RESUMEN
OBJECTIVE: The aim of the study is to explore the contribution and mechanism of circular RNA fibroblast growth factor receptor 1 (circFGFR1) in pancreatic ductal adenocarcinoma (PDAC) progression. METHODS: Expressions of circFGFR1, microRNA (miR)-532-3p, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) were assessed by quantitative real-time polymerase chain reaction or in situ hybridization. Fluorescence in situ hybridization determined the subcellular localization of circFGFR1. Immunohistochemistry was used to detect PIK3CB expression in PDAC tissues. Cell growth was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Wound healing, transwell, and flow cytometry assays examined the migration, invasion, and apoptosis. Dual-luciferase and RNA pull-down assay verified the interactions between circFGFR1/PIK3CB and miR-532-3p. In vivo xenograft tumor growth and lung metastasis were assessed in nude mice. RESULTS: Functionally, knockdown of circFGFR1 restrained in vitro PDAC cell growth, migration, invasion, and in vivo xenograft tumor growth and lung metastasis. In addition, circFGFR1 could sponge miR-532-3p to upregulate PIK3CB level. Rescue experiments revealed that the tumor-suppressive effects caused by miR-532-3p mimics could be reversed by circFGFR1 or PIK3CB overexpression. CONCLUSIONS: Our data revealed that circFGFR1 driven the malignant progression of PDAC by targeting miR-532-3p/PIK3CB axis, suggesting that inhibition of circFGFR1 might be considered as a therapeutic target for PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pulmonares , MicroARNs , Neoplasias Pancreáticas , Animales , Ratones , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , Ratones Desnudos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Hibridación Fluorescente in Situ , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Pulmonares/patología , Proliferación Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Neoplasias PancreáticasRESUMEN
Gallbladder carcinoma (GBC) commonly occurs in gastrointestinal malignancy and has the fifth highest mortality rate among gastrointestinal malignancy. Recently, miR-188-5p, a small noncoding RNA, has been implicated in various types of cancer such as nasopharyngeal carcinoma, oral squamous cell carcinoma, liver cancer, and prostate cancer. However, the effect of miR-188-5p on GBC remains unclear. Here, we demonstrated that miR-188-5p was downregulated in GBC tissues, and downregulation of miR-188-5p correlated with larger tumor size, lymph node metastasis, and extensive metastasis. In addition, the overall survival time of patients with higher miR-188-5p expression was significantly longer than that of patients with low-miR-188-5p expression. Moreover, downregulation of miR-188-5p promoted the proliferation, migration, and invasion of GBC cells, while its overexpression inhibited cell invasion and induced cell apoptosis, and arrested GBC growth in vivo. Importantly, miR-188-5p-dependent tumorigenesis was correlated with Wnt/ß-catenin signaling and p-38/JNK signaling. In conclusion, miR-188-5p plays a direct role in GBC tumorigenesis. Our study suggests that miR-188-5p could serve as a novel diagnosis marker and therapeutic target in GBC.
Asunto(s)
Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/genética , MicroARNs/genética , Proteína Smad2/genética , Proteínas Wnt/genética , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Femenino , Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/cirugía , Glicoproteínas/metabolismo , Humanos , Metástasis Linfática , Masculino , Ratones , MicroARNs/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Transducción de Señal , Proteína Smad2/metabolismo , Análisis de Supervivencia , Carga Tumoral , Proteínas Wnt/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To investigate the effect of transplanted fetal liver epithelial progenitor (FLEP) cells on liver fibrosis in mice. METHODS: FLEP cells were isolated from embryonal day (ED) 14 BALB/c mice and transplanted into female syngenic BALB/c mice (n = 60). After partial hepatectomy (PH), diethylnitrosamine (DEN) was administered to induce liver fibrosis. Controls received FLEP cells and non-supplemented drinking water, the model group received DEN-spiked water, and the experimental group received FLEP cells and DEN. Mice were killed after 1, 2, and 3 mo, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), and laminin (LN) in serum, and hydroxyproline (Hyp) content in liver were assessed. Alpha-smooth muscle actin (alpha-SMA) of liver was tested by immunohistochemistry. Transplanted male mice FLEP cells were identified by immunocytochemistry for sry (sex determination region for Y chromosome) protein. RESULTS: Serum ALT, AST, HA, and LN were markedly reduced by transplanted FLEP cells. Liver Hyp content and alpha-SMA staining in mice receiving FLEP cells were lower than that of the model group, which was consistent with altered liver pathology. Transplanted cells proliferated and differentiated into hepatocytes and bile duct epithelial cells with 30%-50% repopulation in the liver fibrosis induced by DEN after 3 mo. CONCLUSION: Transplanted FLEP cells proliferate and differentiate into hepatocytes and bile duct epithelial cells with high repopulation capacity in the fiberized liver induced by DEN, which restores liver function and reduces liver fibrosis.
