Fig. 7.
Role of ubiquitin-specific peptidase 17 in the positive-feedback loop of the interaction between macrophages and lung cancer cells to promote tumor growth. a To investigate the effect of macrophages on the induction of ubiquitin-specific peptidase 17 (USP17) expression and tumor growth, C57BL/6 mice with or without injection of clodronate liposomes for macrophage depletion were subcutaneously inoculated with 5 × 105 of LLC cells stably transfected with control vector or LLC cells stably overexpressing USP17 following the illustrated schedule. b Tumor growth rates were monitored. c These mice were killed on day 42, USP17 and inflammatory gene expressions in tumors were analyzed by real-time quantitative PCR (RT-qPCR). d–f To investigate the effect of USP17 expression in tumor cells on tumor growth, C57BL/6 mice were inoculated with 1 × 105 control or USP17-overexpressing LLC cells and tumor growth rates were monitored (d). These mice were killed on day 42. USP17 and inflammatory gene expressions in tumors were analyzed by RT-qPCR (e). Stemness-associated gene expressions in tumors were analyzed by RT-qPCR (f). Bars, data represent mean ± standard deviation of three independent analysis, **P < 0.01 compared with LLC and control (b, d), and compared with the control group (c, e, f). g Illustration of the role of ubiquitin-specific peptidase 17 in the positive-feedback loop of the interaction between macrophages and lung cancer cells to promote tumor growth. In lung cancers, macrophages induce ubiquitin-specific peptidase 17 (USP17) expression in cancer cells. USP17 stabilizes and enhances NIK-, c-Rel-, and IRF5-mediated inflammation-associated and stemness-associated gene expressions by disrupting the TNFR-associated factor (TRAF) 2/TRAF3 complex. These effects further recruit macrophages into tumors, driving a positive-feedback interaction between macrophages and cancer cells to promote progression and malignancy of lung cancers