Skip to main content
Log in

MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

MicroRNAs are single-stranded small non-coding RNA molecules which regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and play a role in tumor genesis and progression. MiR-106a is upregulated in several types of malignancies and provides a pro-tumorigenic effect. However, its role in glioma is largely unknown. Our findings demonstrate that the low expression of miR-106a in human glioma specimens is significantly correlated with high levels of E2F1 protein and high-grade glioma. Here, we present the first evidence that miR-106a provides a tumor-suppressive effect via suppressing proliferation of and inducing apoptosis in human glioma cells. We further show that E2F1 is a direct functional target of miR-106a, suggesting that the effect of miR-106a on the glioma suppressive effect may result from inhibition of E2F1 via post-transcriptional regulation. In addition, our results reveal that miR-106a can increase p53 expression via E2F1 inhibition, whereas the effect of miR-106a on the proliferation of glioma cells is independent of p53 status. Further investigations will focus on the therapeutic use of miR-106a-mediated antitumor effects in glioma.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Jansen M, Yip S, Louis DN (2010) Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol 9:717–726. doi:10.1016/S1474-4422(10)70105-8

    Article  PubMed  CAS  Google Scholar 

  2. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507. doi:10.1056/NEJMra0708126

    Article  PubMed  CAS  Google Scholar 

  3. Hadjipanayis CG, Van Meir EG (2009) Tumor initiating cells in malignant gliomas: biology and implications for therapy. J Mol Med 87:363–374. doi:10.1007/s00109-009-0440-9

    Article  PubMed  Google Scholar 

  4. Purow B, Schiff D (2009) Advances in the genetics of glioblastoma: are we reaching critical mass? Nat Rev Neurol 5:419–426. doi:10.1038/nrneurol.2009.96

    Article  PubMed  CAS  Google Scholar 

  5. Gu S, Jin L, Zhang F, Sarnow P, Kay MA (2009) Biological basis for restriction of microRNA targets to the 3′ untranslated region in mammalian mRNAs. Nat Struct Mol Biol 16:144–150. doi:10.1038/nsmb.1552

    Article  PubMed  CAS  Google Scholar 

  6. Suzuki HI, Miyazono K (2010) Dynamics of microRNA biogenesis: crosstalk between p53 network and microRNA processing pathway. J Mol Med 88:1085–1094. doi:10.1007/s00109-010-0650-1

    Article  PubMed  CAS  Google Scholar 

  7. Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389–402. doi:10.1038/nrc2867

    Article  PubMed  CAS  Google Scholar 

  8. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261. doi:10.1073/pnas.0510565103

    Article  PubMed  CAS  Google Scholar 

  9. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK et al (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425–436. doi:10.1001/jama.299.4.425

    Article  PubMed  CAS  Google Scholar 

  10. Zhou H, Guo JM, Lou YR, Zhang XJ, Zhong FD, Jiang Z, Cheng J, Xiao BX (2010) Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using microRNA as a marker. J Mol Med 88:709–717. doi::10.1007/s00109-010-0617-2

    Article  PubMed  CAS  Google Scholar 

  11. Polager S, Ginsberg D (2008) E2F—at the crossroads of life and death. Trends Cell Biol 18:528–535. doi:10.1016/j.tcb.2008.08.003

    Article  PubMed  CAS  Google Scholar 

  12. Polager S, Ginsberg D (2009) p53 and E2f: partners in life and death. Nat Rev Cancer 9:738–748. doi:10.1038/nrc2718

    Article  PubMed  CAS  Google Scholar 

  13. Alonso MM, Fueyo J, Shay JW, Aldape KD, Jiang H, Lee OH, Johnson DG, Xu J, Kondo Y, Kanzawa T et al (2005) Expression of transcription factor E2F1 and telomerase in glioblastomas: mechanistic linkage and prognostic significance. J Natl Cancer Inst 97:1589–1600. doi:10.1093/jnci/dji340

    Article  PubMed  CAS  Google Scholar 

  14. Alla V, Engelmann D, Niemetz A, Pahnke J, Schmidt A, Kunz M, Emmrich S, Steder M, Koczan D, Putzer BM (2010) E2F1 in melanoma progression and metastasis. J Natl Cancer Inst 102:127–133. doi:10.1093/jnci/djp458

    Article  PubMed  CAS  Google Scholar 

  15. Lee JS, Leem SH, Lee SY, Kim SC, Park ES, Kim SB, Kim SK, Kim YJ, Kim WJ, Chu IS (2010) Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors. J Clin Oncol 28:2660–2667. doi:10.1200/JCO.2009.25.0977

    Article  PubMed  CAS  Google Scholar 

  16. Zhi F, Chen X, Wang S, Xia X, Shi Y, Guan W, Shao N, Qu H, Yang C, Zhang Y, Wang Q et al (2010) The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma. Eur J Cancer 46:1640–1649. doi:10.1016/j.ejca.2010.02.003

    Article  PubMed  CAS  Google Scholar 

  17. Keck K, Volper EM, Spengler RM, Long DD, Chan CY, Ding Y, McCaffrey AP (2009) Rational design leads to more potent RNA interference against hepatitis B virus: factors effecting silencing efficiency. Mol Ther 17:538–547. doi:10.1038/mt.2008.273

    Article  PubMed  CAS  Google Scholar 

  18. Komata T, Kondo Y, Koga S, Ko SC, Chung LW, Kondo S (2000) Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53. Gene Ther 7:2071–2079. doi:10.1038/sj.gt.3301327

    Article  PubMed  CAS  Google Scholar 

  19. Luan S, Sun L, Huang F (2010) MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line U251. Arch Med Res 41:67–74. doi:10.1016/j.arcmed.2010.02.007

    Article  PubMed  CAS  Google Scholar 

  20. Iorio MV, Croce CM (2009) MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 27:5848–5856. doi:10.1200/JCO.2009.24.0317

    Article  PubMed  CAS  Google Scholar 

  21. Wang B, Hsu SH, Majumder S, Kutay H, Huang W, Jacob ST, Ghoshal K (2010) TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 29:1787–1797. doi:10.1038/onc.2009.468

    Article  PubMed  CAS  Google Scholar 

  22. Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, Taccioli C, Zanesi N, Alder H, Hagan JP et al (2008) MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA 105:12885–12890. doi:10.1073/pnas.0806202105

    Article  PubMed  CAS  Google Scholar 

  23. Nakajima G, Hayashi K, Xi Y, Kudo K, Uchida K, Takasaki K, Yamamoto M, Ju J (2006) Non-coding microRNAs hsa-let-7g and hsa-miR-181b are associated with chemoresponse to S-1 in colon cancer. CANCER GENOMICS PROTEOMICS 3:317–324

    PubMed  CAS  Google Scholar 

  24. Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, You Y (2008) hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res 1236:185–193. doi:10.1016/j.brainres.2008.07.085

    Article  PubMed  CAS  Google Scholar 

  25. Pekarsky Y, Santanam U, Cimmino A, Palamarchuk A, Efanov A, Maximov V, Volinia S, Alder H, Liu CG, Rassenti L et al (2006) Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res 66:11590–11593. doi:10.1158/0008-5472.CAN-06-3613

    Article  PubMed  CAS  Google Scholar 

  26. Pavicic W, Perkio E, Kaur S, Peltomaki P (2011) Altered methylation at microRNA-associated CPG islands in hereditary and sporadic carcinomas: MS-MLPAa-based approach. Mol Med

  27. Gao XN, Lin J, Li YH, Gao L, Wang XR, Wang W et al (2011) MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia. Oncogene

  28. Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1:222–231. doi:10.1038/35106065

    Article  PubMed  CAS  Google Scholar 

  29. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, Russell JL, Conti CJ, Johnson DG (1999) E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model. Mol Cell Biol 19:6408–6414

    PubMed  CAS  Google Scholar 

  30. Vilborg A, Wilhelm MT, Wiman KG (2010) Regulation of tumor suppressor p53 at the RNA level. J Mol Med 88:645–652. doi:10.1007/s00109-010-0609-2

    Article  PubMed  CAS  Google Scholar 

  31. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  PubMed  CAS  Google Scholar 

  32. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    Article  PubMed  CAS  Google Scholar 

  33. Harris LC, Remack JS, Houghton PJ, Brent TP (1996) Wild-type p53 suppresses transcription of the human O6-methylguanine-DNA methyltransferase gene. Cancer Res 56:2029–2032

    PubMed  CAS  Google Scholar 

  34. Natsume A, Ishii D, Wakabayashi T, Tsuno T, Hatano H, Mizuno M, Yoshida J (2005) IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. Cancer Res 65:7573–7579. doi:10.1158/0008-5472.CAN-05-0036

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Special Prophase Project of National Basic Research Program of China (2009cb526404 to ZS) and National Natural Science Foundations of China (30772239 and 30973078 to ZS).

Disclosure statement

The authors declare no conflict of interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shiguang Zhao.

Additional information

Guang Yang, Ruyou Zhang, and Xiaofeng Chen contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, G., Zhang, R., Chen, X. et al. MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status. J Mol Med 89, 1037–1050 (2011). https://doi.org/10.1007/s00109-011-0775-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-011-0775-x

Keywords

Navigation