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Elevated GIGYF2 expression suppresses tumor migration and enhances sensitivity to temozolomide in malignant glioma

Cancer Gene Therapy volume 29, pages 750–757 (2022)Cite this article

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Abstract

Glioma is a common type of malignant and aggressive tumor in the brain. Despite progress on mechanistic studies, current understanding of the initiation and progression of glioma remains incomplete. GIGYF2 is a critical regulator in neural development and degeneration, however, its contribution in glioma is not yet elucidated. In this study, using an integrative approach spanning bioinformatic analysis and functional approaches, we explored the potential contribution of GIGYF2 in glioma. Bioinformatic data from public database and our cohort showed that GIGYF2 expression was closely associated with low glioma malignancy and better patient survival. Elevation of GIGYF2 expression impaired cell migration and enhanced temozolomide sensitivity of human glioma cells. We further establish its molecular mechanism by demonstrating that GIGYF2 inhibits MMP-9 mediated cell migration pathway and pro-survival AKT/Bax/Caspase-3 signaling. Our work identifies the suppressive role of GIGYF2 in gliomas, and clarifies the relationship between GIGYF2 expression and glioma malignancy, which may provide a potential target for future interventions.

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Fig. 1: GIGYF2 expression is decreased in glioma tissues.
Fig. 2: GIGYF2 expression is negatively associated with glioma malignancy.
Fig. 3: GIGYF2 elevation impairs the invasion of glioma cells.
Fig. 4: GIGYF2 elevation increases temozolomide-induced apoptosis of glioma cells.

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References

  1. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310:1842–50.

    Article  CAS  Google Scholar 

  2. Laug D, Glasgow SM, Deneen B. A glial blueprint for gliomagenesis. Nat Rev Neurosci. 2018;19:393–403.

    Article  CAS  Google Scholar 

  3. Shergalis A, Bankhead A 3rd, Luesakul U, Muangsin N, Neamati N. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev. 2018;70:412–45.

    Article  CAS  Google Scholar 

  4. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.

    Article  CAS  Google Scholar 

  5. Alinezhad A, Jafari F. Novel management of glioma by molecular therapies, a review article. Eur J Transl Myol. 2019;29:8209.

    PubMed  PubMed Central  Google Scholar 

  6. Molinaro AM, Taylor JW, Wiencke JK, Wrensch MR. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15:405–17.

    Article  Google Scholar 

  7. Giovannone B, Lee E, Laviola L, Giorgino F, Cleveland KA, Smith RJ. Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling. J Biol Chem. 2003;278:31564–73.

    Article  CAS  Google Scholar 

  8. Lautier C, Goldwurm S, Durr A, Giovannone B, Tsiaras WG, Pezzoli G, et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet. 2008;82:822–33.

    Article  CAS  Google Scholar 

  9. Ruiz-Martinez J, Krebs CE, Makarov V, Gorostidi A, Marti-Masso JF, Paisan-Ruiz C. GIGYF2 mutation in late-onset Parkinson’s disease with cognitive impairment. J Hum Genet. 2015;60:637–40.

    Article  CAS  Google Scholar 

  10. Zhang Y, Sun QY, Yu RH, Guo JF, Tang BS, Yan XX. The contribution of GIGYF2 to Parkinson’s disease: a meta-analysis. Neurological Sci. 2015;36:2073–9.

    Article  Google Scholar 

  11. Giovannone B, Tsiaras WG, de la Monte S, Klysik J, Lautier C, Karashchuk G, et al. GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling. Hum Mol Genet. 2009;18:4629–39.

    Article  CAS  Google Scholar 

  12. Amaya Ramirez CC, Hubbe P, Mandel N, Bethune J. 4EHP-independent repression of endogenous mRNAs by the RNA-binding protein GIGYF2. Nucleic Acids Res. 2018;46:5792–808.

    Article  Google Scholar 

  13. Morita M, Ler LW, Fabian MR, Siddiqui N, Mullin M, Henderson VC, et al. A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Mol Cell Biol. 2012;32:3585–93.

    Article  CAS  Google Scholar 

  14. Kryszke MH, Adjeriou B, Liang F, Chen H, Dautry F. Post-transcriptional gene silencing activity of human GIGYF2. Biochem Biophys Res Commun. 2016;475:289–94.

    Article  CAS  Google Scholar 

  15. Kassambara A, Kosinski M, Biecek P, Fabian S. Package ‘survminer’ (2017).

  16. Li T, Yang W, Li M, Zhang S, Zhou X, Zuo M, et al. Engrailed 2 (EN2) acts as a glioma suppressor by inhibiting tumor proliferation/invasion and enhancing sensitivity to temozolomide. Cancer Cell Int. 2020;20:65.

    Article  Google Scholar 

  17. Nambotin SB, Tomimaru Y, Merle P, Wands JR, Kim M. Functional consequences of WNT3/Frizzled7-mediated signaling in non-transformed hepatic cells. Oncogenesis. 2012;1:e31.

    Article  CAS  Google Scholar 

  18. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  Google Scholar 

  19. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  Google Scholar 

  20. Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med. 2015;372:2499–508.

    Article  CAS  Google Scholar 

  21. Matsuzaki H, Tamatani M, Mitsuda N, Namikawa K, Kiyama H, Miyake S, et al. Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J Neurochemistry. 1999;73:2037–46.

    CAS  Google Scholar 

  22. Zhang M, Sun W, Zhou M, Tang Y. MicroRNA-27a regulates hepatic lipid metabolism and alleviates NAFLD via repressing FAS and SCD1. Sci Rep. 2017;7:14493.

    Article  Google Scholar 

  23. Reardon DA, Wen PY. Glioma in 2014: unravelling tumour heterogeneity-implications for therapy. Nat Rev Clin Oncol. 2015;12:69–70.

    Article  CAS  Google Scholar 

  24. Bigner DD. Biology of gliomas: potential clinical implications of glioma cellular heterogeneity. Neurosurgery. 1981;9:320–6.

    CAS  PubMed  Google Scholar 

  25. Higashi S, Iseki E, Minegishi M, Togo T, Kabuta T, Wada K. GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. J Neurochemistry. 2010;115:423–37.

    Article  CAS  Google Scholar 

  26. Kim M, Semple I, Kim B, Kiers A, Nam S, Park HW, et al. Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis. Autophagy. 2015;11:1358–72.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the grant from Sichuan Province Science and Technology Support Program (2017SZ0006 to Y.L.), and the National Natural Science Foundation of China (31501155 to W.Y. and 81571195 to M.C.).

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Authors and Affiliations

  1. Department of Neurosurgery, West China Hospital, Sichuan University, 610041, Chengdu, People’s Republic of China

    Wanchun Yang, Qiuyun Yuan, Shuxin Zhang, Mingrong Zuo, Tengfei Li, Junhong Li, Xingwang Zhou, Mao Li, Wentao Feng, Xiaoqiang Xia, Mina Chen & Yanhui Liu

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  1. Wanchun Yang
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Correspondence to Mina Chen or Yanhui Liu.

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Yang, W., Yuan, Q., Zhang, S. et al. Elevated GIGYF2 expression suppresses tumor migration and enhances sensitivity to temozolomide in malignant glioma. Cancer Gene Ther 29, 750–757 (2022). https://doi.org/10.1038/s41417-021-00353-1

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