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Tumor Biology

, Volume 36, Issue 7, pp 5561–5569 | Cite as

IRF7 promotes glioma cell invasion by inhibiting AGO2 expression

  • Jun-Kyum Kim
  • Xiong Jin
  • Seok Won Ham
  • Seon Yong Lee
  • Sunyoung Seo
  • Sung-Chan Kim
  • Sung-Hak KimEmail author
  • Hyunggee KimEmail author
Research Article

Abstract

Interferon regulatory factor 7 (IRF7) is the master transcription factor that plays a pivotal role in the transcriptional activation of type I interferon genes in the inflammatory response. Our previous study revealed that IRF7 is an important regulator of tumor progression via the expression of inflammatory cytokines in glioma. Here, we report that IRF7 promotes glioma invasion and confers resistance to both chemotherapy and radiotherapy by inhibiting expression of argonaute 2 (AGO2), a regulator of microRNA biogenesis. We found that IRF7 and AGO2 expression levels were negatively correlated in patients with glioblastoma multiforme. Ectopic IRF7 expression led to a reduction in AGO2 expression, while depletion of IRF7 resulted in increased AGO2 expression in the LN-229 glioma cell line. In an in vitro invasion assay, IRF7 overexpression enhanced glioma cell invasion. Furthermore, reconstitution of AGO2 expression in IRF7-overexpressing cells led to decreased cell invasion, whereas the reduced invasion due to IRF7 depletion was rescued by AGO2 depletion. In addition, IRF7 induced chemoresistance and radioresistance of glioma cells by diminishing AGO2 expression. Finally, AGO2 depletion alone was sufficient to accelerate glioma cell invasion in vitro and in vivo, indicating that AGO2 regulates cancer cell invasion. Taken together, our results indicate that IRF7 promotes glioma cell invasion and both chemoresistance and radioresistance through AGO2 inhibition.

Keywords

Glioblastoma IRF7 AGO2 Invasion Chemoresistance Radioresistance 

Notes

Acknowledgments

We would like to thank all members of the Cell Growth Regulation Laboratory for the helpful discussion and technical assistance. This work was supported by the National Nuclear Technology Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (no. 2013M2A2A7042530 to H. Kim) and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (no. 2011–0024089 to S.-H. Kim). S.W. Ham was supported by a Kwanjeong Educational Foundation Domestic Scholarship.

Conflicts of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.CrossRefPubMedGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefPubMedGoogle Scholar
  3. 3.
    Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavanee WK, et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001;15:1311–33.CrossRefPubMedGoogle Scholar
  4. 4.
    Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003;21:1624–36.CrossRefPubMedGoogle Scholar
  5. 5.
    Sahai E. Mechanisms of cancer cell invasion. Curr Opin Genet Dev. 2005;15:87–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Ortensi B, Setti M, Osti D, Pelicci G. Cancer stem cell contribution to glioblastoma invasiveness. Stem Cell Res Ther. 2013;4:18.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rao JS. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer. 2003;3:489–501.CrossRefPubMedGoogle Scholar
  8. 8.
    Wu Y, Zhou BP. TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer. 2010;102:639–44.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Solinas G, Marchesi F, Garlanda C, Mantovani A, Allavena P. Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Rev. 2010;29:243–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.CrossRefPubMedGoogle Scholar
  11. 11.
    Radisky ES, Radisky DC. Stromal induction of breast cancer: inflammation and invasion. Rev Endocr Metab Disord. 2007;8:279–87.CrossRefPubMedGoogle Scholar
  12. 12.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  15. 15.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu X, Rennard SI. MicroRNA and cytokines. Mol Cell Pharmacol. 2011;3:143–51.Google Scholar
  18. 18.
    Asirvatham AJ, Magner WJ, Tomasi TB. miRNA regulation of cytokine genes. Cytokine. 2009;45:58–69.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Anderson P. Post-transcriptional control of cytokine production. Nat Immunol. 2008;9:353–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Suzuki HI, Arase M, Matsuyama H, Choi YL, Ueno T, Mano H, et al. MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol Cell. 2011;44:424–36.CrossRefPubMedGoogle Scholar
  21. 21.
    Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50.CrossRefPubMedGoogle Scholar
  22. 22.
    Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27:1788–93.CrossRefPubMedGoogle Scholar
  23. 23.
    Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10:704–14.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, et al. A microRNA targeting dicer for metastasis control. Cell. 2010;141:1195–207.CrossRefPubMedGoogle Scholar
  26. 26.
    Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 2005;96:111–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Selever J, Gu G, Lewis MT, Beyer A, Herynk MH, Covington KR, et al. Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells. Clin Cancer Res. 2011;17:6510–21.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jin X, Kim SH, Jeon HM, Beck S, Sohn YW, Yin Y, et al. Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and notch signaling. Brain. 2012;135:1055–69.CrossRefPubMedGoogle Scholar
  29. 29.
    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.CrossRefPubMedGoogle Scholar
  30. 30.
    Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM, et al. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006;20:2202–7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004;305:1437–41.CrossRefPubMedGoogle Scholar
  32. 32.
    Cheloufi S, Dos Santos CO, Chong MM, Hannon GJ. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature. 2010;465:584–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cifuentes D, Xue H, Taylor DW, Patnode H, Mishima Y, Cheloufi S, et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science. 2010;328:1694–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kim MS, Oh JE, Kim YR, Park SW, Kang MR, Kim SS, et al. Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers. J Pathol. 2010;221:139–46.CrossRefPubMedGoogle Scholar
  35. 35.
    Völler D, Reinders J, Meister G, Bosserhoff AK. Strong reduction of AGO2 expression in melanoma and cellular consequences. Br J Cancer. 2013;109:3116–24.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hagiwara K, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Ochiya T. Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity. Sci Rep. 2012;2:314.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhang X, Graves P, Zeng Y. Overexpression of human Argonaute2 inhibits cell and tumor growth. Biochim Biophys Acta. 1830;2013:2553–61.Google Scholar
  38. 38.
    O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10:111–22.CrossRefPubMedGoogle Scholar
  39. 39.
    Raisch J, Darfeuille-Michaud A, Nguyen HT. Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol. 2013;19:2985–96.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat Rev Immunol. 2010;10:24–35.CrossRefPubMedGoogle Scholar
  41. 41.
    Wang D, Zhang Z, O’Loughlin E, Lee T, Houel S, O’Carroll D, et al. Quantitative functions of argonaute proteins in mammalian development. Genes Dev. 2012;26:693–704.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Chi SW, Zang JB, Mele A, Darnell RB. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature. 2009;460:479–86.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, et al. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol. 2010;52:698–704.CrossRefPubMedGoogle Scholar
  44. 44.
    Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102:13944–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Yu F, Deng H, Yao H, Liu Q, Su F, Song E. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene. 2010;29:4194–204.CrossRefPubMedGoogle Scholar
  46. 46.
    Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2010;17:193–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Kwon JE, Kim BY, Kwak SY, Bae IH, Han YH. Ionizing radiation-inducible microRNA miR-193a-3p induces apoptosis by directly targeting Mcl-1. Apoptosis. 2013;18:896–909.CrossRefPubMedGoogle Scholar
  48. 48.
    Saini S, Yamamura S, Majid S, Shahryari V, Hirata H, Tanaka Y, et al. MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. Cancer Res. 2011;71:6208–19.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Alexander S, Friedl P. Cancer invasion and resistance: interconnected processes of disease progression and therapy failure. Trends Mol Med. 2012;18:13–26.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jun-Kyum Kim
    • 1
    • 2
    • 3
  • Xiong Jin
    • 1
    • 2
    • 3
  • Seok Won Ham
    • 1
    • 2
  • Seon Yong Lee
    • 2
  • Sunyoung Seo
    • 2
  • Sung-Chan Kim
    • 5
  • Sung-Hak Kim
    • 2
    • 4
    Email author
  • Hyunggee Kim
    • 1
    • 2
    Email author
  1. 1.Department of Biotechnology, School of Life Sciences and BiotechnologyKorea UniversitySeoulRepublic of Korea
  2. 2.Cell Growth Regulation Laboratory, College of Life Sciences and BiotechnologyKorea UniversitySeoulRepublic of Korea
  3. 3.Institute of Animal Molecular BiotechnologyKorea UniversitySeoulRepublic of Korea
  4. 4.Department of Neurological Surgery, James Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA
  5. 5.Department of Biochemistry, College of MedicineHallym UniversityChuncheonRepublic of Korea

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