RESUMEN
As a transcriptional repressor, forkhead box D3 (FOXD3) plays an important role in tumorigenesis and progression of several tumors. However, the function and methylation status of FOXD3 remain unknown in the progression of hepatocellular carcinoma (HCC). In this study, we found that FOXD3 was decreased in HCC tissues and correlated with differentiation, AFP and poor survival of HCC patients (p<0.05). Down-regulation of FOXD3 in HCC tissues was mainly due to promoter hypermethylation. In vitro and in vivo functional results showed that ectopic FOXD3 inhibited the proliferation, migration, epithelial-mesenchymal transition (EMT) and invasion in HepG2 and SMMC-7721 cells, and FOXD3 depletion in HepG2 and QGY-7701 cells showed the adverse effects (p<0.05). Moreover, FOXD3 was sufficient to suppress tumor growth and pulmonary metastatic potential in mice. Our findings suggest that down-regulation of FOXD3, due to promoter hypermethylation plays an important role in the progression of HCC and may be a promising prognostic biomarker for HCC patients.
Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundario , Movimiento Celular , Proliferación Celular , Metilación de ADN , Factores de Transcripción Forkhead/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Carcinoma Hepatocelular/mortalidad , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Neoplasias Hepáticas/mortalidad , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Regiones Promotoras Genéticas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Colorectal cancer (CRC) is one of the most common malignancies. Increasing evidences indicate that dysregulation of miRNAs is a frequent event in CRC and contributes to the pathogenesis of CRC. In this study, we found that over-expression of miR-34a inhibited cell proliferation and invasion, induced a cell cycle arrest and triggered apoptosis, while knockdown of miR-34a showed the opposite effects. Moreover, ectopic miR-34a suppressed tumor growth and metastasis of CRC cells in vivo. FMNL2 and E2F5 were identified as direct targets of miR-34a. Reintroduction of FMNL2 or E2F5 without 3'UTR region reversed the inhibitory effects of miR-34a on cell proliferation and invasion. MiR-34a was down-regulated in CRC cells and inversely correlated with FMNL2 and E2F5 expressions. Our study suggests that miR-34a is an important tumor suppressor of CRC progression by targeting FMNL2 and E2F5, thus providing new insight into the molecular mechanisms underlying CRC progression and establishing a strong potential for the application of miR-34a as a novel therapeutic marker against CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Factor de Transcripción E2F5/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Proteínas/metabolismo , Regiones no Traducidas 3' , Apoptosis/genética , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Regulación hacia Abajo , Factor de Transcripción E2F5/genética , Forminas , Genes Supresores de Tumor , Células HCT116 , Células HT29 , Humanos , MicroARNs/genética , Proteínas/genéticaRESUMEN
F-box only protein 8 (FBX8), a novel component of F-box proteins, has recently been observed in several malignancies. However, its clinical implication in the progression of gastric cancer still remains unclear. The aim of this study was to explore the role of FBX8 in gastric cancer (GC) and analyze its correlation with tumor progression and prognosis. The expression of FBX8 in GC cell lines and matched pairs of fresh gastric cancer tissues were detected by real-time RT-PCR and Western blotting. Immunohistochemistry was used to analyze clinicopathological patterns of FBX8 in 136 cases of clinical paraffin-embedded GC tissues. A series of functional assays were conducted to evaluate the effect of FBX8 on proliferation and invasion in vitro and metastasis in vivo. FBX8 was markedly down-regulated in GC tissues compared to adjacent normal tissues. Patients with low FBX8 had shorter overall survival time and poor prognosis. Knocking down FBX8 obviously promoted proliferation and invasion in BGC823 cells, while over-expression of FBX8 in SGC7901 and AGS cells had the opposite effects. Moreover, FBX8 was sufficient to suppress metastasis in nude mice. Down-regulation of FBX8 significantly correlates with invasion, metastasis and poor survival time in GC patients. FBX8 may serve as a promising therapeutic target for inhibition of GC metastasis.
Asunto(s)
Proteínas F-Box/genética , Neoplasias Gástricas/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Proteínas F-Box/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologíaRESUMEN
Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs' activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC.
Asunto(s)
Proliferación Celular , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , ARN/genética , Adulto , Anciano , Biomarcadores de Tumor/genética , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , ARN CircularRESUMEN
Increasing emphasis has been put on the influence of desmosome related proteins on progress of colorectal cancer (CRC). Pinin (PNN) is a desmosome-associated molecule that has been reported its overexpression could increase desmoglein 2 (DSG2) and E-cadherin (E-ca) levels. However, it was documented that DSG2 and E-ca had opposite functions in CRC. Thus, we attempted to elucidate function and mechanism of PNN in CRC. Herein, we revealed that overexpression of PNN was significantly correlated with the aggressive characteristics and indicated poor overall survival of CRC patients. In addition, the proliferation, invasion in vitro, and tumorigenic growth, metastasis in vivo were also promoted by the up-regulation of PNN. It was also verified that up-regulation of PNN increased the expression of DSG2 and activated the EGFR/ERK signaling pathway. Our findings suggested that PNN, as a valuable marker of prognosis, has important influence on the progression of CRC.