Lysyl oxidase assists tumor-initiating cells to enhance angiogenesis in hepatocellular carcinoma

A highly tumorigenic and malignant sub-population of HCC containing tumor-initiating cells (TICs) are defined by high self-renewal and sphere formation ability. Lysyl oxidase (LOX) regulates various factors involved in extracellular matrix (ECM) maintenance, migration and angiogenesis. Certain reports have demonstrated the role of LOX in ECM crosslinking, however, the cancer-promoting effects of LOX in HCC remain unclear, and whether LOX has a role in the regulation of angiogenesis in HCC TICs has not been elucidated. In the current study, RNA sequencing using next-generation sequencing technology and bioinformatics analyses revealed that LOX gene expression was significantly upregulated in cell spheres. Sphere cells may form tumors with more vascular enrichment compared with tumors produced from adherent cells, as observed in a mouse xenograft model. LOX expression is correlated with increased vascular endothelial growth factor (VEGF) and platelet-derived growth factor, as demonstrated by analyses of The Cancer Genome Atlas and Gene Expression Omnibus databases. Conditioned media obtained from LOX-overexpressing tumor cells stimulated angiogenesis via secreted VEGF and enhanced the tube formation capacity of endothelial cells. Furthermore, these functional behaviors were blocked by the LOX inhibitor beta-aminopropionitrile. These findings provide novel mechanistic insight into the pivotal role of LOX in the regulation of TICs in HCC. Combination of LOX inhibitor with sorafenib is a potentially advantageous strategy for HCC therapy.