IDH1 mutation diminishes aggressive phenotype in glioma stem cells

Yao,Qi; Cai,Gang; Yu,Qi; Shen,Jianhong; Gu,Zhikai; Chen,Jian; Shi,Wei; Shi,Jinlong

doi:10.3892/ijo.2017.4186

IDH1 mutation diminishes aggressive phenotype in glioma stem cells

Authors:
- Qi Yao
- Gang Cai
- Qi Yu
- Jianhong Shen
- Zhikai Gu
- Jian Chen
- Wei Shi
- Jinlong Shi
View Affiliations

Affiliations: Department of Neurosurgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Neurosurgery, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
Published online on: November 3, 2017 https://doi.org/10.3892/ijo.2017.4186
Pages: 270-278

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The R132H mutation in isocitrate dehydrogenase 1 (IDH1-R132H) is associated with better prognosis in glioma patients. Glioma stem cells (GSCs) in glioma are believed to be responsible for glioma growth and maintenance. However, the relation between the R132H mutation and GSCs is not fully understood. In the present study, GSC markers were detected in patients with IDH1-R132H or wild-type IDH1 (IDH1-wt) by tissue microarray immunohistochemistry (TMA-IHC). The relationship between the expression patterns of GSC markers and the clinicopathological characteristics in glioma were analyzed. To confirm this mutation's role in GSCs, the IDH1-R132H in GSCs isolated from glioblastoma patients with IDH1 mutations was overexpressed by using lentiviral constructs in vitro, and then the proliferation, differentiation, apoptosis, migration and invasion of the transfected GSCs were explored. At the molecular level, we detected Wnt/β-catenin signaling expression to verify its role in regulating the cellular properties of GSCs. The results showed that the positive rate of GSCs in patients with IDH1-R132H was significantly less than that in patients with IDH1-wt. The positive rate of GSCs was correlated with IDH1 mutation, TNM stage and poor overall survive. After transfection in vitro, IDH1-R132H overexpression led to reduced GSCs proliferation, migration and invasion, inducing apoptosis and improving GSC differentiation, accompanied by a significant reduction in activity of β-catenin. Several mediators, effectors and targets of the Wnt/β-catenin signaling were downregulated. The data demonstrate that IDH1 mutation reduces the malignant progression of glioma by causing a less aggressive phenotype of GSCs which are involved in the Wnt/β‑catenin signaling.

View Figures

View References

1	Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, et al: Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 21:2683–2710. 2007. View Article : Google Scholar : PubMed/NCBI
2	Gladson CL, Prayson RA and Liu WM: The pathobiology of glioma tumors. Annu Rev Pathol. 5:33–50. 2010. View Article : Google Scholar :
3	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
4	Auffinger B, Tobias AL, Han Y, Lee G, Guo D, Dey M, Lesniak MS and Ahmed AU: Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ. 21:1119–1131. 2014. View Article : Google Scholar : PubMed/NCBI
5	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
6	Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI: Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA. 100:15178–15183. 2003. View Article : Google Scholar : PubMed/NCBI
7	Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U and Beier CP: CD133⁺ and CD133⁻ glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67:4010–4015. 2007. View Article : Google Scholar : PubMed/NCBI
8	Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
9	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
10	Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD and Rich JN: Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66:7843–7848. 2006. View Article : Google Scholar : PubMed/NCBI
11	Dey M, Ulasov IV, Tyler MA, Sonabend AM and Lesniak MS: Cancer stem cells: The final frontier for glioma virotherapy. Stem Cell Rev. 7:119–129. 2011. View Article : Google Scholar :
12	Uno M, Oba-Shinjo SM, Silva R, Miura F, Clara CA, Almeida JR, Malheiros SM, Bianco AM, Brandt R, Ribas GC, et al: IDH1 mutations in a Brazilian series of glioblastoma. Clinics (Sao Paulo). 66:163–165. 2011. View Article : Google Scholar
13	Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 360:765–773. 2009. View Article : Google Scholar : PubMed/NCBI
14	Yan W, Zhang W, You G, Bao Z, Wang Y, Liu Y, Kang C, You Y, Wang L and Jiang T: Correlation of IDH1 mutation with clinico-pathologic factors and prognosis in primary glioblastoma: A report of 118 patients from China. PLoS One. 7:e303392012. View Article : Google Scholar
15	Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI
16	Sonoda Y, Kumabe T, Nakamura T, Saito R, Kanamori M, Yamashita Y, Suzuki H and Tominaga T: Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci. 100:1996–1998. 2009. View Article : Google Scholar : PubMed/NCBI
17	Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 462:739–744. 2009. View Article : Google Scholar : PubMed/NCBI
18	Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, et al: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 19:17–30. 2011. View Article : Google Scholar : PubMed/NCBI
19	Chitneni SK: IDH1 Mutations in Glioma: Considerations for radiotracer development. SM Radiol J. 2:10092016.PubMed/NCBI
20	Cui D, Ren J, Shi J, Feng L, Wang K, Zeng T, Jin Y and Gao L: R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/β-catenin signaling. Int J Biochem Cell Biol. 73:72–81. 2016. View Article : Google Scholar : PubMed/NCBI
21	Reya T and Clevers H: Wnt signalling in stem cells and cancer. Nature. 434:843–850. 2005. View Article : Google Scholar : PubMed/NCBI
22	Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, et al: Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 460:66–72. 2009. View Article : Google Scholar : PubMed/NCBI
23	He H, Niu CS and Li MW: Correlation between glioblastoma stem-like cells and tumor vascularization. Oncol Rep. 27:45–50. 2012.
24	Li Q, Qiao G, Ma J and Li Y: Downregulation of VEGF expression attenuates malignant biological behavior of C6 glioma stem cells. Int J Oncol. 44:1581–1588. 2014. View Article : Google Scholar : PubMed/NCBI
25	Gurung PM, Veerakumarasivam A, Williamson M, Counsell N, Douglas J, Tan WS, Feber A, Crabb SJ, Short SC, Freeman A, et al: Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer. Int J Cancer. 136:709–720. 2015.
26	Dirks PB: Brain tumor stem cells: Bringing order to the chaos of brain cancer. J Clin Oncol. 26:2916–2924. 2008. View Article : Google Scholar : PubMed/NCBI
27	Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, García-Taboada E, Barcia J, Guzmán M and Velasco G: A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther. 10:90–103. 2011. View Article : Google Scholar : PubMed/NCBI
28	Cheema TA, Kanai R, Kim GW, Wakimoto H, Passer B, Rabkin SD and Martuza RL: Enhanced antitumor efficacy of low-dose Etoposide with oncolytic herpes simplex virus in human glioblastoma stem cell xenografts. Clin Cancer Res. 17:7383–7393. 2011. View Article : Google Scholar : PubMed/NCBI
29	Costello JF, Berger MS, Huang HS and Cavenee WK: Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res. 56:2405–2410. 1996.PubMed/NCBI
30	Nobusawa S, Watanabe T, Kleihues P and Ohgaki H: IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 15:6002–6007. 2009. View Article : Google Scholar : PubMed/NCBI
31	Xie F, Tang JJ, Wang X, Liu YH and Mao Q: Correlation between IDH1 mutation and prognosis in supratentorial high-grade astrocytomas. Sichuan Da Xue Xue Bao Yi Xue Ban. 44:184–187. 1922013.In Chinese.
32	Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.PubMed/NCBI
33	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
34	Shen G, Shen F, Shi Z, Liu W, Hu W, Zheng X, Wen L and Yang X: Identification of cancer stem-like cells in the C6 glioma cell line and the limitation of current identification methods. In Vitro Cell Dev Biol Anim. 44:280–289. 2008. View Article : Google Scholar : PubMed/NCBI
35	Zhou XD, Wang XY, Qu FJ, Zhong YH, Lu XD, Zhao P, Wang DH, Huang QB, Zhang L and Li XG: Detection of cancer stem cells from the C6 glioma cell line. J Int Med Res. 37:503–510. 2009. View Article : Google Scholar : PubMed/NCBI