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Ifng-Induced Irgm1 Promotes Tumorigenesis of Melanoma Via Dual Regulation of Apoptosis and Bif-1-Dependent Autophagy

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Ifng-Induced Irgm1 Promotes Tumorigenesis of Melanoma Via Dual Regulation of Apoptosis and Bif-1-Dependent Autophagy Oncogene (2015) 34, 5363–5371 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE IFNg-induced Irgm1 promotes tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy H Dong1,2,5, L Tian1,5,RLi3,CPei1,YFu1, X Dong1, F Xia1, C Wang1,WLi1, X Guo1,CGu1,BLi1, A Liu4, H Ren1, C Wang2 and H Xu1 Interferon gamma (IFNg) has been known as the regulator for both tumor immune surveillance and tumorgenesis. However, mechanisms underlying the resistance of tumor cell to IFNg have yet been fully understood. In the current study, we showed that immunity-related GTPase family member 1 (mouse: Irgm1; human: IRGM) is essential for IFNg-mediated regulation of tumor cell growth in melanoma. IRGM/Irgm1 was highly expressed in human and mouse melanoma. IFNg and starvation synergistically induced Irgm1 expression in melanoma B16 cells. In vivo, injection of Irgm1-siRNA-treated cells significantly reduced the number of tumor nodules and prolonged the mice survival. In vitro, knockdown endogenous or IFNg-induced Irgm1 significantly decreases the proliferation and increases apoptosis of B16 cells. In addition, suppressing Irgm1 decreased the IFNg/starvation-induced autophagy, while overexpressing Irgm1 significantly increased autophagy and rescued starvation-challenged cells. Moreover, IFNg and starvation-induced the co-localization of Irgm1 with Bax-interacting factor 1 (Bif-1). Knockdown of Bif-1 decreased Irgm1-mediated tumor cell autophagy. Taken together, these data reveal an Irgm1-dependent mechanism that promotes the tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy. Oncogene (2015) 34, 5363–5371; doi:10.1038/onc.2014.459; published online 26 January 2015 INTRODUCTION apoptosis and Bax-interacting factor 1 (Bif-1)–dependent Interferon gamma (IFNg) has long been known as an important autophagy. cytokine regulating tumor immune surveillance.1–5 IFNg enhances the proliferation and differentiation of immune cell subsets with RESULTS antitumor capacity, increases major histocompatibility complex-I expression and antigen presentation or directly induces tumor cell IRGM/Irgm1 was overexpressed in human and mouse melanoma – apoptosis.6 8 However, evidences also emerged that IFNg We first characterized the expression of IRGM and Irgm1 in human facilitates the genesis and growth of multiple tumors, such as and mouse melanoma, respectively. Using immunohistochemistry ultraviolet (UV)-induced melanoma.9–13 Studies have shown that staining, we found that IRGM was highly expressed in human IFNg regulates the escape of tumors from immune surveillance melanoma, mainly in the S100-positive cells (Figure 1a). Similarly, through decreasing their responsiveness to NK cells12 or inducing the Irgm1 expression was significantly increased in the tumor tissue of apoptosis of effector immune cells.13 It has also been demonstrated the B16/F10 cell-induced mouse model of melanoma in the that IFNg can promote tumor growth through improving tumor cell lung at both mRNA (Figure 1b) and protein (Figure 1c) level. survival. However, the downstream mechanisms of IFNg-mediated Interestingly, its expression was much higher in the center of the regulation of tumorigenesis remain poorly understood. tumor node than in the peripheral (Figure 1d). These results Here we showed that immunity-related GTPase family member indicated that Irgm1 may be involved in regulating melanoma cell 1 (Irgm1 for mouse and IRGM for human), an IFN-inducible growth under stress or hypoxia condition. molecule, is essential for IFNg-mediated regulation of tumor cell survival and tumorigenesis of melanoma. Mouse Irgm1 has IFNg and starvation synergistically induce Irgm1 expression in been implicated in a wide variety of biological functions, including melanoma B16 cells host resistance to infections by intracellular pathogen, stem cell As previous work has shown that Irgm1 is an IFNg-inducible 14–18 development and atherosclerosis. We have also demon- molecule, we next tested whether Irgm1 is also regulated by strated that Irgm1 can inhibit IFNg-induced T-cell and neuronal IFNg in melanoma cells. We treated B16 cell with different doses cell death.19,20 In the current study, we found that Irgm1 is of IFNg. We found that IFNg strongly induced Irgm1 expression in highly expressed in melanoma and enriched in the center of the B16 cells in a dose-dependent manner (Figures 2a–c). In addition, tumor nodule. In vitro study suggested that Irgm1 can be induced the enrichment of Irgm1-expressing cells in the center of the by IFNg and starvation in melanoma cells (B16), which, in turn, tumor node, where tumor cells are less nourished, suggested that regulates the survival of B16 cells via a dual regulation of starvation may enhance Irgm1 expression in these cells. To test 1Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Harbin, China; 2Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China; 3Neuroinflammation Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada and 4Department of Hematology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China. Correspondence: Professor H Xu, Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, 157# Baojian Road, NanGang District, Harbin, Heilongjiang 150086, China or Professor C Wang, Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian 365000, China. E-mail: [email protected] or [email protected] 5These authors contributed equally to this work. Received 20 November 2014; accepted 28 November 2014; published online 26 January 2015 Irgm1 in tumorigenesis H Dong et al 5364 Non-immune IgG S100 Anti-IRGM 3.0 1.20 * Vehicle B16/F10 2.5 1.00 ** 2.0 0.80 Irgm1 1.5 0.60 1.0 0.40 0.5 ACTB IRGM1/ ACTB 0.20 folds changed of Irgm1 0.0 0.00 Vehicle B16/F10 Vehicle B16/F10 S100Irgm1 DAPI Merge Vehicle B16/F10 Figure 1. IRGM/Irgm1 is highly expressed in human and mouse melanoma. (a) Formalin-fixed and paraffin-embedded human melanoma biopsy samples were stained with either control non-immune IgG or melanoma maker S100 or anti-IRGM Ab. (b–d) C57BL/6 mice (5/group) were injected with either B16/F10 cells or PBS (vehicle) and killed at day 21. Tumor Irgm1 expression was detected by real-time PCR (b), western blotting (c) and immunofluorescence staining (d). *Po0.05, **Po0.01. this, we treated B16 cells either by serum deprivation (starvation) measured by Cell Counting Kit-8 (CCK8) assay (Figure 3d, alone or together with IFNg stimulation. The results showed that, Supplementary Figure S1a). Interestingly, knockdown of Irgm1 although starvation alone cannot induce Irgm1 expression, it also enhance the growth inhibition effect of IFNg (Figure 3d). synergistically increased Irgm1 expression with the co-stimulation Moreover, depletion of Irgm1 strongly enhanced the apoptosis of by IFNg (Figure 2c). These data indicated that the expression of B16 cells in both normal and ‘IFNg+starvation’ condition, as Irgm1 in tumor can be regulated by IFNg and starvation. measured by TUNEL (terminal deoxinucleotidyltransferase- mediated dUTP-biotin nick end-labeling) staining (Figure 3e) and Irgm1 inhibits the apoptosis of B16 cells and promotes growth flow cytometry analysis (Annexin V and propidium iodide (PI) of B16 cell-induced melanoma staining) (Supplementary Figure S1b). In addition, western blotting Next, we asked whether Irgm1 was involved in regulating showed that the apoptosis of Irgm1-suppressed B16 cells was melanoma tumor growth. We knocked down Irgm1 in B16 cells associated with activation of Caspase-3, Bak/Bax and Fox3a using small interfering RNA (siRNA)-targeting Irgm1 (Figure 3a) (Supplementary Figure S1c). These results suggested that Irgm1 and transvenous injected these cells into C57/B6 mice. Compared is required for the survival of B16 cells and resistance of IFNg- and with control-siRNA group, Irgm1 siRNA-treated cells reduced the starvation-induced cell death, which are consistent with our o and others’ findings that Irgm1 inhibits IFNg-induced T-cell and tumor burden (80.2 ± 12.5 vs 21.3 ± 7.6 tumor nodules; P 0.01) 19,20 (Figure 3b) and prolonged the survival time of B16-induced neuronal cell death. melanoma mice (Figure 3c). To figure out the mechanisms of Irgm1-dependent growth of tumor cells, we examined cell Irgm1 promotes B16 cell survival through autophagy proliferation and apoptosis in vitro. The result showed that Studies have shown that Irgm1 is also actively involved in knocking down Irgm1 significantly decreased B16 cell proliferation regulating cell autophagy.15,16,20 Autophagy has a pivotal Oncogene (2015) 5363 – 5371 © 2015 Macmillan Publishers Limited Irgm1 in tumorigenesis H Dong et al 5365 a b Irgm1 DAPI Merge *** 60 *** 50 *** ** 40 - IFNg 30 20 10 Fold changed of Irgm1 0 +IFNg 0 ng 0.1ng 1ng 10ng c 50 *** * IFNg --++ 40 ns Starvation -+-+ 30 20 Irgm1 Irgm1/ ACTB 10 ACTB 0 Nil Starvation IFNg IFNg+Starv. Figure 2. IFNg and starvation synergistically induce Irgm1 expression in B16 cells. B16 cells were treated with IFNg at different concentrations (0.1–10 ng/ml) for 48 h. Irgm1 expression was detected by real-time PCR (a) and immunofluorescence staining (b). B16 cells were treated with IFNg (1 ng/ml) for 24 h and cultured in either complete or nutrient-deprived
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