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Journal of Molecular Neuroscience

, Volume 68, Issue 1, pp 66–77 | Cite as

PAX3 Promotes Proliferation of Human Glioma Cells by WNT/β-Catenin Signaling Pathways

  • Xia Liang
  • Zhao Dong
  • Wu Bin
  • Nie Dekang
  • Zhu Xuhang
  • Zhang Shuyuan
  • Li Liwen
  • Jin Kai
  • Sun CaixingEmail author
Article
  • 109 Downloads

Abstract

The PAX3 (paired box 3) gene plays an important role in embryonic development, diseases, and cancer formation. Our preliminary studies have shown that PAX3 gene is upregulated in glioma cells, which is associated with a worse prognosis. Moreover, PAX3, by facilitating cell proliferation and invasion and inhibiting cell apoptosis, plays an oncogenic role in glioma. However, the specific molecular mechanism of PAX3 acting as an oncogene in glioma remains unclarified. In the present study, we have found that PAX3 overexpression was observed in high grade glioma and predicted a worse prognosis. PAX3 overexpression did not correlate significantly to IDH1 mutation and MGMT methylation. Moreover, the expression of PAX3 was positively correlated with that of β-catenin. In U87 glioma cells, PAX3 interacted with β-catenin, as was confirmed by CO-IP. Besides, PAX3 overexpression promoted cell proliferation and cell cycle progression, while it inhibited cell apoptosis by altering the expressions of important molecules associated with the Wnt signaling pathway, including β-catenin, Myc, VEGF, cyclinD1, MMP7, and Wnt1. In the meantime, it was also proved that PAX3 correlated to β-catenin through a negative regulatory mechanism with respect to the promotion of U87 glioma cell proliferation and cell cycle progression and inhibition of the cell apoptosis. Our experiment demonstrated the role of PAX3 in promoting glioma growth and development, possibly by interacting directly with β-catenin and regulating the Wnt signaling pathway.

Keywords

Glioma PAX3 Wnt β-Catenin Oncogene 

Abbreviations

PAX

Paired box

CO-IP

Co-immunoprecipitation

FCM

Flow cytometry

IDH1

Isocitrate dehydrogenase 1

MGMT

O6-Methylguanine-DNA transferase

GFAP

Glial fibrillary acidic protein

WHO

World Health Organization

KPS

Karnofsky Performance Scale

PD

Paired domain

OCM

Octapeptide motif

HD

Home domain

ID

N-terminal transcription inhibitory domain

TADC

Terminal trans-activation domain

Notes

Authors' Contributions

SCX and XL conceived the project and participated in the study design, supervision of laboratory processes analysis, and interpretation of the results. XL conceived the writing of the manuscript. ZD and XL participated in the study design and drafting the manuscript. ZXH, NDK, and XL helped in vitro experiments and data analysis. ZD participated in the data interpretation and provided the critical review in the manuscript preparation. All authors read and approved the final manuscript.

Funding

The present study was supported by the National Natural Science Foundation of China (Grant No. 81502147), Zhejiang Medical Science and Technology Project (2017194140, 2018KY291, 2018248244), Natural Science Foundation of Jiangsu Province (BK20161318), and the third term “new medical talents of Zhejiang province” project.

Compliance with Ethical Standards

Conflict of Interests

All authors declare that they have no conflict of interests.

Ethics Approval and Consent to Participate

Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Consent for Publication

All the authors report no disclosures relevant to the manuscript.

References

  1. Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13:11–26CrossRefGoogle Scholar
  2. Bae CJ, Park BY, Lee YH, Tobias JW, Hong CS, Saintjeannet JP (2014) Identification of Pax3 and Zic1 targets in the developing neural crest. Dev Biol 386:473–483CrossRefGoogle Scholar
  3. Balana C et al (2018) SEOM clinical guidelines for anaplastic gliomas (2017). Clin Transl Oncol 20:16–21.  https://doi.org/10.1007/s12094-017-1762-7 CrossRefGoogle Scholar
  4. Blake JA, Ziman MR (2014) Pax genes: regulators of lineage specification and progenitor cell maintenance. Development 141:737–751CrossRefGoogle Scholar
  5. Boudjadi S, Chatterjee B, Sun W, Vemu P, Barr FG (2018) The expression and function of PAX3 in development and disease. Gene 666:145–157.  https://doi.org/10.1016/j.gene.2018.04.087 CrossRefGoogle Scholar
  6. Chen J, Xia L, Wu X, Xu L, Nie D, Shi J, Xu X, Ni L, Ju S, Wu X, Zhu H, Shi W (2012) Clinical significance and prognostic value of PAX3 expression in human glioma. J Mol Neurosci 47:52–58.  https://doi.org/10.1007/s12031-011-9677-1 CrossRefGoogle Scholar
  7. Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205.  https://doi.org/10.1016/j.cell.2012.05.012 CrossRefGoogle Scholar
  8. Fang WH, Wang Q, Li HM, Ahmed M, Kumar P, Kumar S (2014) PAX3 in neuroblastoma: oncogenic potential, chemosensitivity and signalling pathways. J Cell Mol Med 18:38–48CrossRefGoogle Scholar
  9. Fodde R, Brabletz T (2007) Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 19:150–158CrossRefGoogle Scholar
  10. Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ, Emanuel BS, Rovera G, Barr FG (1993) Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5:230–235CrossRefGoogle Scholar
  11. Gao L, Chen B, Li J, Yang F, Cen X, Liao Z, Long X (2017) Wnt/β-catenin signaling pathway inhibits the proliferation and apoptosis of U87 glioma cells via different mechanisms. PLoS One 12:e0181346CrossRefGoogle Scholar
  12. Hlubek F, Brabletz T, Budczies J, Pfeiffer S, Jung A, Kirchner T (2007) Heterogeneous expression of Wnt/β-catenin target genes within colorectal cancer. Int J Cancer 121:1941–1948Google Scholar
  13. King TD, Suto MJ, Li Y (2012) The Wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J Cell Biochem 113:13–18CrossRefGoogle Scholar
  14. Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT (2000) The Wnt/Ca 2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 16:279–283CrossRefGoogle Scholar
  15. Kypta RM, Waxman J (2012) Wnt/|[beta]|-catenin signalling in prostate cancer. Nat Rev Urol 9:418CrossRefGoogle Scholar
  16. Liu Y, Zhu H, Liu M, du J, Qian Y, Wang Y, Ding F, Gu X (2011) Downregulation of Pax3 expression correlates with acquired GFAP expression during NSC differentiation towards astrocytes. FEBS Lett 585:1014–1020.  https://doi.org/10.1016/j.febslet.2011.02.034 CrossRefGoogle Scholar
  17. Moon RT, Kohn AD, De Ferrari GV, Kaykas A (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5:691–701CrossRefGoogle Scholar
  18. Muratovska A, Zhou C, He S, Goodyer P, Eccles MR (2003) Paired-box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22:7989–7997.  https://doi.org/10.1038/sj.onc.1206766 CrossRefGoogle Scholar
  19. Navet S, Buresi A, Baratte S, Andouche A, Bonnaudponticelli L, Bassaglia Y (2017) The Pax gene family: highlights from cephalopods. PLoS One 12:e0172719CrossRefGoogle Scholar
  20. Pandur P, Maurus D, Kühl M (2002) Increasingly complex: new players enter the Wnt signaling network. BioEssays 24:881–884Google Scholar
  21. Paul I, Bhattacharya S, Chatterjee A, Ghosh MK (2013) Current understanding on EGFR and Wnt/β-catenin signaling in glioma and their possible crosstalk. Genes Cancer 4:427–446CrossRefGoogle Scholar
  22. Pekny M, Wilhelmsson U (2006) GFAP and astrocyte intermediate filaments. Springer, New York CityCrossRefGoogle Scholar
  23. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850CrossRefGoogle Scholar
  24. Reyaz N, Tayyab M, Khan SA, Siddique T (2005) Correlation of glial fibrillary acidic protein (GFAP) with grading of the neuroglial tumours. J Coll Physicians Surg Pak 15:472–475Google Scholar
  25. Scholl FA, Kamarashev J, Murmann OV, Geertsen R, Dummer R, Schäfer BW (2001) PAX3 is expressed in human melanomas and contributes to tumor cell survival. Cancer Res 61:823Google Scholar
  26. Schulte TW, Toretsky JA, Ress E, Helman L, Neckers LM (1997) Expression of PAX3 in Ewing’s sarcoma family of tumors. Biochem Mol Med 60:121–126CrossRefGoogle Scholar
  27. Stupp R, Tonn JC, Brada M, Pentheroudakis G (2010) High-grade malignant glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v190–v193.  https://doi.org/10.1093/annonc/mdq187 CrossRefGoogle Scholar
  28. Xia L, Huang Q, Nie D, Shi J, Gong M, Wu B, Gong P, Zhao L, Zuo H, Ju S, Chen J, Shi W (2013) PAX3 is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Brain Res 1521:68–78.  https://doi.org/10.1016/j.brainres.2013.05.021 CrossRefGoogle Scholar
  29. Zhang K, Zhang J, Lei H, Pu P, Kang C (2012) Wnt/beta-catenin signaling in glioma. J NeuroImmune Pharmacol 7:740–749CrossRefGoogle Scholar
  30. Zhao T, Gan Q, Stokes A, Lassiter RNT, Wang Y, Chan J, Han JX, Pleasure DE, Epstein JA, Zhou CJ (2014) 尾-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation. Development 141:148–157CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryZhejiang Cancer HospitalHangzhouChina
  2. 2.Department of NeurosurgeryZhejiang HospitalHangzhouChina
  3. 3.Department of NeurosurgeryYancheng First Peoples’ HospitalYanchengChina
  4. 4.Department of Head and Neck SurgeryZhejiang Cancer HospitalHangzhouChina

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