Rab3a promotes brain tumor initiation and progression

Abstract

The Rab protein family is composed of small GTP-binding proteins involved in intracellular vesicle trafficking. In particular, Rab3a which is one of four Rab3 proteins (a, b, c, and d isoforms) is associated with synaptic vesicle trafficking in normal brain. However, despite the elevated level of Rab3a in tumors, its role remains unclear. Here we report a tumorigenic role of Rab3a in brain tumors. Elevated level of Rab3a expression in human was confirmed in both glioma cell lines and glioblastoma multiforme patient specimens. Ectopic Rab3a expression in glioma cell lines and primary astrocytes promoted cell proliferation by increasing cyclin D1 expression, induced resistance to anti-cancer drug and irradiation, and accelerated foci formation in soft agar and tumor formation in nude mice. The overexpression of Rab3a augmented the tumorsphere-forming ability of glioma cells and p53−/− astrocytes and increased expression levels of various stem cell markers. Taken together, our results indicate that Rab3a is a novel oncogene involved in glioma initiation and progression.

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References

  1. 1.

    Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, Depinho RA (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15:1311–1333

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Khasraw M, Lassman AB (2010) Advances in the treatment of malignant gliomas. Curr Oncol Rep 12:26–33

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Reithmeier T, Graf E, Piroth T, Trippel M, Pinsker MO, Nikkhah G (2010) BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors. BMC Cancer 2:10–30

    Google Scholar 

  5. 5.

    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumor initiating cells. Nature 432:396–401

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Vescovi AL, Galli R, Reynolds BA (2006) Brain tumor stem cells. Nat Rev Cancer 6:425–436

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    CAS  PubMed  Google Scholar 

  9. 9.

    Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, Maria RD (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13:1238–1241

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Coleman WL, Bill CA, Bykhovskaia M (2007) Rab3a deletion reduces vesicle docking and transmitter release at the mouse diaphragm synapse. Neuroscience 148:1–6

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Araki K, Horikawa T, Chakraborty AK, Nakagawa K, Itoh H, Oka M, Funasaka Y, Pawelek J, Ichihashi M (2000) Small GTPase Rab3a is associated with melanosomes in melanoma cells. Pigment Cell Melanoma Res 13:332–336

    CAS  Article  Google Scholar 

  12. 12.

    Culine S, Rousseau-Merck MF, Honoré N, Nezelof C, Olofsson B (1992) Specific expression of the ras-related rab3A gene in human normal and malignant neuroendocrine cells. Cancer 70:2552–2556

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Lankat-Buttgereit B, Fehmann HC, Hering BJ, Bretzel RG, Goke B (1994) Expression of the ras-related rab3a gene in human insulinomas and normal human pancreatic islets. Pancreas 9:434–438

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN, Depinho RA (2002) Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1:269–277

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Joo KM, Kim SY, Jin X, Song SY, Kong DS, Lee JI, Jeon JW, Kim MH, Kang BG, Jung Y, Jin J, Hong SC, Park WY, Lee DS, Kim H, Nam DH (2008) Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest 88:808–815

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 −ΔΔCT method. Methods 25:402–408

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    The Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  19. 19.

    Jin X, Yin J, Kim SH, Sohn YW, Beck S, Lim YC, Nam DH, Choi YJ, Kim H (2011) EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res 71:7125–7134

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Jeon HM, Jin X, Lee JS, Oh SY, Sohn YW, Park HJ, Joo KM, Park WY, Nam DH, Depinho RA, Chin L, Kim H (2008) Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling. Genes Dev 22:2028–2033

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  21. 21.

    Lee JS, Gil JE, Kim JH, Kim TK, Jin X, Oh SY, Sohn YW, Jeon HM, Park HJ, Park JW, Shin YJ, Chung YG, Lee JB, You S, Kim H (2008) Brain cancer stem-like cell genesis from p53-deficient mouse astrocytes by oncogenic Ras. Biochem Biophys Res Commun 365:496–502

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Diehl JA (2002) Cycling to cancer with cyclin D1. Cancer Biol Ther 1:226–231

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Cheng KW, Lahad JP, Gray JW, Mills GB (2005) Emerging role of RAB GTPase in cancer and human disease. Cancer Res 65:2516–2519

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Wang JS, Wang FB, Zhang QG, Shen ZZ, Shao ZM (2008) Enhanced expression of Rab27A gene by breast cancer cells promoting invasiveness and the metastasis potential by secretion of insulin-like growth factor-II. Mol Cancer Res 6:372–382

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Fukui K, Tamura S, Wada A, Kamada Y, Igura T, Kiso S, Hayashi N (2007) Expression of Rab5a in hepatocellular carcinoma: possible involvement in epidermal growth factor signaling. Hepatol Res 37:957–965

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Geppert M, Sudhof TC (1998) RAB3 and synaptotagmin: the yin and yang of synaptic membrane fusion. Annu Rev Neurosci 21:75–95

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) Grants funded by the Korea government (MSIP) (No. NRF-2009-0070325 to S.C. Kim and No. 2013M2A2A7042530 to H. Kim) and Hallym University Research Fund (HRF-G-2012-4, to S.C. Kim).

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Correspondence to Hyunggee Kim or Sung-Chan Kim.

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Jun-Kyum Kim and Seung-Yup Lee have contributed equally to this work.

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Kim, JK., Lee, SY., Park, CW. et al. Rab3a promotes brain tumor initiation and progression. Mol Biol Rep 41, 5903–5911 (2014). https://doi.org/10.1007/s11033-014-3465-2

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Keywords

  • Glioblastoma multiforme
  • Rab3a
  • Cyclin D1
  • Gliomagenesis
  • Drug resistance