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The cancer/testis antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling

Oncogene volume 36, pages 1476–1486 (2017)Cite this article

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Abstract

The biological function of MAGEC2, a cancer/testis antigen highly expressed in various cancers, remains largely unknown. Here we demonstrate that expression of MAGEC2 induces rounded morphology and amoeboid-like movement of tumor cells in vitro and promotes tumor metastasis in vivo. The pro-metastasis effect of MAGEC2 was mediated by signal transducer and activator of transcription 3 (STAT3) activation. Mechanistically, MAGEC2 interacts with STAT3 and inhibits the polyubiquitination and proteasomal degradation of STAT3 in the nucleus of tumor cells, resulting in accumulation of phosphorylated STAT3 and enhanced transcriptional activity. Notably, expression levels of MAGEC2 and phosphorylated STAT3 are positively correlated and both are associated with incidence of metastasis in human hepatocellular carcinoma. This study not only reveals a previously unappreciated role of MAGEC2 in promoting tumor metastasis, but also identifies a new molecular mechanism by which MAGEC2 sustains hyperactivation of STAT3 in the nucleus of tumor cells. Thus, MAGEC2 may represent a new antitumor metastasis target for treatment of cancer.

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References

  1. Chaffer CL, Weinberg RA . A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.

    Article  CAS  PubMed  Google Scholar 

  2. Valastyan S, Weinberg RA . Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sahai E, Marshall CJ . Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 2003; 5: 711–719.

    Article  CAS  PubMed  Google Scholar 

  4. Wyckoff JB, Pinner SE, Gschmeissner S, Condeelis JS, Sahai E . ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr Biol 2006; 16: 1515–1523.

    Article  CAS  PubMed  Google Scholar 

  5. Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, Pinner S et al. Rac activation and inactivation control plasticity of tumor cell movement. Cell 2008; 135: 510–523.

    Article  CAS  PubMed  Google Scholar 

  6. Liu YJ, Le Berre M, Lautenschlaeger F, Maiuri P, Callan-Jones A, Heuze M et al. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells. Cell 2015; 160: 659–672.

    Article  CAS  PubMed  Google Scholar 

  7. Sanz-Moreno V, Gaggioli C, Yeo M, Albrengues J, Wallberg F, Viros A et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 2011; 20: 229–245.

    Article  CAS  PubMed  Google Scholar 

  8. Pinner S, Sahai E . Imaging amoeboid cancer cell motility in vivo. J Microsc 2008; 231: 441–445.

    Article  CAS  PubMed  Google Scholar 

  9. Gadea G, de Toledo M, Anguille C, Roux P . Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J Cell Biol 2007; 178: 23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Devarajan E, Huang S . STAT3 as a central regulator of tumor metastases. Curr Mol Med 2009; 9: 626–633.

    Article  CAS  PubMed  Google Scholar 

  11. Jing N, Tweardy DJ . Targeting Stat3 in cancer therapy. Anticancer Drugs 2005; 16: 601–607.

    Article  CAS  PubMed  Google Scholar 

  12. Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F . Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol Cell Biol 1993; 13: 276–288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu H, Jove R . The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105.

    Article  CAS  PubMed  Google Scholar 

  14. Bromberg J . Stat proteins and oncogenesis. J Clin Invest 2002; 109: 1139–1142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C et al. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 2009; 1171: 59–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Johnston PA, Grandis JR . STAT3 signaling: anticancer strategies and challenges. Mol Interv 2011; 11: 18–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weon JL, Potts PR . The MAGE protein family and cancer. Curr Opin Cell Biol 2015; 37: 1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ . Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 2005; 5: 615–625.

    Article  CAS  PubMed  Google Scholar 

  19. Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S . An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 2001; 61: 5544–5551.

    CAS  PubMed  Google Scholar 

  20. Ayyoub M, Scarlata CM, Hamai A, Pignon P, Valmori D . Expression of MAGE-A3/6 in primary breast cancer is associated with hormone receptor negative status, high histologic grade, and poor survival. J Immunother 2014; 37: 73–76.

    Article  CAS  PubMed  Google Scholar 

  21. Yang F, Zhou X, Miao X, Zhang T, Hang X, Tie R et al. MAGEC2, an epithelial-mesenchymal transition inducer, is associated with breast cancer metastasis. Breast Cancer Res Treat 2014; 145: 23–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yin B, Zeng Y, Liu G, Wang X, Wang P, Song Y . MAGE-A3 is highly expressed in a cancer stem cell-like side population of bladder cancer cells. Int J Clin Exp Pathol 2014; 7: 2934–2941.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Curioni-Fontecedro A, Nuber N, Mihic-Probst D, Seifert B, Soldini D, Dummer R et al. Expression of MAGE-C1/CT7 and MAGE-C2/CT10 predicts lymph node metastasis in melanoma patients. PLoS One 2011; 6: e21418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. von Boehmer L, Keller L, Mortezavi A, Provenzano M, Sais G, Hermanns T et al. MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer. PLoS One 2011; 6: e21366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pankova K, Rosel D, Novotny M, Brabek J . The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell Mol Life Sci 2010; 67: 63–71.

    Article  CAS  PubMed  Google Scholar 

  26. Hao J, Song X, Wang J, Guo C, Li Y, Li B et al. Cancer-testis antigen MAGE-C2 binds Rbx1 and inhibits ubiquitin ligase-mediated turnover of cyclin E. Oncotarget 2015; 6: 42028–42039.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Doyle JM, Gao J, Wang J, Yang M, Potts PR . MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell 2010; 39: 963–974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tanaka T, Yamamoto Y, Muromoto R, Ikeda O, Sekine Y, Grusby MJ et al. PDLIM2 inhibits T helper 17 cell development and granulomatous inflammation through degradation of STAT3. Sci Signal 2011; 4: ra85.

    Article  PubMed  Google Scholar 

  29. Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N et al. The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun 2002; 297: 811–817.

    Article  CAS  PubMed  Google Scholar 

  30. Wang Y, Ning H, Ren F, Zhang Y, Rong Y, Su F et al. GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis. Mol Cell 2014; 53: 752–765.

    Article  CAS  PubMed  Google Scholar 

  31. Riener MO, Wild PJ, Soll C, Knuth A, Jin B, Jungbluth A et al. Frequent expression of the novel cancer testis antigen MAGE-C2/CT-10 in hepatocellular carcinoma. Int J Cancer 2009; 124: 352–357.

    Article  CAS  PubMed  Google Scholar 

  32. Li B, Qian XP, Pang XW, Zou WZ, Wang YP, Wu HY et al. HCA587 antigen expression in normal tissues and cancers: correlation with tumor differentiation in hepatocellular carcinoma. Lab Invest 2003; 83: 1185–1192.

    Article  CAS  PubMed  Google Scholar 

  33. Pabst C, Zustin J, Jacobsen F, Luetkens T, Kroger N, Schilling G et al. Expression and prognostic relevance of MAGE-C1/CT7 and MAGE-C2/CT10 in osteolytic lesions of patients with multiple myeloma. Exp Mol Pathol 2010; 89: 175–181.

    Article  CAS  PubMed  Google Scholar 

  34. Zhuang R, Zhu Y, Fang L, Liu XS, Tian Y, Chen LH et al. Generation of monoclonal antibodies to cancer/testis (CT) antigen CT10/MAGE-C2. Cancer Immun 2006; 6: 7.

    PubMed  Google Scholar 

  35. Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014; 14: 736–746.

    Article  CAS  PubMed  Google Scholar 

  36. Yu H, Kortylewski M, Pardoll D . Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7: 41–51.

    Article  CAS  PubMed  Google Scholar 

  37. Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 2003; 4: 540–545.

    Article  CAS  PubMed  Google Scholar 

  38. Lang R, Pauleau AL, Parganas E, Takahashi Y, Mages J, Ihle JN et al. SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol 2003; 4: 546–550.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang X, Guo A, Yu J, Possemato A, Chen Y, Zheng W et al. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci USA 2007; 104: 4060–4064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997; 278: 1803–1805.

    Article  CAS  PubMed  Google Scholar 

  41. Buettner R, Mora LB, Jove R . Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002; 8: 945–954.

    CAS  PubMed  Google Scholar 

  42. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001; 20: 2499–2513.

    Article  CAS  PubMed  Google Scholar 

  43. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007; 117: 3846–3856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 2001; 28: 29–35.

    CAS  PubMed  Google Scholar 

  45. Brantley EC, Nabors LB, Gillespie GY, Choi YH, Palmer CA, Harrison K et al. Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Clin Cancer Res 2008; 14: 4694–4704.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang Q, Raghunath PN, Xue L, Majewski M, Carpentieri DF, Odum N et al. Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J Immunol 2002; 168: 466–474.

    Article  CAS  PubMed  Google Scholar 

  47. Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou YH et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 2015; 160: 715–728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Su S, Minges JT, Grossman G, Blackwelder AJ, Mohler JL, Wilson EM . Proto-oncogene activity of melanoma antigen-A11 (MAGE-A11) regulates retinoblastoma-related p107 and E2F1 proteins. J Biol Chem 2013; 288: 24809–24824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Marcar L, Ihrig B, Hourihan J, Bray SE, Quinlan PR, Jordan LB et al. MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4. PLoS One 2015; 10: e0127713.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Yang B, O'Herrin SM, Wu J, Reagan-Shaw S, Ma Y, Bhat KM et al. MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res 2007; 67: 9954–9962.

    Article  CAS  PubMed  Google Scholar 

  51. Bhatia N, Xiao TZ, Rosenthal KA, Siddiqui IA, Thiyagarajan S, Smart B et al. MAGE-C2 promotes growth and tumorigenicity of melanoma cells, phosphorylation of KAP1, and DNA damage repair. J Invest Dermatol 2013; 133: 759–767.

    Article  CAS  PubMed  Google Scholar 

  52. Sahai E, Garcia-Medina R, Pouyssegur J, Vial E . Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility. J Cell Biol 2007; 176: 35–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R . Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC. Oncogene 2010; 29: 2441–2448.

    Article  CAS  PubMed  Google Scholar 

  54. Parri M, Taddei ML, Bianchini F, Calorini L, Chiarugi P . EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res 2009; 69: 2072–2081.

    Article  CAS  PubMed  Google Scholar 

  55. Elson-Schwab I, Lorentzen A, Marshall CJ . MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion. PLoS One 2010; 5: e13176.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Christoph DC, Kasper S, Gauler TC, Loesch C, Engelhard M, Theegarten D et al. BetaV-tubulin expression is associated with outcome following taxane-based chemotherapy in non-small cell lung cancer. Br J Cancer 2012; 107: 823–830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Drs Xinmin Cao (National University of Singapore), Zhijie Chang (Tsinghua University) and Ning Guo (Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences) for providing vectors. This work was supported by grants from National Natural Science Foundation of China (no. 81472645) and Beijing Natural Science Foundation (7142087).

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Authors and Affiliations

  1. Department of Immunology, Key Laboratory of Medical Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    X Song, J Hao, J Wang, C Guo, Y Wang, H Tang, X Qin, Y Li, Y Zhang & Y Yin

  2. Center of Medical and Health Analysis, Peking University Health Science Center, Beijing, China

    Q He

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Song, X., Hao, J., Wang, J. et al. The cancer/testis antigen MAGEC2 promotes amoeboid invasion of tumor cells by enhancing STAT3 signaling. Oncogene 36, 1476–1486 (2017). https://doi.org/10.1038/onc.2016.314

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