| Summary: | 碩士 === 國立成功大學 === 微生物及免疫學研究所 === 103 === Tumor-associated macrophages (TAM) are considered to be a major cell population in the tumor microenvironment and can be differentiated into M2 phenotype supporting tumor existence. However, the switching mechanisms of polarized TAM by tumor cells are yet to be determined. We previously showed that unknown factors in the hepatoma microenvironment trigger Toll like receptor 2 (TLR2) signaling to induce the degradation of NF-κB p65 via ERK1/2 activation and autophagy promoting the polarization of M2 macrophages. The underlying mechanism is yet to be determined. In this study we found hepatoma conditioned medium stimulates reactive oxygen species (ROS) to trigger ERK1/2 activation, autophagy-mediated NF-κB degradation and M2 macrophage polarization. This ROS-mediated NF-κB p65 degradation was attenuated in NADPH oxidase 2 (NOX2)-deficient cells. In addition, TLR2 signaling was found to be involved in NOX2-regulated M2 macrophage polarization. An endogenous TLR2 ligand, high-mobility group protein B1 (HMGB1), was found to be secreted by hepatoma cells. HMGB1 suppression by RNA-silencing or neutralizing antibody reduces ROS generation, ERK1/2 activation, autophagy-mediated NF-κB p65 degradation and M2 macrophage polarization. Our findings suggest that soluble HMGB1 can trigger TLR2 -dependent autophagy-mediated NF-κB p65 degradation and M2 macrophage polarization. Furthermore, we demonstrated that HMGB1 regulates tumor nodule formation and M2 macrophage recruitment in an in situ mice hepatoma model. In conclusion, we found a novel function of HMGB1 to regulate-TLR2/NOX2 dependent M2 polarization and TAM recruitment in hepatoma.
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