RESUMEN
MYO10, recognized as an important regulator of cytoskeleton remodeling, has been reported to be associated with tumorigenesis. However, its functional implication in cervical cancer and potential mechanism still remain to be undetermined currently. MYO10 level in cervical cancer tissues was analyzed by using data retrieved from The Cancer Genome Atlas and ONCOMINE databases. Messenger RNA and protein expression levels were determined by quantitative real-time polymerase chain reaction and Western blotting. Small-interfering RNA and overexpressing plasmid were used for MYO10 silencing and overexpression, and cell proliferation was analyzed by CCK-8. Transwell assays were performed to investigate the ability of cell migration and invasion. MYO10 was upregulated in cervical cancer tissues and cells when compared to normal controls, and survival analysis showed patients with high MYO10 expression had worse overall survival. Moreover, knockdown/overexpression of MYO10 significantly inhibited/enhanced the proliferation, invasion, and migration capabilities of cervical cells transfected with siRNAs/overexpressing plasmid. Additionally, MYO10 silencing inhibited PI3K/Akt signaling pathway by decreasing the phosphorylation status of PI3K and AKT. Data from the present study indicated that MYO10 were overexpressed in patients with cervical cancer and positively linked with poor prognosis. Experimental results suggested that MYO10 induced a significant encouraging effect in cervical cancer cell proliferation, invasion, and migration, linked with involvement of PI3K/Akt signaling. Collectively, these results emphasize a novel role for MYO10 overexpression in cervical cancer and provide a potent therapeutic strategy against cervical cancer.
Asunto(s)
Eliminación de Gen , Miosinas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Biomarcadores de Tumor , Línea Celular Tumoral , Movimiento Celular/genética , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Miosinas/metabolismo , Pronóstico , Neoplasias del Cuello Uterino/mortalidadRESUMEN
Cervical cancer is one of the most common malignancies of the female reproductive system. Therefore, it is critical to investigate the molecular mechanisms involved in the development and progression of cervical cancer. In this study, we stimulated cervical cancer cells with 5-aza-2'-deoxycytidine (5-Aza-dC) and found that this treatment inhibited cell proliferation and induced apoptosis; additionally, methylation of p16 and O-6-methylguanine-DNA methyltransferase (MGMT) was reversed, although their expression was suppressed. 5-Aza-dC inhibited E6 and E7 expression and up-regulated p53, p21, and Rb expression. Cells transfected with siRNAs targeting p16 and MGMT as well as cells stimulated with 5-Aza-dC were arrested in S phase, and the expression of p53, p21, and Rb was up-regulated more significantly. However, when cells were stimulated with 5-Aza-dC after transfection with siRNAs targeting p16 and MGMT, proliferation decreased significantly, and the percentage of cells in the sub-G1 peak and in S phase was significantly increased, suggesting a marked increase in apoptosis. But E6 and E7 overexpression could rescue the observed effects in proliferation. Furthermore, X-ray radiation caused cells to arrest in G2/M phase, but cells transfected with p16- and MGMT-targeted siRNAs followed by X-ray radiation exhibited a significant decrease in proliferation and were shifted toward the sub-G1 peak, also indicating enhanced apoptosis. In addition, the effects of 5-Aza-dC and X-ray radiation were most pronounced when MGMT expression was down-regulated. Therefore, down-regulation of p16 and MGMT expression enhances the anti-proliferative effects of 5-Aza-dC and X-ray radiation. This discovery may provide novel ideas for the treatment of cervical cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Azacitidina/análogos & derivados , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Metilasas de Modificación del ADN/antagonistas & inhibidores , Enzimas Reparadoras del ADN/antagonistas & inhibidores , Regulación hacia Abajo/efectos de los fármacos , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Azacitidina/química , Azacitidina/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/metabolismo , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Decitabina , Regulación hacia Abajo/genética , Femenino , Humanos , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Rayos XRESUMEN
The standard treatment for node-positive cervical cancer after radical hysterectomy is pelvic radiotherapy and concurrent chemotherapy. Given the potential toxicity of postoperative radiotherapy, we used the lymph node ratio (LNR) to assess the benefit of postoperative radiotherapy in lymph node-positive cervical cancer patients. Data from the Surveillance Epidemiology and End Results database (1988-2010) were analyzed using Kaplan-Meier and Cox regression proportional hazard analysis. A total of 2,269 eligible patients were identified (median follow-up, 78.0 months); 1,863 (82.1%) patients received postoperative radiotherapy. In both univariate and multivariate analysis multivariate analysis, a higher LNR was significantly associated with a poorer outcome. A LNR > 0.16 was associated with poorer cervical cancer-related survival (CCSS) (hazard Ratio [HR] 1.376, confidence interval [CI] 1.082-1.750; P < 0.001) and overall survival (OS) (HR 1.287, CI 1.056-1.569; P = 0.012). Postoperative radiotherapy was only associated with survival benefits in patients with a LNR > 0.16 (CCSS, P < 0.001; OS, P < 0.001) and not in patients with a LNR ≤ 0.16 (CCSS, P = 0.620; OS, P = 0.167); these trends were not affected by number of removed lymph nodes. A higher LNR is associated with a poorer survival in lymph node-positive cervical cancer. The survival benefits of postoperative radiotherapy appear to be limited to patients with a LNR > 0.16.