicated in the control of sensitivity to radiotherapy. The objective of the present study was to identify the association between miR558 and apoptosisassociated tyrosine kinase (AATK), and their importance in regulating the development of resistance to radiotherapy. The current study demonstrated that AATK, a radiosensitization-associated gene, is a target of miR558 in lung cancer cells, using in silico analysis and a luciferase reporter system. Furthermore, it was determined that transfection of 30 or 50 nM miR558 mimics and AATK specific siRNA markedly suppressed the mRNA and protein expression of AATK. To determine whether miR558 was required for lung cancer cell radioresistance, A549 cells were treated with different doses of ionizing radiation, from 0 to 10 Gy, following transfection with miR558 mimics or AATK specific siRNA. It was determined that the administration of miR558 mimics or AATK specific siRNA alone did not significantly alter the survival rate of the cells. By contrast, in the cells exposed to 4, 6 or 8 Gy, the administration of miR558 mimics or AATK specific siRNA significantly promoted cell survival rate and overexpression of AATK reversed this effect. In conclusion, these data demonstrate that the miR558/AATK cascade is important for the radiosensitization of lung cancer cells and may be a potential radiotherapy target.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Proteínas Tirosina Quinasas/genética , Interferencia de ARN , Tolerancia a Radiación/genética , Regiones no Traducidas 3' , Células A549 , Apoptosis/genética , Apoptosis/efectos de la radiación , Sitios de Unión , Humanos , ARN Mensajero/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Radiación Ionizante , RadioterapiaRESUMEN
Breast cancer is one of the most common malignant tumors in women worldwide. The microRNAs (miRNAs) are small, noncoding RNAs that regulate various biological processes, including breast cancer. miR-708 played an important role in a variety of cancers. However, its involvement in breast cancer remains largely unclear. In this study, we found that forced the expression of miR-708 in breast cancer cell lines decreased cell proliferation and invasion, whereas inhibition of miR-708 increased cell growth and invasion. miR-708 could directly target the LSD1 3'UTR to downregulate the expression. Further studies suggested that inhibition of LSD1 could phenocopied function of the miR-708 overexpression in MDA-MB-231 cells .Overexpression of LSD1 could counteract the effects of miR-708 on the proliferation and invasion. Taken together, the results indicate that miR-708 may function as a tumor suppressor gene in breast cancer development, and miR-708/LSD1 axis may be a therapeutic intervention in breast cancer in the future.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Histona Demetilasas/genética , MicroARNs/genética , Regiones no Traducidas 3' , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Interferencia de ARN , ARN Mensajero/genéticaRESUMEN
Lung cancer, predominantly by non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths over the world. Late diagnosis is one of important reasons for high mortality rate in lung cancer. Current diagnostic approaches have disadvantages such as low accuracy, high cost, invasive procedure, etc. MicroRNAs were previously proposed as promising novel biomarkers in cancer screening. In this study, we evaluated the predictive power of four candidate miRNAs in NSCLC detection. Our study involved 152 NSCLC patients and 300 healthy controls. Blood samples were obtained from the total 452 subjects. After miRNA extraction from serum, the expression of miRNAs in cases and controls were quantified by qRT-PCR and normalized to the level of U6 small RNA. Statistical analyses were performed to compare miRNA levels between cases and controls. Stratified analyses were employed to compare miRNA levels in NSCLC patients with different clinical characteristics. Serum miR-148a, miR-148b, and miR-152 were significantly downregulated in NSCLC patients. However, overexpression of serum miR-21 was observed in NSCLC patients. The combination of four candidate miRNAs exhibited the highest predictive accuracy in NSCLC screening compared with individual miRNAs (AUC = 0.97). Low level of miRNA-148/152 members may associate with advanced stage, large tumor size, malignant cell differentiation, and metastasis. High expression of miR-21 was possibly correlated with large size tumor and advanced cancer stage. Our results showed the dysregulation of miR-148/152 family and miR-21 in NSCLC patients. Hence, the four candidate miRNAs have great potential to serve as promising novel biomarkers in NSCLC screening. Further large-scale studies are needed to validate our results.