RESUMEN
Prostate cancer is one of the biggest health problems for the aging male. To the present, the roles of dysregulated microRNAs in prostate cancer are still unclear. Here, we evaluated the anti-proliferative role of miR-378 in prostate cancer. And, we found that the expression of miR-378 was significantly downregulated in clinical prostate cancer tissues. In vitro assay suggested that overexpression of miR-378-suppressed prostate cancer cell migration and invasion promoted cell apoptosis. Furthermore, we identified and validated MAPK1 as a direct target of miR-378. Ectopic expression of MAPK1 rescues miR-378-suppressed cell migration and invasion. In vivo assay demonstrated that the stably miR-378-overexpressed prostate cancer cells displayed a significantly reduction in tumor growth. Taken together, our data suggested that miR-378 may act as a potential therapeutic target against human prostate cancer.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , Proteína Quinasa 1 Activada por Mitógenos/biosíntesis , Neoplasias de la Próstata/patología , Adulto , Anciano , Animales , Apoptosis/genética , Western Blotting , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/genética , Neoplasias de la Próstata/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
INTRODUCTION: The roles of dysregulated microRNAs in prostate cancer metastasis are still unknown. In this study, we found that the expression of miR-345 was significantly downregulated in prostate cancer and clinical prostate cancer tissues. MATERIALS, METHODS AND RESULTS: Overexpression of miR-345 in prostate cancer cells suppressed proliferation, migration and invasion. Using nude mice model, we revealed that miR-345 inhibits the growth of prostate cancer cells in vivo and in vitro. Furthermore, we identified and validated Smad1 as a direct target of miR-345. Ectopic expression of Smad1 without its 3'-UTR rescued miR-345-induced cell migration and invasion inhibition. CONCLUSION: Taken together, our data suggest that miR-345 exerts a suppressive effect on prostate cancer proliferation, invasion and migration through downregulation of Smad1.
Asunto(s)
MicroARNs/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteína Smad1/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Western Blotting , Adhesión Celular , Movimiento Celular , Proliferación Celular , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/mortalidad , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Smad1/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ras and Rab interactor 1 (RIN1) is an effector of H-Ras, which plays an important role in the development and progression of carcinomas, but it has not been reported in bladder cancer. Hence, the association of RIN1 expression with prognosis of bladder urothelial carcinoma (UC) was examined. RIN1 mRNA and protein expression in 20 paired UCs and the adjacent normal tissues was detected by quantitative reverse transcription polymerase chain reaction and Western blot. The expression of RIN1 protein in 96 specimens of UCs and 22 specimens of adjacent normal bladder tissues were analyzed by immunohistochemistry. The overall survival (OS) was assessed by univariate and multivariate analysis. Moreover, the progression-free survival (PFS) and recurrence-free survival (RFS), classified by the clinicopathologic features with RIN1 expression, were assessed by multivariate analysis. RIN1 mRNA and protein level was higher in UCs than in the adjacent normal tissues (P < 0.01). Enhanced RIN1 immunoexpression was associated with high histologic grades (P = 0.046), cancer progression (P = 0.047) as well as Ki-67 expression (P = 0.023). Furthermore, the 5-year survival rate was 29% in the subgroup with high level of RIN1 expression, while it was 43% in the subgroup with normal level of RIN1 expression (P < 0.05). Importantly, RIN1 level was revealed as the significant independent prognostic factor for death (P = 0.023) and progression (P = 0.003), but a weak contribution for recurrence (P = 0.063). Collectively, RIN1 expression could be a potential prognostic predictor for UC patients.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
OBJECTIVE: Normal prostate tissues have a unique function of accumulating high levels of zinc. This capability is lost during the early stage in the development of prostate malignancy. ZIP4 is an important zinc transporter. In this study, we explore the expression of ZIP4 in prostate carcinoma and invest the functional contributions of ZIP4 to cancer growth in vitro. METHODS: ZIP4 expression was detected in 14 prostate carcinoma and 20 BPH tissues by real-time RT-PCR and western blot. To invest the biological function of ZIP4 in prostate carcinoma cells, ZIP4 stable over-expression in cells was established in prostate carcinoma cell line DU145 (DU145-ZIP4) and ZIP4 short hairpin RNA(shRNA) expression in stable cells was also established in prostate carcinoma cell line 22RV1(22RV1-shRNA). The proliferation, migration, and invasion ability of the prostate carcinoma cells were detected. RESULTS: The expression of ZIP4 mRNA and protein are significantly down-regulated in prostate carcinoma tissues compared with that in BPH tissues. However, we found that there was no correlation between the ZIP4 expression and the pathologic grade of prostate carcinoma. In in vitro studies, over-expression of ZIP4 not only inhibits the proliferation but also inhibits the invasive ability of prostate carcinoma cell line DU145-ZIP4. At the same time, we found silencing of ZIP4 was associated with increased cell proliferation and invasion ability in 22RV1-shRNA cell line. However, both DU145-ZIP4 and 22RV1-shRNA cells showed a significant reduction on cell migration ability compared with the control. CONCLUSION: The results indicate that ZIP4 expression is down-regulated in prostate carcinoma and it may serve as a promising biomarker for prostate carcinoma. ZIP4 has an inhibitory effect on prostate carcinoma cell proliferation and invasion. It suggests that ZIP4 may be a tumor suppressor gene and down-regulation of ZIP4 may be a critical early event in the development of prostate carcinoma.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma/metabolismo , Proteínas de Transporte de Catión/biosíntesis , Neoplasias de la Próstata/metabolismo , Western Blotting , Carcinoma/genética , Carcinoma/patología , Proteínas de Transporte de Catión/análisis , Movimiento Celular/genética , Proliferación Celular , Regulación hacia Abajo , Humanos , Masculino , Clasificación del Tumor , Invasividad Neoplásica/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
The fragile histidine triad gene (FHIT) functions as tumor suppressor in many epithelial cell types. Although the exact mechanisms remain unclear, it is apparent that in its absence, cell cycle homeostasis is often perturbed resulting in the development of soft tissue tumors. Here, we investigated the role of FHIT expression in bladder carcinogenesis and progression using immunohistochemistry. Bladder carcinoma tissue and the 5637 cell line were also studied for FHIT expression by RT-PCR and Western blotting, respectively. FHIT was found to be expressed in carcinoma and adjacent normal tissues at both mRNA and protein levels, but the 17 kDa FHIT was lower in tumors (P<0.05), this being confirmed immunohistochemically. There was a negative correlation between FHIT expression and histological grade of bladder transitional cell carcinoma (P<0.05), but no clear relationship with clinical stage or relapse (P>0.05). Overexpression of FHIT could induce apoptosis in bladder carcinoma 5637 cells, which could be enhanced by adding adriamycin (ADR). These findings suggest important roles of FHIT in bladder cancer development and provide support for the feasibility of FHIT-based gene therapy.
