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miR-155 drives oncogenesis by promoting and cooperating with mutations in the c-Kit oncogene

Oncogene volume 38, pages 2151–2161 (2019)Cite this article

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Abstract

MicroRNAs (miRNAs) have emerged as crucial players in the development and maintenance of disease. miR-155 is an inflammation-associated, oncogenic miRNA, frequently overexpressed in hematological malignancies and solid tumors. However, the mechanism of oncogenesis by miR-155 is not well characterized, and research has focused primarily on individual, direct targets, which does not recapitulate the complexities of cancer. Using a powerful, inducible transgenic mouse model that overexpresses miR-155 and develops miR-155-addicted hematological malignancy, we describe here a multi-step process of oncogenesis by miR-155, which involves cooperation between miR-155, its direct targets, and other oncogenes. miR-155 is known to target DNA-repair proteins, leading to a mutator phenotype, and we find that over 93% of tumors in our miR-155 overexpressing mice contain activating mutations in a single oncogene, c-Kit. Treating mice with dasatinib or imatinib, which target c-Kit, resulted in complete tumor regression, indicating that c-Kit activity is crucial in the oncogenic process. Interestingly, c-Kit expression is high when miR-155 is overexpressed, indicating further cooperation between miR-155 and c-Kit. Our findings support a multi-step model of oncogenesis by miR-155 in which miR-155 promotes both a mutator phenotype and a cellular environment particularly susceptible to mutations in a given oncogene.

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References

  1. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.

    Article  CAS  Google Scholar 

  2. Faraoni I, Antonetti FR, Cardone J, Bonmassar E. miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta. 2009;1792:497–505.

    Article  CAS  Google Scholar 

  3. Thai T, Calado D, Casola S, Ansel K, Xiao C, Xue Y. et al. Regulation of the Germinal Center Response by MicroRNA-155. Science. 2007;316:604–9.

    Article  CAS  Google Scholar 

  4. Fulci V, Chiaretti S, Goldoni M, Azzalin G, Carucci N, Tavolaro S, et al. Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood. 2007;109:4944–52.

    Article  CAS  Google Scholar 

  5. O’Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205:585–94.

    Article  Google Scholar 

  6. Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA. 2005;102:3627–32.

    Article  CAS  Google Scholar 

  7. Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.

    Article  CAS  Google Scholar 

  8. Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci Usa. 2006;103:7024–9.

    Article  CAS  Google Scholar 

  9. Babar IA, Cheng CJ, Booth CJ, Liang X, Weidhaas JB, Saltzman WM. et al. Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci. 2012;109:E1695–704.

    Article  CAS  Google Scholar 

  10. Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, Ralfkiaer E, et al. Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med. 2009;1:288–95.

    Article  CAS  Google Scholar 

  11. O’Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA. 2009;106:7113–8.

    Article  Google Scholar 

  12. Costinean S, Sandhu SK, Pedersen IM, Tili E, Trotta R, Perrotti D. et al. Src homology 2 domain – containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of E(mu) -MiR-155 transgenic mice. Blood. 2009;114:1374–82.

    Article  CAS  Google Scholar 

  13. Gironella M, Seux M, Xie M, Cano C, Tomasini R, Gommeaux J. et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA. 2007;104:1–6.

    Article  Google Scholar 

  14. Dorsett Y, McBride KM, Jankovic M, Gazumyan A, Thai T-H, Robbiani DF, et al. MicroRNA-155 Suppresses Activation-Induced Cytidine Deaminase-Mediated Myc-Igh Translocation. Immunity. 2008;28:630–8.

    Article  CAS  Google Scholar 

  15. Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell. 2000;100:57–70.

    Article  CAS  Google Scholar 

  16. Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, et al. Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci USA. 2010;107:6982–7.

    Article  CAS  Google Scholar 

  17. Tili E, Michaille J-J, Wernicke D, Alder H, Costinean S, Volinia S, et al. Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc Natl Acad Sci USA. 2011;108:4908–13.

    Article  CAS  Google Scholar 

  18. Czochor JR, Sulkowski P, Glazer PM. miR-155 Over-expression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-prone DSB Repair. Mol Cancer Res. 2016;14:363–73.

    Article  CAS  Google Scholar 

  19. Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012;92:1619–49.

    Article  CAS  Google Scholar 

  20. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.

    Article  CAS  Google Scholar 

  21. Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, et al. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem. 2004;279:31655–63.

    Article  CAS  Google Scholar 

  22. Ning Z, Li J, Arceci RJ. Signal transducer and activator of transcription 3 activation is required for Asp 816 mutant c-Kit – mediated cytokine-independent survival and proliferation in human leukemia cells. Blood. 2001;97:3559–68.

    Article  CAS  Google Scholar 

  23. Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66:473–81.

    Article  CAS  Google Scholar 

  24. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–32.

    CAS  PubMed  Google Scholar 

  25. Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C. et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 2015;518:107–10.

    Article  CAS  Google Scholar 

  26. Larizza L, Magnani I, Beghini A. The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. Leuk Lymphoma. 2005;46:247–55.

    Article  CAS  Google Scholar 

  27. Klimenko OV, Shtilman MI. Transfection of Kasumi-1 cells with a new type of polymer carriers loaded with miR-155 and antago-miR-155. Cancer Gene Ther. 2013;20:237–41.

    Article  CAS  Google Scholar 

  28. Wallace JA, Kagele DA, Eiring AM, Kim CN, Hu R, Runtsch MC. et al. miR-155 promotes FLT3-ITD— induced myeloproliferative disease through inhibition of the interferon response. Blood. 2017;129:3074–86.

    Article  CAS  Google Scholar 

  29. Vandenbark GR, Chen Y, Friday E, Pavlik K, Anthony B, deCastro C. et al. Complex regulation of human c-kit transcription by promoter repressors, activators, and specific myb elements. Cell Growth Differ.1996;7:1383–92.

    CAS  PubMed  Google Scholar 

  30. Ratajczak MZ, Perrotti D, Melotti P, Powzaniuk M, Calabretta B, Onodera K, et al. Myb and ets proteins are candidate regulators of c-kit expression in human hematopoietic cells. Blood. 1998;91:1934–46.

    CAS  PubMed  Google Scholar 

  31. Kosmider O, Denis N, Lacout C, Vainchenker W, Dubreuil P, Moreau-Gachelin F. Kit-activating mutations cooperate with Spi-1/PU.1 overexpression to promote tumorigenic progression during erythroleukemia in mice. Cancer Cell. 2005;8:467–78.

    Article  CAS  Google Scholar 

  32. Kastner P, Chan S. PU 1: A crucial and versatile player in hematop and leukemia. Int J Biochem Cell Bio. 2008;40(22):7

    Google Scholar 

  33. Kosmider O, Moreau-Gachelin F. From Mice to Human: The “Two-Hit Model” of Leukemogenesis. Cell Cycle. 2006;5:569–70.

    Article  CAS  Google Scholar 

  34. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci. 2010;107:21098–103.

    Article  CAS  Google Scholar 

  35. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–21.

    Article  CAS  Google Scholar 

  36. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G. et al. Patterns of somatic mutation in human cancer genomes. Nature. 1007;446:153–8.

    Article  Google Scholar 

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Acknowledgements

We wish to thank Bohyung Yoon and Eleni Anastasiadou for assistance with animal care and Jacob Witten for critical reading of the manuscript. The work was supported by the Ludwig Center at Harvard.

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Author notes

  1. Christopher J. Cheng

    Present address: Casebia Therapeutics, 610 Main Street, Cambridge, MA, 02139, USA

Authors and Affiliations

  1. HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02115, USA

    Lisa W. Witten & Frank J. Slack

  2. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, 06511, USA

    Christopher J. Cheng

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  1. Lisa W. Witten
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Correspondence to Frank J. Slack.

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Witten, L.W., Cheng, C.J. & Slack, F.J. miR-155 drives oncogenesis by promoting and cooperating with mutations in the c-Kit oncogene. Oncogene 38, 2151–2161 (2019). https://doi.org/10.1038/s41388-018-0571-y

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