Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Downregulation of Wnt2 and β-catenin by siRNA suppresses malignant glioma cell growth

Cancer Gene Therapy volume 16, pages 351–361 (2009)Cite this article

Abstract

Increasing evidence suggests that aberrant activation of Wnt signaling is involved in tumor development and progression. Our earlier study on gene expression profile in human gliomas by microarray found that some members of Wnt family were overexpressed. To further investigate the involvement of Wnt signaling in gliomas, the expression of core components of Wnt signaling cascade in 45 astrocytic glioma specimens with different tumor grades was examined by reverse transcription-PCR and immunohistochemistry. Wnt2, Wnt5a, frizzled2 and β-catenin were overexpressed in gliomas. Knockdown of Wnt2 and its key mediator β-catenin in the canonical Wnt pathway by siRNA in human U251 glioma cells inhibited cell proliferation and invasive ability, and induced apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous U251 gliomas with siRNA targeting Wnt2 and β-catenin intratumorally also delayed the tumor growth. In both in vitro and in vivo studies, downregulation of Wnt2 and β-catenin was associated with the decrease of PI3K/p-AKT expression, indicating the interplay between Wnt/β-catenin and PI3K/AKT signaling cascades. In conclusion, the canonical Wnt pathway is of critical importance in the gliomagenesis and intervention of this pathway may provide a new therapeutic approach for malignant gliomas.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Miller JR . The Wnts. Genomic Biol 2001; 3: 1–8.

    Google Scholar 

  2. Karim R, Tse Q, Putti T, Scolyer R, Lee S . The significance of the Wnt pathway in the pathology of human cancers. Pathology 2004; 36: 120–128.

    Article  CAS  PubMed  Google Scholar 

  3. Mikels AJ, Nusse R . Wnts as ligands: processing, secretion and reception. Oncogene 2006; 25: 7461–7468.

    Article  CAS  PubMed  Google Scholar 

  4. van Es JH, Barker N, Clevers H . You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev 2003; 13: 28–33.

    Article  CAS  PubMed  Google Scholar 

  5. Clevers H . Wnt/β-catenin signaling in development and disease. Cell 2006; 127: 469–480.

    Article  CAS  PubMed  Google Scholar 

  6. Polakis P . Wnt signaling and cancer. Genes Dev 2000; 14: 1837–1851.

    CAS  PubMed  Google Scholar 

  7. Mikels AJ, Nusse R . Purified Wnt5a protein: activates or inhibits β-catenin-TCF signaling depending on receptor context. PLOS Biol 2006; 4: e115.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Giles RH, van Es JH, Clevers H . Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1–24.

    CAS  PubMed  Google Scholar 

  9. Schweizer L, Varmus H . Wnt/Wingless signaling through β-catenin requires the function of both LRP/Arrow and frizzled classes of receptors. BMC Cell Biol 2003; 4: 4.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M et al. Target genes of β-catenin-T-cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci USA 1999; 96: 1603–1608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Polakis P . The many ways of Wnt in cancer. Curr Opin Genet Dev 2007; 17: 45–51.

    Article  CAS  PubMed  Google Scholar 

  12. Jiang RC, Pu PY, Shen CH, Yu SZ, Jiao BH, Kang CS . Preliminary study on cancer-related gene expression profiles in 63 cases of gliomas by cDNA array. Chin J Neurosurg 2004; 20: 18–21.

    Google Scholar 

  13. Jiang RC, Pu PY, Shen CH, Jiao BH, Yu SZ, Kang CS et al. Preliminary study on the gene expression profiles of ependymomas with cDNA array. Chin J Surg 2003; 41: 770–772.

    PubMed  Google Scholar 

  14. Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T et al. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res 2006; 66: 10439–10448.

    Article  CAS  PubMed  Google Scholar 

  15. Pu P, Kang C, Zhang Z, Liu X, Jiang H . Downregulation of PIK3CB by siRNA suppresses malignant glioma cell growth in vitro and in vivo. Tech Cancer Res Treat 2006; 5: 271–280.

    Article  CAS  Google Scholar 

  16. Kang CS, Zhang ZY, Jia ZF, Wang GX, Qiu MZ, Zhou HX et al. Suppression of EGFR expression by antisense or small interference RNA inhibits U251 glioma cell growth in vitro and in vivo. Cancer Gene Ther 2006; 13: 530–538.

    Article  CAS  PubMed  Google Scholar 

  17. Howng SL, Wu CH, Cheng TS, Sy WD, Lin PC, Wang C et al. Differential expression of Wnt genes, β-catenin and E-cadherin in human brain tumors. Cancer Lett 2002; 183: 95–101.

    Article  CAS  PubMed  Google Scholar 

  18. Rhee CS, Sen M, Lu D, Wu C, Leoni L, Rubin J et al. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 2002; 21: 6598–6605.

    Article  CAS  PubMed  Google Scholar 

  19. Mazieres J, You L, He B, Xu Z, Twogood S, Lee AY et al. Wnt2 as a new therapeutic target in malignant pleural mesothelioma. Int J Cancer 2005; 117: 326–332.

    Article  CAS  PubMed  Google Scholar 

  20. Pham K, Milovanovic T, Barr RJ, Truong T, Holcombe RF . Wnt ligand expression in malignant melanoma: pilot study indicating correlation with histopathological features. J Clin Pathol Mol Pathol 2003; 56: 280–285.

    Article  CAS  Google Scholar 

  21. Katoh M . Frequent upregulation of Wnt2 in primary gastric cancer and colorectal cancer. Int J Oncol 2001; 19: 1003–1007.

    CAS  PubMed  Google Scholar 

  22. Katoh M . Wnt2 and human gastrointestinal cancer. Int J Mol Med 2003; 12: 811–816.

    CAS  PubMed  Google Scholar 

  23. Utsuki S, Sato Y, Oka H, Tsuchiya B, Suzuki S, Fujii K . Relationship between the expression of E-, N-cadherins and beta-catenin and tumor grade in astrocytomas. J Neurooncol 2002; 57: 187–192.

    Article  PubMed  Google Scholar 

  24. Moon RT, Kohn AD, De Ferrari GV, Kaykas A . Wnt and β-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 5: 689–699.

    Article  Google Scholar 

  25. Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C et al. β-Catenin mutation is a frequent cause of Wnt pathway activation on gastric cancer. Cancer Res 2002; 62: 3503–3506.

    CAS  PubMed  Google Scholar 

  26. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 1998; 95: 8847–8851.

    Article  CAS  PubMed  Google Scholar 

  27. Morin PJ . β-catenin signaling and cancer. Bioassays 1999; 21: 1021–1030.

    Article  CAS  Google Scholar 

  28. Gilbertson RJ . Medulloblastoma: signaling a change in treatment. Lancet Oncol 2004; 5: 209–218.

    Article  PubMed  Google Scholar 

  29. Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 2001; 93: 445–449.

    Article  CAS  PubMed  Google Scholar 

  30. Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE et al. Beta-catenin status predicts a favorable outcome in childhood medulloblastoma. J Clin Oncol 2005; 23: 7951–7957.

    Article  CAS  PubMed  Google Scholar 

  31. Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba H et al. Role of Wnt pathway in medulloblastoma oncogenesis. Int J Cancer 2002; 101: 198–201.

    Article  CAS  PubMed  Google Scholar 

  32. Bourguignon LY, Peyrollier K, Gilad E, Brightman A . Hyaluronan-CD44 interaction with neural Wiskott–Aldrich syndrome protein (N-WASP) promotes actin polymerization and ErbB2 activation leading to beta-catenin nuclear translocation, transcriptional up-regulation, and cell migration in ovarian tumor cells. J Biol Chem 2007; 282: 1265–1280.

    Article  CAS  PubMed  Google Scholar 

  33. Ventura AC, Sepulchre JA, Merajver SD . A hidden feedback in signaling cascades is revealed. PLoS Comput Biol 2007; 4: e1000041.

    Article  Google Scholar 

  34. You Z, Saims D, Chen S, Zhang Z, Guttridge DC, Guan KL et al. Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J Cell Biol 2002; 157: 429–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kolligs FT, Hu G, Dang CV, Fearon ER . Neoplastic transformation of RK3E by mutant β-catenin requires deregulation of Tcf/Lef transcription but not activation of c-Myc expression. Mol Cell Biol 1999; 19: 5696–5706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Takayama S, Rogatsky J, Schwarcz LE, Darimont BD . The glucocorticoid receptor represses cyclin D1 by targeting the TCF/beta-catenin complex. J Biol Chem 2006; 281: 17856–17863.

    Article  CAS  PubMed  Google Scholar 

  37. Tan X, Apte U, Micsenyi A, Kotsagrelos E, Luo JH, Ranganathan S et al. Epidermal growth factor receptor: a novel target of the Wnt/beta catenin pathway in liver. Gastroenterology 2005; 129: 285–302.

    Article  CAS  PubMed  Google Scholar 

  38. Musgrove EA . Wnt signaling via the epidermal growth factor receptor: a role in breast cancer? Breast Cancer Res 2004; 6: 65–68.

    Article  CAS  PubMed  Google Scholar 

  39. Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I et al. Activation of Notch 1 signaling is required for β-catenin-mediated human primary melanoma progression. J Clin Invest 2005; 115: 3166–3176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maeda O, Kondo M, Fujita T, Usami N, Fukui T, Shimokata K et al. Enhancement of GLI1-transcription activity by β-catenin in human cancer cells. Oncol Rep 2006; 16: 91–96.

    CAS  PubMed  Google Scholar 

  41. Huang M, Wang Y, Sun D, Zhu H, Yin Y, Zhang W et al. Identification of genes regulated by Wnt/β-catenin and involved in apoptosis via microarray analysis. BMC Cancer 2006; 6: 221–231.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Sangkhathat S, Kusafuka T, Miao J, Yoneda A, Nara K, Yamamoto S et al. In vitro RNA interference against beta-catenin inhibits the proliferation of pediatric hepatic tumors. Int J Oncol 2006; 28: 715–722.

    CAS  PubMed  Google Scholar 

  43. Herbst A, Kolligs FT . Wnt signaling as a therapeutic target for cancer. Methods Mol Biol 2007; 361: 63–91.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by National Natural Science Foundation of China, Grant number: 30300365, Program for New Century Excellent Talents in University (NCET-07-0615) and Tianjin Science and Technology Committee, Grant Number 06YFSZSF01100.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Tianjin Medical University General Hospital,

    P Pu, Z Zhang, C Kang, R Jiang, Z Jia & G Wang

  2. Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, People's Republic of China

    P Pu, Z Zhang, C Kang, R Jiang, Z Jia & G Wang

  3. Department of Neurology, Henry Ford Hospital, Detroit, MI, USA

    H Jiang

Authors
  1. P Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Pu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pu, P., Zhang, Z., Kang, C. et al. Downregulation of Wnt2 and β-catenin by siRNA suppresses malignant glioma cell growth. Cancer Gene Ther 16, 351–361 (2009). https://doi.org/10.1038/cgt.2008.78

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2008.78

Keywords

This article is cited by

Search

Advanced search

Quick links