Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a long-term consequence of chronic inflammatory liver injury. Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products including lipopolysaccharide (LPS), which promotes hepatocarcinogenesis. Despite its clinical significance, the molecular mediator linking chronic inflammation with HCC development remains to be clarified. In this study, we explored the significant dual functions of active signal transducer and activator of transcription 3 (STAT3) in LPS-induced angiogenesis of HCC. The in vitro effects of active STAT3 in tumor cells and endothelial cells were assessed using angiogenesis assay, ELISA, confocal assay, flow cytometry and western blot. The in vivo role of active STAT3 was assessed in xenografts model in nude mice. Here we report a novel mechanism by which LPS/STAT3 signaling promotes the angiogenesis of HCC both in vitro and in vivo. STAT3 activated by LPS increases the production of vascular endothelial growth factor (VEGF) by tumor cells, which not only promotes the proliferation of HCC cells but also stimulates the migration and tubulogenesis of endothelial cells through STAT3 activation and hence promotes angiogenesis in HCC. Our findings not only provide a potential mechanism by which bacterial infection enhances HCC oncogenesis through promoting the angiogenesis in liver, but also suggest that targeting STAT3 might be an effective therapeutic strategy in HCC treatment considering the dual roles of STAT3 in angiogenesis.