Role of endothelin B receptor in oligodendroglioma proliferation and survival: In vitro and in vivo evidence

Wan,Xin; Zhang,Longbo; Jiang,Bing

doi:10.3892/mmr.2013.1746

2014-January Volume 9 Issue 1

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2014-January Volume 9 Issue 1

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Article

Role of endothelin B receptor in oligodendroglioma proliferation and survival: In vitro and in vivo evidence

Authors:
- Xin Wan
- Longbo Zhang
- Bing Jiang
View Affiliations / Copyright

Affiliations: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China
Pages: 229-234
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Published online on: October 22, 2013

https://doi.org/10.3892/mmr.2013.1746
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Abstract

In this study, the role of the endothelin B receptor (ETBR) in oligodendroglioma cell proliferation and survival was investigated in vitro and in vivo. The overexpression and knockdown of ETBR was conducted in Hs683 human oligodendroglioma cells, and cell proliferation and activation (phosphorylation) of extracellular signal-regulated kinase (ERK) were measured in vitro. An orthotopic xenograft oligodendroglioma mouse model was established. Mouse survival times and immunohistochemical Ki67 staining in the xenografts were examined. In vitro experiments demonstrated that the overexpression of ETBR significantly enhanced the proliferation of oligodendroglioma cells and the activation of ERK compared with the controls, which was eliminated by the selective ETBR inhibitor BQ788 and ERK-specific inhibitor U0126, but not selective endothelin A receptor inhibitor BQ123. By contrast, the knockdown of endogenous ETBR markedly decreased oligodendroglioma cell proliferation and the activation of ERK compared with the controls. Overexpression of ETBR significantly increased immunohistochemical Ki67 staining in the Hs683 cell orthotopic xenograft and decreased animal survival. By contrast, knockdown of ETBR significantly decreased Ki67 staining and increased mouse survival times. Intratumoral injection of BQ788, but not BQ123, significantly decreased Ki67 staining and prolonged mouse survival times. In conclusion, ETBR was demonstrated to mediate the proliferation of oligodendroglioma cells according to an ERK-dependent mechanism. Using an orthotopic xenograft oligodendroglioma mouse model, it was demonstrated in vivo that ETBR promotes oligodendroglioma proliferation and that the selective ETBR antagonist effectively inhibits the proliferation of oligodendroglioma cells and prolongs survival times. This study provides a novel insight into the role of ETBR in oligodendroglioma proliferation and survival, and provides the first in vivo evidence that ETBR-specific antagonists are a potential therapeutic alternative for oligodendrogliomas.

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1	Anguelova E, Beuvon F, Leonard N, et al: Functional endothelin ET B receptors are selectively expressed in human oligodendrogliomas. Brain Res Mol Brain Res. 137:77–88. 2005. View Article : Google Scholar : PubMed/NCBI
2	Chen HL, Chew LJ, Packer RJ and Gallo V: Modulation of the Wnt/beta-catenin pathway in human oligodendroglioma cells by Sox17 regulates proliferation and differentiation. Cancer Lett. 35:361–371. 2013. View Article : Google Scholar : PubMed/NCBI
3	Ohgaki H and Kleihues P: Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 64:479–489. 2005.PubMed/NCBI
4	Burton E and Prados M: New chemotherapy options for the treatment of malignant gliomas. Curr Opin Oncol. 11:157–161. 1999. View Article : Google Scholar : PubMed/NCBI
5	Nutt CL, Noble M, Chambers AF and Cairncross JG: Differential expression of drug resistance genes and chemosensitivity in glial cell lineages correlate with differential response of oligodendrogliomas and astrocytomas to chemotherapy. Cancer Res. 60:4812–4818. 2000.PubMed/NCBI
6	Branle F, Lefranc F, Camby I, et al: Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy. Cancer. 95:641–655. 2002. View Article : Google Scholar
7	Levin ER: Endothelins. New Engl J Med. 333:356–363. 1995. View Article : Google Scholar
8	Schinelli S: Pharmacology and physiopathology of the brain endothelin system: an overview. Curr Med Chem. 13:627–638. 2006. View Article : Google Scholar : PubMed/NCBI
9	Egidy G, Eberl LP, Valdenaire O, et al: The endothelin system in human glioblastoma. Lab Invest. 80:1681–1689. 2000. View Article : Google Scholar
10	Paolillo M, Barbieri A, Zanassi P and Schinelli S: Expression of endothelins and their receptors in glioblastoma cell lines. J Neurooncol. 79:1–7. 2006. View Article : Google Scholar : PubMed/NCBI
11	Paolillo M, Russo MA, Curti D, Lanni C and Schinelli S: Endothelin B receptor antagonists block proliferation and induce apoptosis in glioma cells. Pharmacol Res. 61:306–315. 2010. View Article : Google Scholar : PubMed/NCBI
12	Mathieu V, De Nève N, Le Mercier M, et al: Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia. 10:1383–1392. 2008.
13	Le Mercier M, Fortin S, Mathieu V, et al: Galectin 1 proangiogenic and promigratory effects in the Hs683 oligodendroglioma model are partly mediated through the control of BEX2 expression. Neoplasia. 11:485–496. 2009.PubMed/NCBI
14	Schilling H, Sehu KW and Lee WR: A histologic study (including DNA quantification and Ki-67 labeling index) in uveal melanomas after brachytherapy with ruthenium plaques. Invest Ophthalmol Vis Sci. 38:2081–2092. 1997.PubMed/NCBI
15	Bagnato A, Loizidou M, Pflug BR, Curwen J and Growcott J: Role of the endothelin axis and its antagonists in the treatment of cancer. Br J Pharmacol. 163:220–233. 2011. View Article : Google Scholar : PubMed/NCBI
16	Grimshaw MJ, Hagemann T, Ayhan A, Gillett CE, Binder C and Balkwill FR: A role for endothelin-2 and its receptors in breast tumor cell invasion. Cancer Res. 64:2461–2468. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tanese K, Fukuma M, Ishiko A and Sakamoto M: Endothelin-2 is upregulated in basal cell carcinoma under control of Hedgehog signaling pathway. Biochem Biophys Res Commun. 391:486–491. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wiesmann F, Veeck J, Galm O, et al: Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer. Breast Cancer Res. 11:R342009. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Role of endothelin B receptor in oligodendroglioma proliferation and survival: In vitro and in vivo evidence

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