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MicroRNA-21 regulates the sensitivity of diffuse large B-cell lymphoma cells to the CHOP chemotherapy regimen

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Abstract

Numerous studies have demonstrated that microRNA-21 (miR-21), as an oncogene, is involved in the occurrence of many types of tumor and the sensitivity of tumor cells to chemotherapeutic drugs. In the present study, we investigated whether miR-21 is involved in regulating the sensitivity of the diffuse large B-cell lymphoma (DLBCL) cell line CRL2631 to the cyclophosphamide, vincristine, Adriamycin, and prednisone (CHOP) chemotherapeutic regimen. Knockdown of miR-21 with antisense oligonucleotides significantly increased the cytotoxic effects of the CHOP regimen in CRL2631 cells. A luciferase reporter assay showed that PTEN is a target gene of miR-21 in CRL2631 cells, and subsequent experiments demonstrated that miR-21 impacts the PI3K/AKT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen. Furthermore, knockdown of NF-κB decreased miR-21 expression and sensitized CRL2631 cells to CHOP treatment. These results provide evidence that it may be possible to overcome microRNA-based DLBCL drug resistance.

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References

  1. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Müller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.

    Article  PubMed  CAS  Google Scholar 

  2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin lymphoma. N Engl J Med. 1993;328:1002–6.

    Article  PubMed  CAS  Google Scholar 

  3. Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002;8:68–74.

    Article  PubMed  CAS  Google Scholar 

  4. Wilson WH. Drug resistance in diffuse large B-cell lymphoma. Semin Hematol. 2006;43:230–9.

    Article  PubMed  CAS  Google Scholar 

  5. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.

    Article  PubMed  CAS  Google Scholar 

  6. Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell. 2005;122:6–7.

    Article  PubMed  CAS  Google Scholar 

  7. Blower PE, Chung JH, Verducci JS, Lin S, Park JK, Dai ZY, Liu CG, Schmittgen TD, Reinhold WC, Croce CM, Weinstein JN, Sadee W. MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther. 2008;7:1–9.

    Article  PubMed  CAS  Google Scholar 

  8. Krichevsky AM, Gabriely G. miR-21: a small multi-faceted RNA. J Cell Mol Med. 2009;13:39–53.

    Article  PubMed  CAS  Google Scholar 

  9. Maxwell SA, Li Z, Jaye D, Ballard S, Ferrell J, Fu H. 14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen. J Biol Chem. 2009;284:22379–89.

    Article  PubMed  CAS  Google Scholar 

  10. Maxwell SA, Cherry EM, Bayless KJ. Akt, 14-3-3ζ, and vimentin mediate a drug-resistant invasive phenotype in diffuse large B-cell lymphoma. Leuk Lymphoma. 2011;52:849–64.

    Article  PubMed  CAS  Google Scholar 

  11. Ageberg M, Rydström K, Lindén O, Linderoth J, Jerkeman M, Drott K. Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines. Exp Cell Res. 2011;317:1179–91.

    Article  PubMed  CAS  Google Scholar 

  12. Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005;33:e179.

    Article  PubMed  Google Scholar 

  13. Bai H, Xu R, Cao Z, Wei D, Wang C. Involvement of miR-21 in resistance to daunorubicin by regulating PTEN expression in the leukaemia K562 cell line. FEBS Lett. 2011;585:402–8.

    Article  PubMed  CAS  Google Scholar 

  14. Lawrie CH, Soneji S, Marafioti T, Cooper CD. MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer. 2007;121:1156–61.

    Article  PubMed  CAS  Google Scholar 

  15. Steelman LS, Navolanic PM, Sokolosky ML, Taylor JR, Lehmann BD, Chappell WH, Abrams SL, Wong EWT, Stadelman KM, Terrian DM, Leslie NR, Martelli AM, Stivala F, Libra M, Franklin RA, McCubrey JA. Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene. 2008;27:4086–95.

    Article  PubMed  CAS  Google Scholar 

  16. Mellinghoff IK, Cloughesy TF, Mischel PS. PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res. 2007;13:378–81.

    Article  PubMed  CAS  Google Scholar 

  17. Giovannetti E, Funel N, Peters GJ, Del Chiaro M, Erozenci LA, Vasile E, Leon LG, Pollina LE, Groen A, Falcone A, Danesi R, Campani D, Verheul HM, Boggi U. MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res. 2010;70:4528–38.

    Article  PubMed  CAS  Google Scholar 

  18. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029–33.

    Article  PubMed  CAS  Google Scholar 

  19. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065–70.

    Article  PubMed  CAS  Google Scholar 

  20. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.

    Article  PubMed  CAS  Google Scholar 

  21. Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010;467:86–90.

    Article  PubMed  CAS  Google Scholar 

  22. Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E. Hyaluronan–CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem. 2009;284:26533–46.

    Article  PubMed  CAS  Google Scholar 

  23. Shi L, Chen J, Yang J, Pan T, Zhang S, Wang Z. miR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res. 2010;1352:255–64.

    Article  PubMed  CAS  Google Scholar 

  24. Li Y, Li W, Yang Y, Lu Y, He C, Hu G, Liu H, Chen J, He J, Yu H. MicroRNA-21 targets LRRFIP1 and contributes to VM-26 resistance in glioblastoma multiforme. Brain Res. 2009;1286:13–8.

    Article  PubMed  CAS  Google Scholar 

  25. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27:2128–36.

    Article  PubMed  CAS  Google Scholar 

  26. Li T, Li D, Sha J, Sun P, Huang Y. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun. 2009;383:280–5.

    Article  PubMed  CAS  Google Scholar 

  27. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282:14328–36.

    Article  PubMed  CAS  Google Scholar 

  28. Meng F, Henson R, Lang M, Wehbe H, Maheshwari S, Mendell JT, Jiang J, Schmittgen TD, Patel T. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology. 2006;130:2113–29.

    Article  PubMed  CAS  Google Scholar 

  29. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647–58.

    Article  PubMed  CAS  Google Scholar 

  30. Fridberg M, Servin A, Anagnostaki L, Linderoth J, Berglund M, Söderberg O, Enblad G, Rosén A, Mustelin T, Jerkeman M, Persson JL, Wingren AG. Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN. Leuk Lymphoma. 2007;48:2221–32.

    Article  PubMed  CAS  Google Scholar 

  31. Wendel HG, Malina A, Zhao Z, Zender L, Kogan SC, Cordon-Cardo C, Pelletier J, Lowe SW. Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res. 2006;66:7639–46.

    Article  PubMed  CAS  Google Scholar 

  32. Vu C, Fruman DA. Target of rapamycin signaling in leukemia and lymphoma. Clin Cancer Res. 2010;16:5374–80.

    Article  PubMed  CAS  Google Scholar 

  33. Uddin S, Hussain AR, Siraj AK, Manogaran PS, Al-Jomah NA, Moorji A, Atizado V, Al-Dayel F, Belgaumi A, El-Solh H, Ezzat A, Bavi P, Al-Kuraya KS. Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood. 2006;108:4178–86.

    Article  PubMed  CAS  Google Scholar 

  34. Vega F, Medeiros LJ, Leventaki V, Atwell C, Cho-Vega JH, Tian L, Claret FX, Rassidakis GZ. Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res. 2006;66:6589–97.

    Article  PubMed  CAS  Google Scholar 

  35. Pavan A, Spina M, Canzonieri V, Sansonno S, Toffoli G, De Re V. Recent prognostic factors in diffuse large B-cell lymphoma indicate NF-kappaB pathway as a target for new therapeutic strategies. Leuk Lymphoma. 2008;49(11):2048–58. (review).

    Article  PubMed  CAS  Google Scholar 

  36. Mohammad Ramzi M, Al-Katib Ayad, Aboukameel Amro, Doerge Daniel R, Sarkar Fazlul, Kucuk Omer. Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Mol Cancer Ther. 2003;2:1361–8.

    PubMed  CAS  Google Scholar 

  37. Liu YY, Leboeuf C, Shi JY, Li JM, Wang L, Shen Y, Garcia JF, Shen ZX, Chen Z, Janin A, Chen SJ, Zhao WL. Rituximab plus CHOP (R-CHOP) overcomes PRDM1-associated resistance to chemotherapy in patients with diffuse large B-cell lymphoma. Blood. 2007;110(1):339–44.

    Article  PubMed  CAS  Google Scholar 

  38. Niu J, Shi Y, Tan G, Yang CH, Fan M, Pfeffer LM, Wu ZH. DNA damage induces NF-κB-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion. J Biol Chem. 2012;287(26):21783–95.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China grant (30600722) and Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital (061138).

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The authors declare that they have no conflict of interest.

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Correspondence to Rang Xu.

Additional information

H. Bai and J. Wei contributed equally to this work.

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Bai, H., Wei, J., Deng, C. et al. MicroRNA-21 regulates the sensitivity of diffuse large B-cell lymphoma cells to the CHOP chemotherapy regimen. Int J Hematol 97, 223–231 (2013). https://doi.org/10.1007/s12185-012-1256-x

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  • DOI: https://doi.org/10.1007/s12185-012-1256-x

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