Molecular Biology Reports

, Volume 41, Issue 9, pp 5903–5911 | Cite as

Rab3a promotes brain tumor initiation and progression

  • Jun-Kyum Kim
  • Seung-Yup Lee
  • Chang-Won Park
  • Suk-Hwang Park
  • Jinlong Yin
  • Jaebong Kim
  • Jae-Bong Park
  • Jae-Yong Lee
  • Hyunggee Kim
  • Sung-Chan Kim
Article

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.

Keywords

Glioblastoma multiforme Rab3a Cyclin D1 Gliomagenesis Drug resistance 

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 15:1311–1333CrossRefPubMedGoogle Scholar
  2. 2.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507CrossRefPubMedGoogle Scholar
  3. 3.
    Khasraw M, Lassman AB (2010) Advances in the treatment of malignant gliomas. Curr Oncol Rep 12:26–33CrossRefPubMedGoogle 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 2:10–30Google 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 352:987–996CrossRefPubMedGoogle 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 432:396–401CrossRefPubMedGoogle Scholar
  7. 7.
    Vescovi AL, Galli R, Reynolds BA (2006) Brain tumor stem cells. Nat Rev Cancer 6:425–436CrossRefPubMedGoogle 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 63:5821–5828PubMedGoogle 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 13:1238–1241CrossRefPubMedGoogle Scholar
  10. 10.
    Coleman WL, Bill CA, Bykhovskaia M (2007) Rab3a deletion reduces vesicle docking and transmitter release at the mouse diaphragm synapse. Neuroscience 148:1–6CrossRefPubMedGoogle 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 13:332–336CrossRefGoogle 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 70:2552–2556CrossRefPubMedGoogle 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 9:434–438CrossRefPubMedGoogle 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 1:269–277CrossRefPubMedGoogle 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 88:808–815CrossRefPubMedGoogle Scholar
  16. 16.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2T−ΔΔC method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  17. 17.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefPubMedGoogle Scholar
  18. 18.
    The Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRefGoogle 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 71:7125–7134CrossRefPubMedGoogle 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 22:2028–2033PubMedCentralCrossRefPubMedGoogle 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 365:496–502CrossRefPubMedGoogle Scholar
  22. 22.
    Diehl JA (2002) Cycling to cancer with cyclin D1. Cancer Biol Ther 1:226–231CrossRefPubMedGoogle 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 9:391–403CrossRefPubMedGoogle Scholar
  24. 24.
    Cheng KW, Lahad JP, Gray JW, Mills GB (2005) Emerging role of RAB GTPase in cancer and human disease. Cancer Res 65:2516–2519CrossRefPubMedGoogle 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 6:372–382CrossRefPubMedGoogle 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 37:957–965CrossRefPubMedGoogle Scholar
  27. 27.
    Geppert M, Sudhof TC (1998) RAB3 and synaptotagmin: the yin and yang of synaptic membrane fusion. Annu Rev Neurosci 21:75–95CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Jun-Kyum Kim
    • 1
  • Seung-Yup Lee
    • 1
    • 2
  • Chang-Won Park
    • 3
  • Suk-Hwang Park
    • 3
  • Jinlong Yin
    • 1
    • 5
  • Jaebong Kim
    • 3
    • 4
  • Jae-Bong Park
    • 3
    • 4
  • Jae-Yong Lee
    • 3
    • 4
  • Hyunggee Kim
    • 1
  • Sung-Chan Kim
    • 3
    • 4
  1. 1.Department of Biotechnology, School of Life Sciences and BiotechnologyKorea UniversitySeoulRepublic of Korea
  2. 2.Department of OphthalmologySoon Chun Hyang University HospitalSeoulRepublic of Korea
  3. 3.Department of Biochemistry, College of MedicineHallym UniversityChuncheonRepublic of Korea
  4. 4.Institute of Cell Differentiation and Aging, College of MedicineHallym UniversityChuncheonRepublic of Korea
  5. 5.National Cancer CenterResearch Institute and HospitalGoyangRepublic of Korea

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