Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma.

ABSTRACT

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.