Skip to main content
Springer Nature Link
Log in

mRNA stability alterations mediated by HuR are necessary to sustain the fast growth of glioma cells

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Regulation of mRNA decay is an important mechanism controlling gene expression. Steady state levels of mRNAs can be markedly altered by changes in the decay rate. The control of mRNA stability depends on sequences in the transcript itself and on RNA-binding proteins that dynamically bind to these sequences. A well characterized sequence motif, which has been shown to be present in many short-lived mRNAs, is the de-stabilizing adenylate/uridylate-rich element (ARE) located at the 3′ untranslated region (3′UTR) of mRNAs. HuR is an RNA-binding protein, which binds to AREs and in doing so, increases the half-life and steady state levels of the corresponding mRNA. Using tissue microarray technology, we found that HuR is over-expressed in human gliomas. We also found that there is a change in HuR localization from being solely in the nucleus to being expressed at high levels in the cytosol. Moreover, a positive correlation was found between total HuR levels, cytosolic localization and tumor grade. We also studied the decay rate of several HuR target mRNAs and found that these mRNAs have a slower rate of decay in glioma cell lines than in astrocytes. Finally, we have been able to decrease both the stability and steady state level of these transcripts in glioma cells using an RNA decoy. More importantly, the decoy transfected cells and cells exposed to a HuR inhibitor have reduced cell growth. In addition, pharmacological inhibition of HuR also resulted in glioma cell growth inhibition. In conclusion, our data suggest that post-transcriptional control abnormalities mediated by HuR are necessary to sustain the rapid growth of this devastating type of cancer.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Legler JM, Gloeckler Ries LA, Smith MA et al (1999) Brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst 91:1382–1390

    Article  PubMed  CAS  Google Scholar 

  2. Wrensch M, Minn Y, Chew T et al (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 4:278–299

    PubMed  Google Scholar 

  3. Rich JN, Bigner DD (2004) Development of novel targeted therapies in the treatment of malignant glioma. Nat Rev Drug Discov 3:430–446

    Article  PubMed  CAS  Google Scholar 

  4. Holland EC (2000) Glioblastoma multiforme: the terminator. Proc Natl Acad Sci USA 97:6242–6244

    Article  PubMed  CAS  Google Scholar 

  5. Moore MJ (2005) From birth to death: the complex lives of eukaryotic mRNAs. Science 309:1514–1518

    Article  PubMed  CAS  Google Scholar 

  6. Wilusz CJ, Wormington M, Peltz SW (2001) The cap-to-tail guide to mRNA turnover. Nat Rev Mol Cell Biol 2:237–246

    Article  PubMed  CAS  Google Scholar 

  7. Perrone-Bizzozero N, Bolognani F (2002) Role of HuD and other RNA-binding proteins in neural development and plasticity. J Neurosci Res 68:121–126

    Article  PubMed  CAS  Google Scholar 

  8. Bolognani F, Perrone-Bizzozero NI (2008) RNA-protein interactions and control of mRNA stability in neurons. J Neurosci Res 86:481–489

    Article  PubMed  CAS  Google Scholar 

  9. Ross J (1995) mRNA stability in mammalian cells. Microbiol Rev 59:423–450

    PubMed  CAS  Google Scholar 

  10. Chen CY, Shyu AB (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20:465–470

    Article  PubMed  CAS  Google Scholar 

  11. Hinman MN, Lou H (2008) Diverse molecular functions of Hu proteins. Cell Mol Life Sci 65:3168–3181

    Article  PubMed  CAS  Google Scholar 

  12. Wang W, Fan J, Yang X et al (2002) AMP-activated kinase regulates cytoplasmic HuR. Mol Cell Biol 22:3425–3436

    Article  PubMed  CAS  Google Scholar 

  13. Peng SS, Chen CY, Xu N, Shyu AB (1998) RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J 17:3461–3470

    Article  PubMed  CAS  Google Scholar 

  14. Keene JD (2001) Ribonucleoprotein infrastructure regulating the flow of genetic information between the genome and the proteome. Proc Natl Acad Sci USA 98:7018–7024

    Article  PubMed  CAS  Google Scholar 

  15. Dalmau J, Furneaux HM, Gralla RJ, Kris MG, Posner JB (1990) Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer—a quantitative western blot analysis. Ann Neurol 27:544–552

    Article  PubMed  CAS  Google Scholar 

  16. Nabors LB, Gillespie GY, Harkins L, King PH (2001) HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res 61:2154–2161

    PubMed  CAS  Google Scholar 

  17. López de Silanes I, Fan J, Yang X et al (2003) Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene 22:7146–7154

    Article  PubMed  Google Scholar 

  18. Erkinheimo TL, Lassus H, Sivula A et al (2003) Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res 63:7591–7594

    PubMed  CAS  Google Scholar 

  19. Denkert C, Weichert W, Pest S et al (2004) Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression. Cancer Res 64:189–195

    Article  PubMed  CAS  Google Scholar 

  20. Denkert C, Weichert W, Winzer KJ et al (2004) Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma. Clin Cancer Res 10:5580–5586

    Article  PubMed  CAS  Google Scholar 

  21. Heinonen M, Bono P, Narko K et al (2005) Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res 65:2157–2161

    Article  PubMed  CAS  Google Scholar 

  22. Heinonen M, Fagerholm R, Aaltonen K et al (2007) Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res 13:6959–6963

    Article  PubMed  CAS  Google Scholar 

  23. Mrena J, Wiksten JP, Thiel A et al (2005) Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 11:7362–7368

    Article  PubMed  CAS  Google Scholar 

  24. Denkert C, Koch I, von Keyserlingk N et al (2006) Expression of the ELAV-like protein HuR in human colon cancer: association with tumor stage and cyclooxygenase-2. Mod Pathol 19:1261–1269

    Article  PubMed  CAS  Google Scholar 

  25. Koljonen V, Böhling T, Haglund C, Ristimäki A (2008) Expression of HuR in Merkel cell carcinoma and in normal skin. J Cutan Pathol 35:10–14

    PubMed  Google Scholar 

  26. Niesporek S, Kristiansen G, Thoma A et al (2008) Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse an linked to COX-2 expression. Int J Oncol 32:341–347

    PubMed  CAS  Google Scholar 

  27. Sakuma T, Nakagawa T, Ido K, Takeuchi H, Sato K, Kubota T (2008) Expression of vascular endothelial growth factor-A and mRNA stability factor HuR in human meningiomas. J Neurooncol 88:143–155

    Article  PubMed  CAS  Google Scholar 

  28. Wang H, Wang H, Zhang W, Fuller GN (2006) Overexpression of IGFBP5, but not IGFBP3, correlates with the histologic grade of human diffuse glioma: a tissue microarray and immunohistochemical study. Technol Cancer Res Treat 5:195–199

    PubMed  CAS  Google Scholar 

  29. Lehr HA, Mankoff DA, Corwin D, Santeusanio G, Gown A (1997) Application of Photoshop-based image analysis to quantification of hormone receptor expression in breast cancer. J Histochem Cytochem 45:1559–1565

    Article  PubMed  CAS  Google Scholar 

  30. Meisner N-C, Hintersteiner M, Mueller K et al (2007) Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR. Nat Chem Biol 3:508–515

    Article  PubMed  CAS  Google Scholar 

  31. Mazroui R, Di Marco S, Clair E, von Roretz C, Tenenbaum SA, Keene JD, Saleh M, Gallouzi IE (2008) Caspase-mediated cleavage of HuR in the cytoplasm contributes to pp32/PHAP-I regulation of apoptosis. J Cell Biol 180:113–127

    Article  PubMed  CAS  Google Scholar 

  32. Hara A, Okayasu I (2004) Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance. Acta Neuropathol 108:43–48

    Article  PubMed  CAS  Google Scholar 

  33. Shono T, Tofilon PJ, Bruner JM, Owolabi O, Lang FF (2001) Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res 61:4375–4381

    PubMed  CAS  Google Scholar 

  34. Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H (1996) Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem 271:8144–8151

    Article  PubMed  CAS  Google Scholar 

  35. Levy NS, Chung S, Furneaux H, Levy AP (1998) Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem 273:6417–6423

    Article  PubMed  CAS  Google Scholar 

  36. Berkman RA, Merrill MJ, Reinhold WC et al (1993) Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91:153–159

    Article  PubMed  CAS  Google Scholar 

  37. Orian JM, Vasilopoulos K, Yoshida S, Kaye AH, Chow CW, Gonzales MF (1992) Overexpression of multiple oncogenes related to histological grade of astrocytic glioma. Br J Cancer 66(1):106–112

    Article  PubMed  CAS  Google Scholar 

  38. Dixon DA, Tolley ND, King PH et al (2001) Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. J Clin Invest 108:1657–1665

    PubMed  CAS  Google Scholar 

  39. King PH (2000) RNA-binding analyses of HuC and HuD with the VEGF and c-myc 3′-untranslated regions using a novel ELISA-based assay. Nucleic Acids Res 28:E20

    Article  PubMed  CAS  Google Scholar 

  40. Marderosian M, Sharma A, Funk AP et al (2006) Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamacycinin an Akt-dependent manner via p38 MAPK signaling. Oncogene 25:6277–6290

    Article  PubMed  CAS  Google Scholar 

  41. L’Ecuyer TJ, Tompach PC, Morris E, Fulton AB (1995) Transdifferentiation of chicken embryonic cells into muscle cells by the 3′ untranslated region of muscle tropomyosin. Proc Natl Acad Sci USA 92:7520–7524

    Article  PubMed  Google Scholar 

  42. Suswam E, Li Y, Zhang X et al (2008) Tristetraprolin down-regulates interleukin-8 and vascular endothelial growth factor in malignant glioma cells. Cancer Res 68:674–682

    Article  PubMed  CAS  Google Scholar 

  43. Sabourin LA, Tamai K, Narang MA, Korneluk RG (1997) Overexpression of 3′-untranslated region of the myotonic dystrophy kinase cDNA inhibits myoblast differentiation in vitro. J Biol Chem 272:29626–29635

    Article  PubMed  CAS  Google Scholar 

  44. Neve RL, Ivins KJ, Tsai KC, Rogers SL, Perrone-Bizzozero NI (1999) Cis-acting regulatory elements in the GAP-43 mRNA 3′-untranslated region can function in trans to suppress endogenous GAP-43 gene expression. Brain Res 65:52–60

    Article  CAS  Google Scholar 

  45. Mason CAE, Bigras J-L, O’Blenes SB et al (1999) Gene transfer in utero biologically engineers a patent ductus arteriosus in lambs by arresting fibronectin-dependent neointimal formation. Nat Med 5:176–182

    Article  PubMed  CAS  Google Scholar 

  46. Mallon BS, Macklin WB (2002) Overexpression of the 3′-untranslated region of myelin proteolipid protein mRNA leads to reduced expression of endogenous proteolipid mRNA. Neurochem Res 27:1349–1360

    Article  PubMed  CAS  Google Scholar 

  47. Storbeck CJ, Drmanic S, Daniel K et al (2004) Inhibition of myogenesis in transgenic mice expressing the human DMPK 3′-UTR. Hum Mol Genet 13:589–600

    Article  PubMed  CAS  Google Scholar 

  48. Westmark PR, Shin HC, Westmark CJ, Soltaninassab SR, Reinke EK, Malter JS (2006) Decoy mRNAs reduce beta-amyloid precursor protein mRNA in neuronal cells. Neurobiol Aging 27:787–796

    Article  PubMed  CAS  Google Scholar 

  49. Shir A, Ogris M, Wagner E, Levitzki A (2006) EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PloS Med 3:e6

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Gregory N. Fuller, M.D. Anderson Cancer Center, Houston, Texas for providing the Tissue Microarrays used in the present studies, and Dr. Martyn A. Sharpe and Ms. Marsha Widmayer for critical reading of the manuscript. Funding for this research was generously provided by: Research Allocation Committee Grant, University of New Mexico School of Medicine and the Childhood Brain Tumor Foundation to FB, and The Henry J.N.Taub Fund for Neurological Research, The Pauline Sterne Wolff Memorial Foundation, Golfers Against Cancer, and the Methodist Hospital Foundation to DSB.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The Methodist Hospital and The Methodist Hospital Research Institute, 6560 Fannin Street, Scurlock Tower Suite 944, Houston, TX, 77030, USA

    Federico Bolognani & David S. Baskin

  2. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland

    Anne-Isabelle Gallani, Lena Sokol & Nicole Meisner-Kober

Authors
  1. Federico Bolognani
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Anne-Isabelle Gallani
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Lena Sokol
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. David S. Baskin
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Nicole Meisner-Kober
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Federico Bolognani.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 51 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bolognani, F., Gallani, AI., Sokol, L. et al. mRNA stability alterations mediated by HuR are necessary to sustain the fast growth of glioma cells. J Neurooncol 106, 531–542 (2012). https://doi.org/10.1007/s11060-011-0707-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-011-0707-1

Keywords