Skip to main content

Advertisement

SpringerLink
Log in

MiR-181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Temozolomide (TMZ) is a promising chemotherapeutic agent to treat Glioblastoma multiforme (GBM). However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells’ resistance to TMZ are not fully understood. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. Recently, miRNAs have been discovered to play important roles in drug resistance. A previous study showed that miR-181b in involved in glioma tumorigenesis. Thus, it would be valuable to explore the functions and mechanisms of miR-181b in regulating GMB cells’ sensitivity to TMZ. In this study, quantitative real-time reverse transcription PCR (qRT-PCR) data indicated that miR-181b was significantly downregulated in recurrent GBM tissues compared with initial GBM tissues. We also found that miR-181b overexpression increased the chemo-sensitivity of GBM cells to TMZ and potentiated TMZ-induced apoptosis in vitro and in vivo. Moreover, we demonstrated that the epidermal growth factor receptor (EGFR) was a direct target of miR-181b: restoration of EGFR rescued the inhibitory effects of miR-181b and TMZ treatment. Taken together, our data support strongly an important role for miR-181b in conferring TMZ resistance by targeting EGFR expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Cloughesy TF, Cavenee WK, Mischel PS (2014) Glioblastoma: from molecular pathology to targeted treatment. Ann Rev Pathol 9:1–25. doi:10.1146/annurev-pathol-011110-130324

    Article  CAS  Google Scholar 

  2. Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A (2015) Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol 129:829–848. doi:10.1007/s00401-015-1432-1

    Article  CAS  PubMed  Google Scholar 

  3. Wen PY, Reardon DA (2016) Neuro-oncology in 2015: progress in glioma diagnosis, classification and treatment. Nat Rev Neurol 12:69–70. doi:10.1038/nrneurol.2015.242

    Article  CAS  PubMed  Google Scholar 

  4. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. Jama 310:1842–1850. doi:10.1001/jama.2013.280319

    Article  CAS  PubMed  Google Scholar 

  5. Messaoudi K, Clavreul A, Lagarce F (2015) Toward an effective strategy in glioblastoma treatment: part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today 20:899–905. doi:10.1016/j.drudis.2015.02.011

    Article  CAS  PubMed  Google Scholar 

  6. Fan CH, Liu WL, Cao H, Wen C, Chen L, Jiang G (2013) O6-methylguanine DNA methyltransferase as a promising target for the treatment of temozolomide-resistant gliomas. Cell Death Dis 4:e876. doi:10.1038/cddis.2013.388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710. doi:10.1101/gad.1596707

    Article  CAS  PubMed  Google Scholar 

  8. Stupp R, Hegi ME, Gilbert MR, Chakravarti A (2007) Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 25:4127–4136. doi:10.1200/JCO.2007.11.8554

    Article  CAS  PubMed  Google Scholar 

  9. Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193. doi:10.3322/caac.20069

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dancey JE, Freidlin B (2003) Targeting epidermal growth factor receptor–are we missing the mark? Lancet 362:62–64. doi:10.1016/S0140-6736(03)13810-X

    Article  CAS  PubMed  Google Scholar 

  11. Ohashi K, Maruvka YE, Michor F, Pao W (2013) Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 31:1070–1080. doi:10.1200/JCO.2012.43.3912

    Article  CAS  Google Scholar 

  12. Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6:32–43. doi:10.1038/nrm1548

    Article  CAS  PubMed  Google Scholar 

  13. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174. doi:10.1056/NEJMra0707704

    Article  CAS  PubMed  Google Scholar 

  14. Maire CL, Ligon KL (2014) Molecular pathologic diagnosis of epidermal growth factor receptor. Neuro-Oncol. doi:10.1093/neuonc/nou294

    Google Scholar 

  15. Huang PH, Xu AM, White FM (2009) Oncogenic EGFR signaling networks in glioma. Sci Signal. doi:10.1126/scisignal.287re6

    Google Scholar 

  16. Chong CR, Janne PA (2013) The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19:1389–1400. doi:10.1038/nm.3388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pao W, Chmielecki J (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10:760–774. doi:10.1038/nrc2947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wheeler DL, Dunn EF, Harari PM (2010) Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 7: 493–507. doi:10.1038/nrclinonc.2010.97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P (2014) Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis 5:e1145. doi:10.1038/cddis.2014.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hobbs J, Nikiforova MN, Fardo DW, Bortoluzzi S, Cieply K, Hamilton RL, Horbinski C (2012) Paradoxical relationship between the degree of EGFR amplification and outcome in glioblastomas. Am J Surg Pathol 36:1186–1193. doi:10.1097/PAS.0b013e3182518e12

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hammond SM (2015) An overview of microRNAs. Adv Drug Deliv Rev 87:3–14. doi:10.1016/j.addr.2015.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cheng G (2015) Circulating miRNAs: roles in cancer diagnosis, prognosis and therapy. Adv Drug Deliv Rev 81:75–93. doi:10.1016/j.addr.2014.09.001

    Article  CAS  PubMed  Google Scholar 

  23. Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12: 847–865. doi:10.1038/nrd4140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Squadrito ML, Etzrodt M, De Palma M, Pittet MJ (2013) MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol 34:350–359. doi:10.1016/j.it.2013.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A, Sun J, Lovat F, Alder H, Condorelli G, Engelman JA, Ono M, Rho JK, Cascione L, Volinia S, Nephew KP, Croce CM (2012) EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 18:74–82. doi:10.1038/nm.2577

    CAS  Google Scholar 

  26. De Cola A, Volpe S, Budani MC, Ferracin M, Lattanzio R, Turdo A, D’Agostino D, Capone E, Stassi G, Todaro M, Di Ilio C, Sala G, Piantelli M, Negrini M, Veronese A, De Laurenzi V (2015) miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance. Cell Death Dis 6: e1823. doi:10.1038/cddis.2015.192

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhou JY, Chen X, Zhao J, Bao Z, Chen X, Zhang P, Liu ZF, Zhou JY (2014) MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET. Cancer Lett 351:265–271. doi:10.1016/j.canlet.2014.06.010

    Article  CAS  PubMed  Google Scholar 

  28. Zhang KL, Zhou X, Han L, Chen LY, Chen LC, Shi ZD, Yang M, Ren Y, Yang JX, Frank TS, Zhang CB, Zhang JX, Pu PY, Zhang JN, Jiang T, Wagner EJ, Li M, Kang CS (2014) MicroRNA-566 activates EGFR signaling and its inhibition sensitizes glioblastoma cells to nimotuzumab. Mol Cancer 13:63. doi:10.1186/1476-4598-13-63

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shi ZM, Wang XF, Qian X, Tao T, Wang L, Chen QD, Wang XR, Cao L, Wang YY, Zhang JX, Jiang T, Kang CS, Jiang BH, Liu N, You YP (2013) MiRNA-181b suppresses IGF-1R and functions as a tumor suppressor gene in gliomas. Rna 19:552–560. doi:10.1261/rna.035972.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Detry JM (1993) Clinical features of an anti-anginal drug in angina pectoris. Eur Heart J 14(Suppl G): 18–24

    Article  PubMed  Google Scholar 

  31. Tatar Z, Thivat E, Planchat E, Gimbergues P, Gadea E, Abrial C, Durando X (2013) Temozolomide and unusual indications: review of literature. Cancer Treat Rev 39:125–135. doi:10.1016/j.ctrv.2012.06.002

    Article  CAS  PubMed  Google Scholar 

  32. Wang Z, Yang J, Xu G, Wang W, Liu C, Yang H, Yu Z, Lei Q, Xiao L, Xiong J, Zeng L, Xiang J, Ma J, Li G, Wu M (2015) Targeting miR-381-NEFL axis sensitizes glioblastoma cells to temozolomide by regulating stemness factors and multidrug resistance factors. Oncotarget 6:3147–3164. doi:10.18632/oncotarget.3061

    Article  PubMed  Google Scholar 

  33. Wang J, Sai K, Chen FR, Chen ZP (2013) miR-181b modulates glioma cell sensitivity to temozolomide by targeting MEK1. Cancer Chemother Pharmacol 72:147–158. doi:10.1007/s00280-013-2180-3

    Article  CAS  PubMed  Google Scholar 

  34. Zhi F, Wang Q, Deng D, Shao N, Wang R, Xue L, Wang S, Xia X, Yang Y (2014) MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma. PLoS ONE 9:e109124. doi:10.1371/journal.pone.0109124

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sun YC, Wang J, Guo CC, Sai K, Wang J, Chen FR, Yang QY, Chen YS, Wang J, To TS, Zhang ZP, Mu YG, Chen ZP (2014) MiR-181b sensitizes glioma cells to teniposide by targeting MDM2. BMC Cancer 14:611. doi:10.1186/1471-2407-14-611

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lu F, Zhang J, Ji M, Li P, Du Y, Wang H, Zang S, Ma D, Sun X, Ji C (2014) miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1. Int J Oncol 45:383–392. doi:10.3892/ijo.2014.2390

    CAS  PubMed  Google Scholar 

  37. Sezeur A, Leandri J, Rey P, Daumet P, Vouron J (1982) An experimental study of “slowly resorbed suture material” in the tracheal sutures (author’s transl). Ann Chir 36:121–125

    CAS  PubMed  Google Scholar 

  38. Ramalingam SS, Owonikoko TK, Khuri FR (2011) Lung cancer: New biological insights and recent therapeutic advances. CA Cancer J Clin 61:91–112. doi:10.3322/caac.20102

    Article  PubMed  Google Scholar 

  39. Nicholson S, Sainsbury JR, Halcrow P, Chambers P, Farndon JR, Harris AL (1989) Expression of epidermal growth factor receptors associated with lack of response to endocrine therapy in recurrent breast cancer. Lancet 1:182–185

    Article  CAS  PubMed  Google Scholar 

  40. Messersmith WA, Ahnen DJ (2008) Targeting EGFR in colorectal cancer. N Engl J Med 359:1834–1836. doi:10.1056/NEJMe0806778

    Article  CAS  PubMed  Google Scholar 

  41. Zhang KL, Han L, Chen LY, Shi ZD, Yang M, Ren Y, Chen LC, Zhang JX, Pu PY, Kang CS (2014) Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas. Cancer Lett 342:139–149. doi:10.1016/j.canlet.2013.08.043

    Article  CAS  PubMed  Google Scholar 

  42. Katakowski M, Zheng X, Jiang F, Rogers T, Szalad A, Chopp M (2010) MiR-146b-5p suppresses EGFR expression and reduces in vitro migration and invasion of glioma. Cancer Invest 28:1024–1030. doi:10.3109/07357907.2010.512596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the National Natural Science Foundation of China [Grant Nos. 81302184, 81302182, 81672501, 81472362, 81372709], and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou road, Nanjing, People’s Republic of China

      Yunxiang Chen, Rui Li, Zhumei Shi, Wei Yan, Ning Liu, Yongping You, Junxia Zhang & Xiefeng Wang

    2. Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou road, Nanjing, People’s Republic of China

      Minhong Pan

    Authors
    1. Yunxiang Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Rui Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Minhong Pan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Zhumei Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Wei Yan
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ning Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yongping You
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Junxia Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Xiefeng Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Junxia Zhang or Xiefeng Wang.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Ethical approval

    This study was approved by the Hospital Ethics Committee.

    Informed consent

    For the glioma tissues, written informed consent was obtained from all patients.

    Additional information

    Yunxiang Chen, Rui Li and Minhong Pan have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chen, Y., Li, R., Pan, M. et al. MiR-181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor. J Neurooncol 133, 477–485 (2017). https://doi.org/10.1007/s11060-017-2463-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11060-017-2463-3

    Keywords

    Search

    Navigation