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.
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References
Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.
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.
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.
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.
Sahai E. Mechanisms of cancer cell invasion. Curr Opin Genet Dev. 2005;15:87–96.
Ortensi B, Setti M, Osti D, Pelicci G. Cancer stem cell contribution to glioblastoma invasiveness. Stem Cell Res Ther. 2013;4:18.
Rao JS. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer. 2003;3:489–501.
Wu Y, Zhou BP. TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer. 2010;102:639–44.
Solinas G, Marchesi F, Garlanda C, Mantovani A, Allavena P. Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Rev. 2010;29:243–8.
Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.
Radisky ES, Radisky DC. Stromal induction of breast cancer: inflammation and invasion. Rev Endocr Metab Disord. 2007;8:279–87.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.
Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.
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.
Liu X, Rennard SI. MicroRNA and cytokines. Mol Cell Pharmacol. 2011;3:143–51.
Asirvatham AJ, Magner WJ, Tomasi TB. miRNA regulation of cytokine genes. Cytokine. 2009;45:58–69.
Anderson P. Post-transcriptional control of cytokine production. Nat Immunol. 2008;9:353–9.
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.
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.
Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27:1788–93.
Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10:704–14.
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.
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.
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.
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.
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.
Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.
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.
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.
Cheloufi S, Dos Santos CO, Chong MM, Hannon GJ. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature. 2010;465:584–9.
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.
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.
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.
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.
Zhang X, Graves P, Zeng Y. Overexpression of human Argonaute2 inhibits cell and tumor growth. Biochim Biophys Acta. 1830;2013:2553–61.
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.
Raisch J, Darfeuille-Michaud A, Nguyen HT. Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol. 2013;19:2985–96.
Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat Rev Immunol. 2010;10:24–35.
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.
Chi SW, Zang JB, Mele A, Darnell RB. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature. 2009;460:479–86.
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.
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.
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.
Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2010;17:193–9.
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.
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.
Alexander S, Friedl P. Cancer invasion and resistance: interconnected processes of disease progression and therapy failure. Trends Mol Med. 2012;18:13–26.
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.
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Kim, JK., Jin, X., Ham, S.W. et al. IRF7 promotes glioma cell invasion by inhibiting AGO2 expression. Tumor Biol. 36, 5561–5569 (2015). https://doi.org/10.1007/s13277-015-3226-4
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DOI: https://doi.org/10.1007/s13277-015-3226-4