Protumoral TSP50 Regulates Macrophage Activities and Polarization via Production of TNF-α and IL-1β, and Activation of the NF-κB Signaling Pathway

Testes-specific protease 50 (TSP50) is abnormally overexpressed in many kinds of cancers and promotes cell proliferation and migration. However, whether TSP50 can influence the tumor microenvironment, especially the function of immune cells in the microenvironment, remains largely unknown. We demonstrated that exposure to the conditioned medium from TSP50-overexpressing cells, or co-culture with TSP50-overexpressing cells, enhanced the cytokine production and phagocytic activities of macrophages, and induced M2b polarization. Further investigation showed that production of TNF-α and IL-1β was strongly induced by TSP50 in TSP50-overexpressing cells. TSP50-induced TNF-α and IL-1β were main factors that mediated the effects of TSP50-overexpressing cells on macrophages. The NF-κB pathway could be activated in macrophages upon the treatment of conditioned medium of TSP50-overexpressing cells and its activation is necessary for the observed effects on macrophages. Taken together, our results suggested that oncogenic TSP50 expressed in cells could activate surrounding macrophages and induce M2b polarization, partly through inducing TNF-α/ IL-1β secretion and subsequent NF-κB pathway activation. This implies a potential mechanism by which oncogene TSP50 regulates tumor microenvironment to support tumor development.

睾丸特异性蛋白酶50（Testes-specific protease 50）在多种癌症中呈现异常高表达，并可促进细胞增殖与迁移。然而，TSP50是否能够调控肿瘤微环境，尤其是微环境中免疫细胞的功能，目前仍在很大程度上尚不明确。本研究证实，经TSP50过表达细胞的条件培养基处理，或与TSP50过表达细胞直接共培养，可增强巨噬细胞的细胞因子分泌能力与吞噬活性，并诱导其发生M2b极化。进一步研究发现，TSP50过表达细胞可显著诱导TNF-α与IL-1β的产生。TSP50诱导生成的TNF-α与IL-1β是介导TSP50过表达细胞对巨噬细胞发挥调控作用的关键因子。经TSP50过表达细胞条件培养基处理后，巨噬细胞内的NF-κB通路可被激活，且该通路的激活是上述巨噬细胞效应得以实现的必要条件。综上，本研究结果表明，细胞中表达的致癌性TSP50可激活周围巨噬细胞并诱导其发生M2b极化，这一过程部分通过诱导TNF-α与IL-1β的分泌，以及后续NF-κB通路的激活完成。该研究揭示了致癌基因TSP50通过调控肿瘤微环境以促进肿瘤发生发展的潜在分子机制。