RESUMO
BACKGROUND: Lysyl oxidase (LOX) is frequently overexpressed in a variety of malignancies and involved in tumor invasion and metastasis. Furthermore, it has been shown that LOX is closely related to vascular endothelial growth factor (VEGF). AIMS: In this study, we aimed to investigate the exact role of LOX and the correlation between LOX and VEGF in hepatocellular carcinoma (HCC). METHODS: The expression levels of LOX in HCC tissue and adjacent noncancerous tissue were evaluated by quantitative reverse transcription polymerase chain reaction and immunohistochemical analysis. The effect of LOX knockdown on cell proliferation, migration, and invasion was investigated in vitro. The role of LOX in the regulation of VEGF was further characterized in HCC cells that had been treated with transforming growth factor beta (TGF-ß). RESULTS: Our study showed that LOX was up-regulated in HCC cell lines and tissue. HCC patients with elevated expression of LOX had relatively shorter disease-free survival and overall survival. Knockdown of LOX reduced the proliferation, migration, and invasion of HCC cells. Additionally, the expression level of LOX positively correlated with that of VEGF. After treatment with TGF-ß, the levels of LOX and VEGF were both up-regulated in a dose-dependent manner. In the cells treated with siRNA of LOX, levels of VEGF and phosphorylated p38 were significantly decreased and could not be up-regulated by TGF-ß. Inhibition of p38 MAPK signaling abrogated TGF-ß-mediated up-regulation of VGEF but did not affect LOX expression. CONCLUSIONS: LOX appears to be a predictor of less favorable outcomes and may regulate the expression of VEGF via p38 MAPK signaling.
Assuntos
Carcinoma Hepatocelular/mortalidade , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/mortalidade , Proteína-Lisina 6-Oxidase/genética , Fator A de Crescimento do Endotélio Vascular/genética , Idoso , Biópsia por Agulha , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos de Amostragem , Transdução de Sinais/genética , Estatísticas não Paramétricas , Análise de Sobrevida , Células Tumorais Cultivadas , Regulação para CimaRESUMO
microRNAs (miRNAs) are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC). miR-128-3p was recently reported to be deregulated in several types of cancer. However, the biological function and potential mechanisms of miR-128-3p in HCC remain unknown. In the present study, we found that miR-128-3p was frequently downregulated in HCC tissues and cell lines by qRT-PCR analysis. Moreover, functional assays showed that overexpression of miR-128-3p markedly suppressed HCC cell proliferation by inducing G1 phase cell arrest and migration. Mechanistically, miR-128-3p was confirmed to regulate PIK3R1 (p85α) expression thereby suppressing phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation using qRT-PCR and western blot analysis. Furthermore, correlation analysis and Kaplan-Meier estimates revealed an inverse correlation between miR-128-3p and p85α as well as a shorter disease-free survival (DFS) period after HCC resection in patients with low miR-128-3p expression. Hence, we conclude that miR-128-3p, which is frequently downregulated in HCC, inhibits HCC progression by regulating PIK3R1 and PI3K/AKT activation, and is a prognostic marker for HCC patients.
