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http://dx.doi.org/10.14348/molcells.2018.0025

Validation of Neurotensin Receptor 1 as a Therapeutic Target for Gastric Cancer  

Akter, Hafeza (Molecular Recognition Research Center, Korea Institute of Science and Technology)
Yoon, Jung Hwan (Department of Pathology, College of Medicine, The Catholic University of Korea)
Yoo, Young Sook (Molecular Recognition Research Center, Korea Institute of Science and Technology)
Kang, Min-Jung (Molecular Recognition Research Center, Korea Institute of Science and Technology)
Publication Information
Molecules and Cells / v.41, no.6, 2018 , pp. 591-602 More about this Journal
Abstract
Gastric cancer is the fifth most common type of malignancy worldwide, and the survival rate of patients with advanced-stage gastric cancer is low, even after receiving chemotherapy. Here, we validated neurotensin receptor 1 (NTSR1) as a potential therapeutic target in gastric cancer. We compared NTSR1 expression levels in sixty different gastric cancer-tissue samples and cells, as well as in other cancer cells (lung, breast, pancreatic, and colon), by assessing NTSR1 expression via semi-quantitative real-time reverse transcription polymerase chain reaction, immunocytochemistry and western blot. Following neurotensin (NT) treatment, we analyzed the expression and activity of matrix metalloproteinase-9 (MMP-9) and further determined the effects on cell migration and invasion via wound-healing and transwell assays. Our results revealed that NTSR1 mRNA levels were higher in gastric cancer tissues than non-cancerous tissues. Both of NTSR1 mRNA levels and expression were higher in gastric cancer cell lines relative to levels observed in other cancer-cell lines. Moreover, NT treatment induced MMP-9 expression and activity in all cancer cell lines, which was significantly decreased following treatment with the NTSR1 antagonist SR48692 or small-interfering RNA targeting NTSR1. Furthermore, NT-mediated metastases was confirmed by observing epithelial-mesenchymal transition markers SNAIL and E-cadherin in gastric cancer cells. NT-mediated invasion and migration of gastric cancer cells were reduced by NTSR1 depletion through the Erk signaling. These findings strongly suggested that NTR1 constitutes a potential therapeutic target for the inhibition of gastric cancer invasion and metastasis.
Keywords
gastric cancer; MMP-9; neurotensin; NTSR1;
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1 Hasan, M., Seo, J.E., Rahaman, K.A., Kang, M.J., Jung, B.H., and Kwon, O.S. (2016). Increased levels of brain serotonin correlated with MMP-9 activity and IL-4 levels resulted in severe experimental autoimmune encephalomyelitis (EAE). in obese mice. Neuroscience 319, 168-182.   DOI
2 Hwang, T.L., Changchien, T.T., Wang, C.C., and Wu, C.M. (2014). Claudin-4 expression in gastric cancer cells enhances the invasion and is associated with the increased level of matrix metalloproteinase-2 and -9 expression. Oncol. Lett. 8, 1367-1371.   DOI
3 Kang, M.H., Kim, J.S., Seo, J.E., Oh, S.C., and Yoo, Y.A. (2010). BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Exp. Cell Res. 316, 24-37.   DOI
4 Kim, Y.M., Ku, M.J., Son, Y.J., Yun, J.M., Kim, S.H., and Lee, S.Y. (2013). Anti-metastatic effect of cantharidin in A549 human lung cancer cells. Arch. Pharm. Res. 36, 479-484.   DOI
5 Knall, C., Young, S., Nick, J.A., Buhl, A.M., Worthen, G.S., and Johnson, G.L. (1996). Interleukin-8 regulation of the Ras/Raf/mitogen-activated protein kinase pathway in human neutrophils. J. Biol. Chem. 271, 2832-2838.   DOI
6 Leifler, K.S., Svensson, S., Abrahamsson, A., Bendrik, C., Robertson, J., Gauldie, J., Olsson, A.K., and Dabrosin, C. (2013). Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer. J. Immunol. 190, 4420-4430.   DOI
7 Nagarajan, D., Melo, T., Deng, Z., Almeida, C., and Zhao, W. (2012). ERK/GSK3beta/Snail signaling mediates radiation-induced alveolar epithelial-to-mesenchymal transition. Free Radic. Biol. Med. 52, 983-992.   DOI
8 Li, H., Zhang, K., Liu, L.H., Ouyang, Y., Bu, J., Guo, H.B., and Xiao, T. (2014). A systematic review of matrix metalloproteinase 9 as a biomarker of survival in patients with osteosarcoma. Tumour Biol. 35, 5487-5491.   DOI
9 Maatta, M., Soini, Y., Liakka, A., and Autio-Harmainen, H. (2000). Differential expression of matrix metalloproteinase (MMP).-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: implications for tumor progression and clinical prognosis. Clin. Cancer Res. 6, 2726-2734.
10 Muller, K.M., Tveteraas, I.H., Aasrum, M., Odegard, J., Dawood, M., Dajani, O., Christoffersen, T., and Sandnes, D.L. (2011). Role of protein kinase C and epidermal growth factor receptor signalling in growth stimulation by neurotensin in colon carcinoma cells. BMC Cancer 11, 421.   DOI
11 Al-Batran, S.E., Pauligk, C., Wirtz, R., Werner, D., Steinmetz, K., Homann, N., Schmalenberg, H., Hofheinz, R.D., Hartmann, J.T., Atmaca, A., et al. (2012). The validation of matrix metalloproteinase-9 mRNA gene expression as a predictor of outcome in patients with metastatic gastric cancer. Ann. Oncol. 23, 1699-1705.   DOI
12 Aalinkeel, R., Nair, B.B., Reynolds, J.L., Sykes, D.E., Mahajan, S.D., Chadha, K.C., and Schwartz, S.A. (2011). Overexpression of MMP-9 contributes to invasiveness of prostate cancer cell line LNCaP. Immunol. Invest. 40, 447-464.   DOI
13 Abrahao-Machado, L.F., and Scapulatempo-Neto, C. (2016). HER2 testing in gastric cancer: An update. World J. Gastroenterol. 22, 4619-4625.   DOI
14 Akter, H., Park, M., Kwon, O.S., Song, E.J., Park, W.S., and Kang, M.J. (2015). Activation of matrix metalloproteinase-9 (MMP-9) by neurotensin promotes cell invasion and migration through ERK pathway in gastric cancer. Tumour Biol. 36, 6053-6062.   DOI
15 Shimizu, S., Tsukada, J., Sugimoto, T., Kikkawa, N., Sasaki, K., Chazono, H., Hanazawa, T., Okamoto, Y., and Seki, N. (2008). Identification of a novel therapeutic target for head and neck squamous cell carcinomas: a role for the neurotensin-neurotensin receptor 1 oncogenic signaling pathway. Int. J. Cancer 123, 1816-1823.   DOI
16 Ocejo-Garcia, M., Ahmed, S.I., Coulson, J.M., and Woll, P.J. (2001). Use of RT-PCR to detect co-expression of neuropeptides and their receptors in lung cancer. Lung Cancer (Amsterdam, Netherlands) 33, 1-9.   DOI
17 Pfaffl, M.W. (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45.   DOI
18 Pryczynicz, A., Guzinska-Ustymowicz, K., Dymicka-Piekarska, V., Czyzewska, J., and Kemona, A. (2007). Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation. Folia histochemica et cytobiologica 45, 37-40.
19 Rovere, C., Barbero, P., Maoret, J.J., Laburthe, M., and Kitabgi, P. (1998). Pro-neurotensin/neuromedin N expression and processing in human colon cancer cell lines. Biochem. Biophys. Res. Commun. 246, 155-159.   DOI
20 Seethalakshmi, L., Mitra, S.P., Dobner, P.R., Menon, M., and Carraway, R.E. (1997). Neurotensin receptor expression in prostate cancer cell line and growth effect of NT at physiological concentrations. Prostate 31, 183-192.   DOI
21 Sier, C.F., Kubben, F.J., Ganesh, S., Heerding, M.M., Griffioen, G., Hanemaaijer, R., van Krieken, J.H., Lamers, C.B., and Verspaget, H.W. (1996). Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Brit. J. Cancer 74, 413-417.   DOI
22 Sillem, M., Prifti, S., Koumouridis, A., and Runnebaum, B. (1999). Invasiveness corresponds to differentiation rather than to proteinase secretion in endometrial cancer cell lines. Eur. J. Gynaecol. Oncol. 20, 367-370.
23 Correa, P. (1996). Helicobacter pylori and gastric cancer: state of the art. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 5, 477-481.
24 Alifano, M., Souaze, F., Dupouy, S., Camilleri-Broet, S., Younes, M., Ahmed-Zaid, S.M., Takahashi, T., Cancellieri, A., Damiani, S., Boaron, M., et al. (2010). Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin. Cancer Res. 16, 4401-4410.   DOI
25 Bakirtzi, K., Hatziapostolou, M., Karagiannides, I., Polytarchou, C., Jaeger, S., Iliopoulos, D., and Pothoulakis, C. (2011). Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors. Gastroenterology 141, 1749-1761.e1741.   DOI
26 Bang, Y.J., Van Cutsem, E., Feyereislova, A., Chung, H.C., Shen, L., Sawaki, A., Lordick, F., Ohtsu, A., Omuro, Y., Satoh, T., et al. (2010). Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA).: a phase 3, open-label, randomised controlled trial. Lancet 376, 687-697.   DOI
27 Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A.A., Kim, S., Wilson, C.J., Lehar, J., Kryukov, G.V., Sonkin, D., et al. (2012). The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607.   DOI
28 Carraway, R.E., and Plona, A.M. (2006). Involvement of neurotensin in cancer growth: evidence, mechanisms and development of diagnostic tools. Peptides 27, 2445-2460.   DOI
29 Dupouy, S., Doan, V.K., Wu, Z., Mourra, N., Liu, J., De Wever, O., Llorca, F.P., Cayre, A., Kouchkar, A., Gompel, A., et al. (2014). 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 5, 8235-8251.
30 Souaze, F., Dupouy, S., Viardot-Foucault, V., Bruyneel, E., Attoub, S., Gespach, C., Gompel, A., and Forgez, P. (2006). Expression of neurotensin and NT1 receptor in human breast cancer: a potential role in tumor progression. Cancer Res. 66, 6243-6249.   DOI
31 Valerie, N.C., Casarez, E.V., Dasilva, J.O., Dunlap-Brown, M.E., Parsons, S.J., Amorino, G.P., and Dziegielewski, J. (2011). Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation. Cancer Res. 71, 6817-6826.   DOI
32 Venkatakrishnan, G., Salgia, R., and Groopman, J.E. (2000). Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase via the epidermal growth factor receptor in ovarian cancer cells. J. Biol. Chem. 275, 6868-6875.   DOI
33 Vincent, J.P., Mazella, J., and Kitabgi, P. (1999). Neurotensin and neurotensin receptors. Trends Pharmacol. Sci. 20, 302-309.   DOI
34 Wagner, A.D., Grothe, W., Haerting, J., Kleber, G., Grothey, A., and Fleig, W.E. (2006). Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J. Clin. Oncol. 24, 2903-2909.   DOI
35 Wang, A.X., and Qi, X.Y. (2013). Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB life 65, 748-758.   DOI
36 Wang, J.G., Li, N.N., Li, H.N., Cui, L., and Wang, P. (2011). Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1. Neuropeptides 45, 151-156.   DOI
37 Weiss, M.B., Abel, E.V., Mayberry, M.M., Basile, K.J., Berger, A.C., and Aplin, A.E. (2012). TWIST1 is an ERK1/2 effector that promotes invasion and regulates MMP-1 expression in human melanoma cells. Cancer Res. 72, 6382-6392.   DOI
38 Evers, B.M. (2006). Neurotensin and growth of normal and neoplastic tissues. Peptides 27, 2424-2433.   DOI
39 Dupouy, S., Viardot-Foucault, V., Alifano, M., Souaze, F., Plu-Bureau, G., Chaouat, M., Lavaur, A., Hugol, D., Gespach, C., Gompel, A., et al. (2009). The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression. PloS one 4, e4223.   DOI
40 Elek, J., Pinzon, W., Park, K.H., and Narayanan, R. (2000). Relevant genomics of neurotensin receptor in cancer. Anticancer Res. 20, 53-58.
41 Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., and Bray, F. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359-386.   DOI
42 Groblewska, M., Siewko, M., Mroczko, B., and Szmitkowski, M. (2012). The role of matrix metalloproteinases (MMPs)., and their inhibitors (TIMPs). in the development of esophageal cancer. Folia Histochemica et Cytobiologica 50, 12-19.   DOI
43 Guha, S., Rey, O., and Rozengurt, E. (2002). Neurotensin induces protein kinase C-dependent protein kinase D activation and DNA synthesis in human pancreatic carcinoma cell line PANC-1. Cancer Res. 62, 1632-1640.
44 Zheng, S., Chang, Y., Hodges, K.B., Sun, Y., Ma, X., Xue, Y., Williamson, S.R., Lopez-Beltran, A., Montironi, R., and Cheng, L. (2010). Expression of KISS1 and MMP-9 in non-small cell lung cancer and their relations to metastasis and survival. Anticancer Res. 30, 713-718.
45 Yu, J., Ren, X., Chen, Y., Liu, P., Wei, X., Li, H., Ying, G., Chen, K., Winkler, H., and Hao, X. (2013). 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 8, e56069.   DOI
46 Zhao, D., and Pothoulakis, C. (2006). Effects of NT on gastrointestinal motility and secretion, and role in intestinal inflammation. Peptides 27, 2434-2444.   DOI