Advertisement

Tumor Biology

, Volume 36, Issue 12, pp 9357–9364 | Cite as

Glucose-regulated protein 94 is a novel glioma biomarker and promotes the aggressiveness of glioma via Wnt/β-catenin signaling pathway

  • Tieyi Hu
  • Niqi Xie
  • Chuan Qin
  • Jiasheng Wang
  • Yi You
Research Article

Abstract

Malignant glioma is the most common type of primary brain tumor and represents one of the most aggressive and lethal human cancer types. Glioma recurrence is a common event; however, the relevant molecular mechanisms in this setting are not well-understood. In this study, we investigated glucose-regulated protein 94 (GRP94) expressions in human glioma and aimed to determine the roles of GRP94 expression affects cell proliferation, invasion, and regulatory signaling in human glioma U87 cells. Our results showed that GRP94 was overexpressed at both mRNA and protein levels in high-grade glioblastoma as compared with normal brain tissues. High GRP94 levels also predict shorter overall survival of glioma patients. RNAi-mediated silencing of GRP94 suppressed cellular proliferation, colony formation ability in glioma cells. Depletion of GRP94 also inhibited cell migration and invasion ability in glioma cell. Furthermore, gene microarray analysis revealed that GRP94 depletion caused the dysregulation of critical pathway, Wnt/β-catenin signaling pathway. We next demonstrated GRP94 regulates Wnt/β-catenin signaling pathway to promote the proliferation of glioblastoma cells. Conclusion, our findings establish GRP94 as progression markers and druggable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/β-catenin signaling pathway.

Keywords

GRP94 Proliferation Migration Invasion Wnt/β-catenin pathway 

Notes

Conflicts of interest

None

References

  1. 1.
    Taylor LP. Diagnosis, treatment, and prognosis of glioma: five new things. Neurology. 2010;75:S28–32.CrossRefPubMedGoogle Scholar
  2. 2.
    Dali-Youcef N, Froelich S, Moussallieh FM, Chibbaro S, Noel G, Namer IJ, et al. Gene expression mapping of histone deacetylases and co-factors, and correlation with survival time and (1)H-HRMAS metabolomic profile in human gliomas. Sci Rep. 2015;5:9087.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Shen Z, Hou X, Chen B, Chen P, Zhang Q. NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients. Medicine (Baltimore). 2015;94:e482.CrossRefGoogle Scholar
  4. 4.
    Zhu X, Morales FC, Agarwal NK, Dogruluk T, Gagea M, Georgescu MM. Moesin is a glioma progression marker that induces proliferation and Wnt/beta-catenin pathway activation via interaction with CD44. Cancer Res. 2013;73:1142–55.CrossRefPubMedGoogle Scholar
  5. 5.
    Sukumari-Ramesh S, Prasad N, Alleyne CH, Vender JR, Dhandapani KM. Overexpression of Nrf2 attenuates Carmustine-induced cytotoxicity in U87MG human glioma cells. BMC Cancer. 2015;15:118.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hu B, Emdad L, Bacolod MD, Kegelman TP, Shen XN, Alzubi MA, et al. Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis. Cancer Res. 2014;74:7321–32.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Seidler PM, Shinsky SA, Hong F, Li Z, Cosgrove MS, Gewirth DT. Characterization of the Grp94/OS-9 chaperone-lectin complex. J Mol Biol. 2014;426:3590–605.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rebl A, Brietzke A, Goldammer T, Seyfert HM. GRP94 is encoded by two differentially expressed genes during development of rainbow trout (Oncorhynchus mykiss). Fish Physiol Biochem. 2014;40:1917–26.CrossRefPubMedGoogle Scholar
  9. 9.
    Rosenbaum M, Andreani V, Kapoor T, Herp S, Flach H, Duchniewicz M, et al. MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress. Genes Dev. 2014;28:1165–78.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Duzgun A, Bedir A, Ozdemir T, Nar R, Kilinc V, Salis O, et al. Effect of dexamethasone on unfolded protein response genes (MTJ1, Grp78, Grp94, CHOP, HMOX-1) in HEp2 cell line. Indian J Biochem Biophys. 2013;50:505–10.PubMedGoogle Scholar
  11. 11.
    Fu Z, Deng H, Wang X, Yang X, Wang Z, Liu L. Involvement of ER-alpha36 in the malignant growth of gastric carcinoma cells is associated with GRP94 overexpression. Histopathology. 2013;63:325–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Liu B, Staron M, Hong F, Wu BX, Sun S, Morales C, et al. Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway. Proc Natl Acad Sci U S A. 2013;110:6877–82.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Boelens J, Jais JP, Vanhoecke B, Beck I, Van Melckebeke H, Philippe J, et al. ER stress in diffuse large B cell lymphoma: GRP94 is a possible biomarker in germinal center versus activated B-cell type. Leuk Res. 2013;37:3–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Luo B, Tseng CC, Adams GB, Lee AS. Deficiency of GRP94 in the hematopoietic system alters proliferation regulators in hematopoietic stem cells. Stem Cells Dev. 2013;22:3062–73.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Vitadello M, Gherardini J, Gorza L. The stress protein/chaperone Grp94 counteracts muscle disuse atrophy by stabilizing subsarcolemmal neuronal nitric oxide synthase. Antioxid Redox Signal. 2014;20:2479–96.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Molina JR, Agarwal NK, Morales FC, Hayashi Y, Aldape KD, Cote G, et al. PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene. 2012;31:1264–74.CrossRefPubMedGoogle Scholar
  17. 17.
    Barton ER, Park S, James JK, Makarewich CA, Philippou A, Eletto D, et al. Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production. FASEB J. 2012;26:3691–702.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Duerfeldt AS, Peterson LB, Maynard JC, Ng CL, Eletto D, Ostrovsky O, et al. Development of a Grp94 inhibitor. J Am Chem Soc. 2012;134:9796–804.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jiang L, Wu J, Yang Y, Liu L, Song L, Li J, et al. Bmi-1 promotes the aggressiveness of glioma via activating the NF-kappaB/MMP-9 signaling pathway. BMC Cancer. 2012;12:406.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tao D, Pan Y, Jiang G, Lu H, Zheng S, Lin H, et al. B-Myb regulates snail expression to promote epithelial-to-mesenchymal transition and invasion of breast cancer cell. Med Oncol. 2015;32:412.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang M, Pan Y, Zhou Y. Depletion of ALX1 causes inhibition of migration and induction of apoptosis in human osteosarcoma. Tumour Biol. 2015.Google Scholar
  22. 22.
    Dejeans N, Glorieux C, Guenin S, Beck R, Sid B, Rousseau R, et al. Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: implications for tumor recurrence. Free Radic Biol Med. 2012;52:993–1002.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Tieyi Hu
    • 1
  • Niqi Xie
    • 2
  • Chuan Qin
    • 3
  • Jiasheng Wang
    • 4
  • Yi You
    • 5
  1. 1.Department of NeurologyDazu District People’s HospitalChongqingChina
  2. 2.Department of Clinical LaboratoryDazu District People’s HospitalChongqingChina
  3. 3.Department of NeurosurgeryDazu District People’s HospitalChongqingChina
  4. 4.Department of Intensive Care UnitDazu District People’s HospitalChongqingChina
  5. 5.Department of Prevention and Health CareDazu District People’s HospitalChongqingChina

Personalised recommendations