RESUMO
Accumulating documents have revealed that microRNAs (miRNAs) play critical roles in the development and progression of tumors. MiR-429 has been reported to be involved in regulating various cellular processes. However, its biological role and underlying mechanism in hepatocellular carcinoma (HCC) still need to be further studied. The present study aimed to investigate the function of miR-429 in the progression of HCC. In terms of this paper, it was found that miR-429 was down-regulated in HCC tissues and cells. After being transfected with miR-429 mimics, miR-429 decreased the migratory capacity and reversed the EMT to MET in HCC cells. RAB23 was confirmed as a target of miR-429. Rescue assays further verified that the function of miR-429 in HCC cells was exerted through targeting RAB23. In general, it was concluded that the signal pathway miR-429/RAB23 might be a potential target for HCC treatment.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas rab de Ligação ao GTP/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Mimetismo Molecular , Transdução de Sinais , Transfecção , Regulação para Cima , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Based on the severity of liver fibrosis, low or high-risk profile of developing end-stage liver disease was present in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms inducing transition from mild to advanced NAFLD are still elusive. We performed a system-level study on fibrosing-NAFLD by weighted gene co-expression network analysis (WGCNA) to identify significant modules in the network, and followed by functional and pathway enrichment analyses. Moreover, hub genes in the module were analyzed by network feature selection. As a result, fourteen distinct gene modules were identified, and seven modules showed significant associations with the status of NAFLD. Module preservation analysis confirmed that these modules can also be found in diverse independent datasets. After network feature analysis, the magenta module demonstrated a remarkably correlation with NAFLD fibrosis. The top hub genes with high connectivity or gene significance in the module were ultimately determined, including LUM, THBS2, FBN1 and EFEMP1. These genes were further verified in clinical samples. Finally, the potential regulators of magenta module were characterized. These findings highlighted a module and affiliated genes as playing important roles in the regulation of fibrosis in NAFLD, which may point to potential targets for therapeutic interventions.
Assuntos
Redes Reguladoras de Genes , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Transcriptoma , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Biomarcadores/metabolismo , Biologia Computacional , Conjuntos de Dados como Assunto , Progressão da Doença , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrilina-1/genética , Fibrilina-1/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Lumicana/genética , Lumicana/metabolismo , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Trombospondinas/genética , Trombospondinas/metabolismoRESUMO
BACKGROUND/AIMS: Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase, and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (HCC) as well as underlying mechanisms remain unknown. METHODS: The IDH2 and matrix metalloproteinase 9 (MMP9) levels in the specimens from 24 HCC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels and MMP9 levels were modified in a human HCC cell line. The effects of IDH2 or MMP9 modulation on the expression of the other were analyzed. The effects of IDH2 on cell invasion were analyzed in a transwell cell invasion assay. The dependence of nuclear factor x03BA;B (NF-x03BA;B) signaling was examined using a specific inhibitor. RESULTS: The IDH2 levels significantly decreased in HCC, and were lower in HCC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP9 levels in HCC. HCC patients with Low IDH2 had lower 5-year survival. MMP9 levels did not regulate IDH2 levels, while IDH2 inhibited MMP9 levels in HCC cells, in a NF-x03BA;B signaling dependent manner, possibly through ix03BA;B, to suppress HCC cell invasion. CONCLUSIONS: Down regulation of IDH2 may promote HCC cell invasion via NF-x03BA;B-dependent increases in MMP9 activity. IDH2 may be a potential therapeutic target for HCC.