The critical role of cyclin d2 in cell cycle progression and tumorigenicity of glioblastoma stem cells

ABSTRACT Cancer stem cells are believed to be responsible for tumor initiation and development. Much current research on human brain tumors is focused on the stem-like properties of

glioblastoma stem cells (GSCs). However, little is known about the molecular mechanisms of cell cycle regulation that discriminate between GSCs and differentiated glioblastoma cells. Here we

show that cyclin D2 is the cyclin that is predominantly expressed in GSCs and suppression of its expression by RNA interference causes G1 arrest _in vitro_ and growth retardation of GSCs

xenografted into immunocompromised mice _in vivo_. We also demonstrate that the expression of _cyclin_ _D2_ is suppressed upon serum-induced differentiation similar to what was observed for

the cancer stem cell marker _CD133._ Taken together, our results demonstrate that cyclin D2 has a critical role in cell cycle progression and the tumorigenicity of GSCs. Access through your

institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print

issues and online access $259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to

local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT

BEING VIEWED BY OTHERS CDK8 MAINTAINS STEMNESS AND TUMORIGENICITY OF GLIOMA STEM CELLS BY REGULATING THE C-MYC PATHWAY Article 16 March 2021 CREB5 PROMOTES THE PROLIFERATION AND SELF-RENEWAL

ABILITY OF GLIOMA STEM CELLS Article Open access 28 February 2024 INHIBITION OF GLI2 SUPPRESSES TUMORIGENICITY IN GLIOBLASTOMA STEM CELLS DERIVED FROM A _DE NOVO_ MURINE BRAIN CANCER MODEL

Article 07 January 2021 REFERENCES * Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A _et al_. Malignant astrocytic glioma: genetics, biology, and paths to treatment. _Genes

Dev_ 2007; 21: 2683–2710. Article  CAS  PubMed  Google Scholar  * Alison MR, Lim SM, Nicholson LJ . Cancer stem cells: problems for therapy? _J Pathol_ 2011; 223: 147–161. Article  CAS 

PubMed  Google Scholar  * Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J _et al_. Identification of a cancer stem cell in human brain tumors. _Cancer Res_ 2003; 63: 5821–5828.

CAS  PubMed  Google Scholar  * Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM _et al_. 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_ 2006; 9: 391–403. Article  CAS  PubMed  Google Scholar  * Sherr CJ, Roberts JM . Living with or

without cyclins and cyclin-dependent kinases. _Genes Dev_ 2004; 18: 2699–2711. Article  CAS  PubMed  Google Scholar  * Sherr CJ, McCormick F . The RB and p53 pathways in cancer. _Cancer

Cell_ 2002; 2: 103–112. Article  CAS  PubMed  Google Scholar  * Cancer Genome Atlas Research Network Comprehensive genomic characterization defines human glioblastoma genes and core

pathways. _Nature_ 2008; 455: 1061–1068. Article  Google Scholar  * Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P _et al_. An integrated genomic analysis of human glioblastoma

multiforme. _Science_ 2008; 321: 1807–1812. Article  CAS  PubMed  PubMed Central  Google Scholar  * Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J _et al_. Transcriptional

profiles of CD133+ and CD133− glioblastoma-derived cancer stem cell lines suggest different cells of origin. _Cancer Res_ 2010; 70: 2030–2040. Article  CAS  PubMed  Google Scholar  * Mizrak

D, Brittan M, Alison MR . CD133: molecule of the moment. _J Pathol_ 2008; 214: 3–9. Article  CAS  PubMed  Google Scholar  * Lendahl U, Zimmerman LB, McKay RD . CNS stem cells express a new

class of intermediate filament protein. _Cell_ 1990; 60: 585–595. Article  CAS  PubMed  Google Scholar  * Sanai N, Alvarez-Buylla A, Berger MS . Neural stem cells and the origin of gliomas.

_N Engl J Med_ 2005; 353: 811–822. Article  CAS  PubMed  Google Scholar  * Kowalczyk A, Filipkowski RK, Rylski M, Wilczynski GM, Konopacki FA, Jaworski J _et al_. The critical role of cyclin

D2 in adult neurogenesis. _J Cell Biol_ 2004; 167: 209–213. Article  CAS  PubMed  PubMed Central  Google Scholar  * Walzlein JH, Synowitz M, Engels B, Markovic DS, Gabrusiewicz K, Nikolaev

E _et al_. The antitumorigenic response of neural precursors depends on subventricular proliferation and age. _Stem Cells_ 2008; 26: 2945–2954. Article  CAS  PubMed  Google Scholar  * Mayr

C, Bartel DP . Widespread shortening of 3’UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. _Cell_ 2009; 138: 673–684. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Zhang X, Zhao M, Huang AY, Fei Z, Zhang W, Wang XL . The effect of cyclin D expression on cell proliferation in human gliomas. _J Clin Neurosci_ 2005; 12: 166–168.

Article  CAS  PubMed  Google Scholar  * Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S _et al_. Neuronal and glioma-derived stem cell factor induces angiogenesis within the

brain. _Cancer Cell_ 2006; 9: 287–300. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by Research Program of Innovative Cell Biology by

Innovative Technology (Integrated Systems Analysis of Cellular Oncogenic Signaling Networks), Grants-in-Aid for Scientific Research on Innovative Areas (Integrative Research on Cancer

Microenvironment Network), Takeda Science Foundation and in part by Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms), MEXT, Japan. AUTHOR

INFORMATION Author notes * R Koyama-Nasu and Y Nasu-Nishimura: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Laboratory of Molecular and Genetic Information,

Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan, R Koyama-Nasu, Y Nasu-Nishimura, K Funato, K Echizen, H Sugano, R Haruta, M Matsui, R

Takahashi, E Manabe, T Oda & T Akiyama * Department of Neurosurgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan, T Todo, Y Ino & N Saito * Genome Science Division,

Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan H Aburatani Authors * R Koyama-Nasu View author publications You can also search for

this author inPubMed Google Scholar * Y Nasu-Nishimura View author publications You can also search for this author inPubMed Google Scholar * T Todo View author publications You can also

search for this author inPubMed Google Scholar * Y Ino View author publications You can also search for this author inPubMed Google Scholar * N Saito View author publications You can also

search for this author inPubMed Google Scholar * H Aburatani View author publications You can also search for this author inPubMed Google Scholar * K Funato View author publications You can

also search for this author inPubMed Google Scholar * K Echizen View author publications You can also search for this author inPubMed Google Scholar * H Sugano View author publications You

can also search for this author inPubMed Google Scholar * R Haruta View author publications You can also search for this author inPubMed Google Scholar * M Matsui View author publications

You can also search for this author inPubMed Google Scholar * R Takahashi View author publications You can also search for this author inPubMed Google Scholar * E Manabe View author

publications You can also search for this author inPubMed Google Scholar * T Oda View author publications You can also search for this author inPubMed Google Scholar * T Akiyama View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to T Akiyama. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 (JPG 739 KB)

SUPPLEMENTARY FIGURE 2 (JPG 94 KB) SUPPLEMENTARY FIGURE 3 (JPG 656 KB) SUPPLEMENTARY FIGURE 4 (JPG 568 KB) SUPPLEMENTARY FIGURE 5 (JPG 258 KB) SUPPLEMENTARY FIGURE 6 (JPG 402 KB)

SUPPLEMENTARY FIGURE 7 (JPG 213 KB) SUPPLEMENTARY FIGURE 8 (JPG 233 KB) SUPPLEMENTARY FIGURE 9 (JPG 964 KB) SUPPLEMENTARY TABLE 1 (XLS 10 KB) SUPPLEMENTARY INFORMATION (DOC 26 KB) RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Koyama-Nasu, R., Nasu-Nishimura, Y., Todo, T. _et al._ The critical role of cyclin D2 in cell cycle progression and

tumorigenicity of glioblastoma stem cells. _Oncogene_ 32, 3840–3845 (2013). https://doi.org/10.1038/onc.2012.399 Download citation * Received: 22 February 2012 * Revised: 29 June 2012 *

Accepted: 20 July 2012 * Published: 10 September 2012 * Issue Date: 15 August 2013 * DOI: https://doi.org/10.1038/onc.2012.399 SHARE THIS ARTICLE Anyone you share the following link with

will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative KEYWORDS * cancer stem cells * cell cycle * cyclin D2 * glioblastoma