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IFNg-induced Irgm1 promotes tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy

Oncogene volume 34, pages 5363–5371 (2015)Cite this article

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Abstract

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.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

IFNg:

interferon gamma

Irgm1:

immunity-related GTPase member 1

Bif-1:

Bax-interacting factor 1.

References

  1. Ikeda H, Old LJ, Schreiber RD . The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002; 13: 95–109.

    Article  CAS  Google Scholar 

  2. Dighe AS, Richards E, Old LJ, Schreiber RD . Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN γ receptors. Immunity 1994; 1: 447–456.

    Article  CAS  Google Scholar 

  3. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ et al. Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998; 95: 7556–7561.

    Article  CAS  Google Scholar 

  4. Street SE, Trapani JA, MacGregor D, Smyth MJ . Suppression of lymphoma and epithelial malignancies effected by interferon γ. J Exp Med 2002; 196: 129–134.

    Article  CAS  Google Scholar 

  5. Street SE, Cretney E, Smyth MJ . Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis. Blood 2001; 97: 192–197.

    Article  CAS  Google Scholar 

  6. Boehm U, Klamp T, Groot M, Howard JC . Cellular responses to interferon-γ. Annu Rev Immunol 1997; 15: 749–795.

    Article  CAS  Google Scholar 

  7. Seliger B, Ruiz-Cabello F, Garrido F . IFN inducibility of major histocompatibility antigens in tumors. Adv Cancer Res 2008; 101: 249–276.

    Article  CAS  Google Scholar 

  8. Brown TJ, Lioubin MN, Marquardt H . Purification and characterization of cytostatic lymphokines produced by activated human T lymphocytes. Synergistic antiproliferative activity of transforming growth factor beta 1, interferon-gamma, and oncostatin M for human melanoma cells. J Immunol 1987; 139: 2977–2983.

    CAS  PubMed  Google Scholar 

  9. Taniguchi K, Petersson M, Höglund P, Kiessling R, Klein G, Kärre K . Interferon gamma induces lung colonization by intravenously inoculated B16 melanoma cells in parallel with enhanced expression of class I major histocompatibility complex antigens. Proc Natl Acad Sci USA 1987; 84: 3405–3409.

    Article  CAS  Google Scholar 

  10. He YF, Wang XH, Zhang GM, Chen HT, Zhang H, Feng ZH . Sustained low-level expression of interferon-gamma promotes tumor development: potential insights in tumor prevention and tumor immunotherapy. Cancer Immunol Immunother 2005; 54: 891–897.

    Article  CAS  Google Scholar 

  11. Zaidi MR, Davis S, Noonan FP, Graff-Cherry C, Hawley TS, Walker RL et al. Interferon-γ links ultraviolet radiation to melanomagenesis in mice. Nature 2011; 469: 548–553.

    Article  CAS  Google Scholar 

  12. Lollini PL, Bosco MC, Cavallo F, De Giovanni C, Giovarelli M, Landuzzi L et al. Inhibition of tumor growth and enhancement of metastasis after transfection of the gamma-interferon gene. Int J Cancer 1993; 55: 320–329.

    Article  CAS  Google Scholar 

  13. Bernabei P, Coccia EM, Rigamonti L, Bosticardo M, Forni G, Pestka S et al. Interferon-gamma receptor 2 expression as the deciding factor in human T, B, and myeloid cell proliferation or death. J Leukoc Biol 2001; 70: 950–960.

    CAS  PubMed  Google Scholar 

  14. Taylor GA, Jeffers M, Largaespada DA, Jenkins NA, Copeland NG, Woude GF . Identification of a novel GTPase, the inducibly expressed GTPase, that accumulates in response to interferon gamma. J Biol Chem 1996; 271: 20399–20405.

    Article  CAS  Google Scholar 

  15. Singh SB, Davis AS, Taylor GA, Deretic V . Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 2006; 8: 1438–1441.

    Article  Google Scholar 

  16. Tiwari S, Choi HP, Matsuzawa T, Pypaert M, MacMicking JD . Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) promotes immunity to mycobacteria. Nat Immunol 2009; 10: 907–917.

    Article  CAS  Google Scholar 

  17. Feng CG, Weksberg DC, Taylor GA, Sher A, Goodell MA . The p47 GTPase Lrg-47 (Irgm1) links host defense and hematopoietic stem cell proliferation. Cell Stem Cell 2008; 2: 83–89.

    Article  CAS  Google Scholar 

  18. Xia F, Li R, Wang C, Yang S, Tian L, Dong H et al. Irgm1 regulates oxidized LDL uptake by macrophage via actin-dependent receptor internalization during atherosclerosis. Sci Rep 2013; 3: 1867.

    Article  Google Scholar 

  19. Xu H, Wu ZY, Fang F, Guo L, Chen D, Chen JX et al. Genetic deficiency of Irgm1 (LRG-47) suppresses induction of experimental autoimmune encephalomyelitis by promoting apoptosis of activated CD4+ T cells. FASEB J 2010; 24: 1583–1592.

    Article  CAS  Google Scholar 

  20. He S, Wang C, Dong H, Xia F, Zhou H, Jiang X et al. Immune-related GTPase M (Irgm1) regulates neuronal autophagy in a mouse model of stroke. Autophagy 2012; 8: 1621–1627.

    Article  CAS  Google Scholar 

  21. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.

    Article  CAS  Google Scholar 

  22. Guo JY, Xia B, White E . Autophagy-mediated tumor promotion. Cell 2013; 155: 1216–1219.

    Article  CAS  Google Scholar 

  23. Altman BJ, Rathmell JC . Autophagy: not good OR bad, but good AND bad. Autophagy 2009; 5: 569–570.

    Article  Google Scholar 

  24. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2012; 8: 445–544.

    Article  CAS  Google Scholar 

  25. Takahashi Y, Karbowski M, Yamaguchi H, Kazi A, Wu J, Sebti S et al. Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis. Mol Cell Biol 2005; 25: 9369–9382.

    Article  CAS  Google Scholar 

  26. Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9: 1142–1151.

    Article  CAS  Google Scholar 

  27. Takahashi Y, Meyerkord CL, Wang HG . BARgaining membranes for autophagosome formation: regulation of autophagy and tumorigenesis by Bif-1/Endophilin B1. Autophagy 2008; 4: 121–124.

    Article  CAS  Google Scholar 

  28. Takahashi Y, Meyerkord CL, Wang HG . Bif-1/endophilin B1: candidate for crescent driving force in autophagy. Cell Death Differ 2009; 16: 947–955.

    Article  CAS  Google Scholar 

  29. Feng CG, Zheng L, Jankovic D, Báfica A, Cannons JL, Watford WT et al. The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-gamma-induced cell death. Nat Immunol 2008; 9: 1279–1287.

    Article  CAS  Google Scholar 

  30. Wang Y, Liu DP, Chen PP, Koeffler HP, Tong XJ, Xie D . Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. Cancer Res 2007; 67: 2535–2543.

    Article  CAS  Google Scholar 

  31. Yi Y, Wu H, Gao Q, He HW, Li YW, Cai XY et al. Interferon regulatory factor (IRF)-1 and IRF-2 are associated with prognosis and tumor invasion in HCC. Ann Surg Oncol 2013; 20: 267–276.

    Article  Google Scholar 

  32. Yin X, Cao L, Kang R, Yang M, Wang Z, Peng Y et al. UV irradiation resistance-associated gene suppresses apoptosis by interference with Bax activation. EMBO Rep 2011; 12: 727–734.

    Article  CAS  Google Scholar 

  33. Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 2006; 8: 688–699.

    Article  CAS  Google Scholar 

  34. Overwijk WW, Restifo NP . B16 as a mouse model for human melanoma. Curr Protoc Immunol 2001; Chapter 20: Unit 20.1.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Zhiheng Xu and Professor Hulun Li for project discussion and technical support. These studies were funded by the National Natural Science Foundation Projects (Nos. 81071949 and 31371080) and Heilongjiang Provincial Natural Science Foundation (D201004) to Dr Hongwei Xu and the National Natural Science Foundation Project (No. 81371320) to Dr Chaodong Wang.

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Author notes

  1. H Dong and L Tian: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University, Harbin, China

    H Dong, L Tian, C Pei, Y Fu, X Dong, F Xia, C Wang, W Li, X Guo, C Gu, B Li, H Ren & H Xu

  2. Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China

    H Dong & C Wang

  3. Neuroinflammation Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

    R Li

  4. Department of Hematology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China

    A Liu

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Correspondence to C Wang or H Xu.

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Dong, H., Tian, L., Li, R. et al. IFNg-induced Irgm1 promotes tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy. Oncogene 34, 5363–5371 (2015). https://doi.org/10.1038/onc.2014.459

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