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Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Neurotensin promotes the progression of malignant glioma through NTSR1 and impacts the prognosis of glioma patients

Authors: Qing Ouyang, Xueyang Gong, Hualiang Xiao, Ji Zhou, Minhui Xu, Yun Dai, Lunshan Xu, Hua Feng, Hongjuan Cui, Liang Yi

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

The poor prognosis and minimally successful treatments of malignant glioma indicate a challenge to identify new therapeutic targets which impact glioma progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) overexpression induces neoplastic growth and predicts the poor prognosis in various malignancies. Whether NTS can promote the glioma progression and its prognostic significance for glioma patients remains unclear.

Methods

NTS precursor (ProNTS), NTS and NTSR1 expression levels in glioma were detected by immunobloting Elisa and immunohistochemistry assay. The prognostic analysis was conducted from internet by R2 microarray platform. Glioma cell proliferation was evaluated by CCK8 and BrdU incorporation assay. Wound healing model and Matrigel transwell assay were utilized to test cellular migration and invasion. The orthotopic glioma implantations were established to analyze the role of NTS and NTSR1 in glioma progression in vivo.

Results

Positive correlations were shown between the expression levels of NTS and NTSR1 with the pathological grade of gliomas. The high expression levels of NTS and NTSR1 indicate a worse prognosis in glioma patients. The proliferation and invasiveness of glioma cells could be enhanced by NTS stimulation and impaired by the inhibition of NTSR1. NTS stimulated Erk1/2 phosphorylation in glioma cells, which could be reversed by SR48692 or NTSR1-siRNA. In vivo experiments showed that SR48692 significantly prolonged the survival length of glioma-bearing mice and inhibited glioma cell invasiveness.

Conclusion

NTS promotes the proliferation and invasion of glioma via the activation of NTSR1. High expression levels of NTS and NTSR1 predict a poor prognosis in glioma patients.
Appendix
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Literature
1.
go back to reference Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.CrossRefPubMed Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.CrossRefPubMed
2.
go back to reference Reardon DA, Groves MD, Wen PY, Nabors L, Mikkelsen T, Rosenfeld S, et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Res. 2013;19:900–8.CrossRefPubMed Reardon DA, Groves MD, Wen PY, Nabors L, Mikkelsen T, Rosenfeld S, et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Res. 2013;19:900–8.CrossRefPubMed
3.
go back to reference Polak JM, Bloom SR. The central and peripheral distribution of neurotensin. Ann New York Acad Sci. 1982;400:75–93.CrossRef Polak JM, Bloom SR. The central and peripheral distribution of neurotensin. Ann New York Acad Sci. 1982;400:75–93.CrossRef
4.
go back to reference Cooper PE, Fernstrom MH, Rorstad OP, Leeman SE, Martin JB. The regional distribution of somatostatin, substance P and neurotensin in human brain. Brain Res. 1981;218:219–32.CrossRefPubMed Cooper PE, Fernstrom MH, Rorstad OP, Leeman SE, Martin JB. The regional distribution of somatostatin, substance P and neurotensin in human brain. Brain Res. 1981;218:219–32.CrossRefPubMed
5.
6.
go back to reference Dupouy S, Mourra N, Doan VK, Gompel A, Alifano M, Forgez P. The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers. Biochimie. 2011;93:1369–78.CrossRefPubMed Dupouy S, Mourra N, Doan VK, Gompel A, Alifano M, Forgez P. The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers. Biochimie. 2011;93:1369–78.CrossRefPubMed
7.
go back to reference Alifano M, Loi M, Camilleri-Broet S, Dupouy S, Régnard JF, Forgez P. Neurotensin expression and outcome of malignant pleural mesothelioma. Biochimie. 2010;92:164–70.CrossRefPubMed Alifano M, Loi M, Camilleri-Broet S, Dupouy S, Régnard JF, Forgez P. Neurotensin expression and outcome of malignant pleural mesothelioma. Biochimie. 2010;92:164–70.CrossRefPubMed
8.
go back to reference Yi L, Xiao H, Xu M, Ye X, Hu J, Li F, et al. Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma. J Neuroimmunol. 2011;232:75–82.CrossRefPubMed Yi L, Xiao H, Xu M, Ye X, Hu J, Li F, et al. Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma. J Neuroimmunol. 2011;232:75–82.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference Gravendeel LA, Kouwenhoven MC, Gevaert O, de Rooi JJ, Stubbs AP, Duijm JE, et al. Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer Res. 2009;69:9065–72.CrossRefPubMed Gravendeel LA, Kouwenhoven MC, Gevaert O, de Rooi JJ, Stubbs AP, Duijm JE, et al. Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer Res. 2009;69:9065–72.CrossRefPubMed
11.
go back to reference Kitabgi P, Checler F, Mazella J, Vincent JP. Pharmacology and biochemistry of neurotensin receptors. Rev Clin Basic Pharm. 1985;5:397–486.PubMed Kitabgi P, Checler F, Mazella J, Vincent JP. Pharmacology and biochemistry of neurotensin receptors. Rev Clin Basic Pharm. 1985;5:397–486.PubMed
12.
go back to reference Vincent JP. Neurotensin receptors: binding properties, transduction pathways, and structure. Cell Mol Neurobiol. 1995;15:501–12.CrossRefPubMed Vincent JP. Neurotensin receptors: binding properties, transduction pathways, and structure. Cell Mol Neurobiol. 1995;15:501–12.CrossRefPubMed
13.
go back to reference Vincent JP, Mazella J, Kitabgi P. Neurotensin and neurotensin receptors. Trends Pharmacol Sci. 1999;20:302–9.CrossRefPubMed Vincent JP, Mazella J, Kitabgi P. Neurotensin and neurotensin receptors. Trends Pharmacol Sci. 1999;20:302–9.CrossRefPubMed
14.
go back to reference Hermans E, Maloteaux JM. Mechanisms of regulation of neurotensin receptors. Pharmacol Ther. 1998;79:89–104.CrossRefPubMed Hermans E, Maloteaux JM. Mechanisms of regulation of neurotensin receptors. Pharmacol Ther. 1998;79:89–104.CrossRefPubMed
15.
go back to reference Demont Y, Corbet C, Page A, Ataman-Onal Y, Choquet-Kastylevsky G, Fliniaux I, et al. Pro-nerve growth factor induces autocrine stimulation of breast cancer cell invasion through tropomyosin-related kinase A (TrkA) and sortilin protein. J Biol Chem. 2012;287:1923–31.CrossRefPubMedCentralPubMed Demont Y, Corbet C, Page A, Ataman-Onal Y, Choquet-Kastylevsky G, Fliniaux I, et al. Pro-nerve growth factor induces autocrine stimulation of breast cancer cell invasion through tropomyosin-related kinase A (TrkA) and sortilin protein. J Biol Chem. 2012;287:1923–31.CrossRefPubMedCentralPubMed
16.
go back to reference Souaze F, Dupouy S, Viardot-Foucault V, Bruyneel E, Attoub S, Gespach C, et al. Expression of neurotensin and NT1 receptor in human breast cancer: a potential role in tumor progression. Cancer Res. 2006;66:6243–9.CrossRefPubMed Souaze F, Dupouy S, Viardot-Foucault V, Bruyneel E, Attoub S, Gespach C, et al. Expression of neurotensin and NT1 receptor in human breast cancer: a potential role in tumor progression. Cancer Res. 2006;66:6243–9.CrossRefPubMed
17.
go back to reference Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, et al. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 2012;55:807–20.CrossRefPubMed Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, et al. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 2012;55:807–20.CrossRefPubMed
18.
go back to reference Massa F, Tormo A, Beraud-Dufour S, Coppola T, Mazella J. Neurotensin-induced Erk1/2 phosphorylation and growth of human colonic cancer cells are independent from growth factors receptors activation. Biochem Biophys Res Commun. 2011;414:118–22.CrossRefPubMed Massa F, Tormo A, Beraud-Dufour S, Coppola T, Mazella J. Neurotensin-induced Erk1/2 phosphorylation and growth of human colonic cancer cells are independent from growth factors receptors activation. Biochem Biophys Res Commun. 2011;414:118–22.CrossRefPubMed
19.
go back to reference Bakirtzi K, Hatziapostolou M, Karagiannides I, Polytarchou C, Jaeger S, Iliopoulos D, et al. Neurotensin signaling activates microRNAs-21 and −155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors. Gastroenterology. 2011;141:1749–61. e1741.CrossRefPubMed Bakirtzi K, Hatziapostolou M, Karagiannides I, Polytarchou C, Jaeger S, Iliopoulos D, et al. Neurotensin signaling activates microRNAs-21 and −155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors. Gastroenterology. 2011;141:1749–61. e1741.CrossRefPubMed
20.
go back to reference Mijatovic T, Gailly P, Mathieu V, De Neve N, Yeaton P, Kiss R, et al. Neurotensin is a versatile modulator of in vitro human pancreatic ductal adenocarcinoma cell (PDAC) migration. Cell Oncol. 2007;29:315–26.PubMed Mijatovic T, Gailly P, Mathieu V, De Neve N, Yeaton P, Kiss R, et al. Neurotensin is a versatile modulator of in vitro human pancreatic ductal adenocarcinoma cell (PDAC) migration. Cell Oncol. 2007;29:315–26.PubMed
21.
go back to reference Coppola T, Beraud-Dufour S, Antoine A, Vincent JP, Mazella J. Neurotensin protects pancreatic beta cells from apoptosis. Int J Biochem Cell Biol. 2008;40:2296–302.CrossRefPubMed Coppola T, Beraud-Dufour S, Antoine A, Vincent JP, Mazella J. Neurotensin protects pancreatic beta cells from apoptosis. Int J Biochem Cell Biol. 2008;40:2296–302.CrossRefPubMed
22.
go back to reference Yu SC, Bian XW. Enrichment of cancer stem cells based on heterogeneity of invasiveness. Stem Cell Rev. 2009;5:66–71.CrossRefPubMed Yu SC, Bian XW. Enrichment of cancer stem cells based on heterogeneity of invasiveness. Stem Cell Rev. 2009;5:66–71.CrossRefPubMed
23.
go back to reference Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMed Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMed
25.
go back to reference Watters JJ, Schartner JM, Badie B. Microglia function in brain tumors. J Neurosci Res. 2005;81:447–55.CrossRefPubMed Watters JJ, Schartner JM, Badie B. Microglia function in brain tumors. J Neurosci Res. 2005;81:447–55.CrossRefPubMed
26.
go back to reference Martin S, Dicou E, Vincent JP, Mazella J. Neurotensin and the neurotensin receptor-3 in microglial cells. J Neurosci Res. 2005;81:322–6.CrossRefPubMed Martin S, Dicou E, Vincent JP, Mazella J. Neurotensin and the neurotensin receptor-3 in microglial cells. J Neurosci Res. 2005;81:322–6.CrossRefPubMed
27.
go back to reference Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12.CrossRefPubMed Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12.CrossRefPubMed
28.
go back to reference Olszewski U, Hamilton G. Neurotensin signaling induces intracellular alkalinization and interleukin-8 expression in human pancreatic cancer cells. Mol Oncol. 2009;3:204–13.CrossRefPubMed Olszewski U, Hamilton G. Neurotensin signaling induces intracellular alkalinization and interleukin-8 expression in human pancreatic cancer cells. Mol Oncol. 2009;3:204–13.CrossRefPubMed
29.
go back to reference Yu J, Ren X, Chen Y, Liu P, Wei X, Li H, et al. Dysfunctional activation of neurotensin/IL-8 pathway in hepatocellular carcinoma is associated with increased inflammatory response in microenvironment, more epithelial mesenchymal transition in cancer and worse prognosis in patients. PLoS One. 2013;8:e56069.CrossRefPubMedCentralPubMed Yu J, Ren X, Chen Y, Liu P, Wei X, Li H, et al. Dysfunctional activation of neurotensin/IL-8 pathway in hepatocellular carcinoma is associated with increased inflammatory response in microenvironment, more epithelial mesenchymal transition in cancer and worse prognosis in patients. PLoS One. 2013;8:e56069.CrossRefPubMedCentralPubMed
30.
go back to reference Wang X, Wang Q, Ives KL, Evers BM. Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells. Clin Cancer Res. 2006;12:5346–55.CrossRefPubMedCentralPubMed Wang X, Wang Q, Ives KL, Evers BM. Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells. Clin Cancer Res. 2006;12:5346–55.CrossRefPubMedCentralPubMed
31.
32.
go back to reference Zhao D, Zhan Y, Zeng H, Koon HW, Moyer MP, Pothoulakis C. Neurotensin stimulates expression of early growth response gene-1 and EGF receptor through MAP kinase activation in human colonic epithelial cells. Int J Cancer. 2007;120:1652–6.CrossRefPubMedCentralPubMed Zhao D, Zhan Y, Zeng H, Koon HW, Moyer MP, Pothoulakis C. Neurotensin stimulates expression of early growth response gene-1 and EGF receptor through MAP kinase activation in human colonic epithelial cells. Int J Cancer. 2007;120:1652–6.CrossRefPubMedCentralPubMed
33.
go back to reference Kisfalvi K, Guha S, Rozengurt E. Neurotensin and EGF induce synergistic stimulation of DNA synthesis by increasing the duration of ERK signaling in ductal pancreatic cancer cells. J Cell Physiol. 2005;202:880–90.CrossRefPubMed Kisfalvi K, Guha S, Rozengurt E. Neurotensin and EGF induce synergistic stimulation of DNA synthesis by increasing the duration of ERK signaling in ductal pancreatic cancer cells. J Cell Physiol. 2005;202:880–90.CrossRefPubMed
34.
go back to reference Guha S, Lunn JA, Santiskulvong C, Rozengurt E. Neurotensin stimulates protein kinase C-dependent mitogenic signaling in human pancreatic carcinoma cell line PANC-1. Cancer Res. 2003;63:2379–87.PubMed Guha S, Lunn JA, Santiskulvong C, Rozengurt E. Neurotensin stimulates protein kinase C-dependent mitogenic signaling in human pancreatic carcinoma cell line PANC-1. Cancer Res. 2003;63:2379–87.PubMed
35.
go back to reference Kisfalvi K, Hurd C, Guha S, Rozengurt E. Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells. J Cell Physiol. 2010;223:309–16.PubMedCentralPubMed Kisfalvi K, Hurd C, Guha S, Rozengurt E. Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells. J Cell Physiol. 2010;223:309–16.PubMedCentralPubMed
36.
go back to reference Hassan S, Dobner PR, Carraway RE. Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. Regul Pept. 2004;120:155–66.CrossRefPubMed Hassan S, Dobner PR, Carraway RE. Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. Regul Pept. 2004;120:155–66.CrossRefPubMed
37.
go back to reference Dupouy S, Doan VK, Wu Z, Mourra N, Liu J, De Wever O, et al. Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice. Oncotarget. 2014;30:8235–51. Dupouy S, Doan VK, Wu Z, Mourra N, Liu J, De Wever O, et al. Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice. Oncotarget. 2014;30:8235–51.
38.
go back to reference Younes M, Wu ZS, Lupo AM, Mourra N, Takahashi T, Fléjou JF, et al. Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib. Oncotarget. 2014;5(18):8252–69.PubMedCentralPubMed Younes M, Wu ZS, Lupo AM, Mourra N, Takahashi T, Fléjou JF, et al. Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib. Oncotarget. 2014;5(18):8252–69.PubMedCentralPubMed
39.
go back to reference Amorino GP, Deeble PD, Parsons SJ. Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway. Oncogene. 2007;26:745–56.CrossRefPubMed Amorino GP, Deeble PD, Parsons SJ. Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway. Oncogene. 2007;26:745–56.CrossRefPubMed
40.
go back to reference Feng H, Hu B, Vuori K, Sarkaria JN, Furnari FB, Cavenee WK, et al. EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. Oncogene. 2014;33:2504–12.CrossRefPubMed Feng H, Hu B, Vuori K, Sarkaria JN, Furnari FB, Cavenee WK, et al. EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. Oncogene. 2014;33:2504–12.CrossRefPubMed
41.
go back to reference Sintupisut N, Liu PL, Yeang CH. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes. Nucleic Acids Res. 2013;41:8803–21.CrossRefPubMedCentralPubMed Sintupisut N, Liu PL, Yeang CH. An integrative characterization of recurrent molecular aberrations in glioblastoma genomes. Nucleic Acids Res. 2013;41:8803–21.CrossRefPubMedCentralPubMed
Metadata
Title
Neurotensin promotes the progression of malignant glioma through NTSR1 and impacts the prognosis of glioma patients
Authors
Qing Ouyang
Xueyang Gong
Hualiang Xiao
Ji Zhou
Minhui Xu
Yun Dai
Lunshan Xu
Hua Feng
Hongjuan Cui
Liang Yi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0290-8

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