RESUMEN
The development and progression of CRC are regarded as a complicated network and progressive event including genetic and/or epigenetic alterations. Recent researches revealed that MicroRNAs are biomarkers and regulators of CRC progression. Analyses of published microarray datasets revealed that miR-450b-5p was highly up-regulated in CRC tissues. In addition, high expression of miR-450b-5p was significantly associated with KRAS mutation. However, the role of miR-450b-5p in the progression of CRC remains unknown. Here, we sought to validate the expression of miR-450b-5p in CRC tissues and investigate the role and underlying mechanism of miR-450b-5p in the progression of CRC. The results revealed that miR-450b-5p was up-regulated in CRC tissues, high expression level of miR-450b-5p was positively associated with poor differentiation, advanced TNM classification and poor prognosis. Moreover, miR-450b-5p was especially high in KRAS-mutated cell lines and could be up-regulated by KRAS/AP-1 signaling. Functional validation revealed that overexpression of miR-450b-5p promoted cell proliferation and tumor growth while inhibited apoptosis of CRC cells. Furthermore, we demonstrated that miR-450b-5p directly bound the 3'-UTRs of SFRP2 and SIAH1, and activated Wnt/ß-Catenin signaling. In conclusion, miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression. Collectively, our work helped to understand the precise role of miR-450b-5p in the progression of CRC, and might promote the development of new therapeutic strategies against CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , MicroARNs/metabolismo , Proteínas ras/genética , Regiones no Traducidas 3' , Animales , Apoptosis , Biomarcadores de Tumor/genética , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes ras , Células HCT116 , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Proteínas Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Transducción de Señal , Resultado del Tratamiento , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The Groucho transcriptional co-repressor TLE4 protein has been shown to be a tumor suppressor in a subset of acute myeloid leukemia. However, little is known about its role in development and progression of solid tumor. In this study, we found that the expression of TLE4 in colorectal cancer (CRC) tissues was significantly higher than that in their matched adjacent intestine epithelial tissues. In addition, high expression of TLE4 was significantly correlated with advanced Dukes stage, lymph node metastasis and poor prognosis of CRC. Moreover, enforced expression of TLE4 in CRC cell lines significantly enhanced proliferation, invasion and tumor growth. On the contrary, knock down of TLE4 repressed cell proliferation, invasion and tumor growth. Furthermore, our study exhibited that the TLE4 promoted cell proliferation and invasion partially via activation of JNK-c-Jun pathway and subsequently increased cyclinD1 and decreased P27Kip1 expression. In conclusion, these results suggested that TLE4, a potential prognostic biomarker for CRC, plays an important role in the development and progression of human CRC.
Asunto(s)
Neoplasias Colorrectales/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/biosíntesis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Progresión de la Enfermedad , Activación Enzimática , Células HCT116 , Células HT29 , Humanos , Metástasis Linfática/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica/patología , Trasplante de Neoplasias , Proteínas Nucleares/genética , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas Represoras/genética , Trasplante HeterólogoRESUMEN
The Leucine zipper tumor suppressor gene 1 (LZTS1/FEZ1) gene was originally identified as a potential tumor suppressor. However, the expression pattern and the role of LZTS1 in the progression of colorectal cancer (CRC) have not been well characterized. Herein, we reported that LZTS1 was markedly reduced in CRC tissues compared with matched adjacent normal intestine epithelial tissues. In analysis of 160 CRC specimens, we revealed that decreased expression of LZTS1 was correlated to aggressive characteristics and poor survival of patients with CRC. Moreover, we found that expression of LZTS1 in CRC cells significantly inhibited cell proliferation in vitro and prohibited tumor growth in vitro. On the contrary, silence of LZTS1 promoted cell proliferation and tumor growth in CRC cells. Furthermore, we demonstrated that LZTS1 inhibited cell proliferation and tumor growth in CRC in part via suppression of AMT-mTOR, subsequently down-regulating p27Kip and up-regulating cyclin D1. These findings suggest that LZTS1 plays a potential tumor suppressor role in CRC progression and represents a valuable clinical prognostic marker of this disease.