Diverse expression patterns and tumorigenic role of neurotensin signaling components in colorectal cancer cells

Kim,Ji Tae; Weiss,Heidi L.; Evers,B. Mark

doi:10.3892/ijo.2017.3990

Diverse expression patterns and tumorigenic role of neurotensin signaling components in colorectal cancer cells

Authors:
- Ji Tae Kim
- Heidi L. Weiss
- B. Mark Evers
View Affiliations

Affiliations: Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
Published online on: May 9, 2017 https://doi.org/10.3892/ijo.2017.3990
Pages: 2200-2206

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

Colorectal cancer (CRC), which is one of the most common malignancies worldwide, results from an accumulation of genetic and epigenetic modifications including DNA methylation. Neurotensin (NTS), a hormone localized to the gut and central nervous system, mediates its physiological and pathological effects, including growth stimulation for a variety of cancers, through three distinct NTS receptors (NTSRs). Most NTS functions are mediated through the high-affinity receptor NTSR1, and expression of NTSR1 is increased in many cancers including CRC. In this study, we investigated the expression profiles and cellular functions of the NTSRs, especially NTSR1, in CRC cells. We showed that expression levels for NTS and NTSR1 varied, that NTSR2 expression was not detectable and that NTSR3 was consistently expressed in all CRC cell lines examined. Treatment with the demethylating agent, 5-aza-2'-deoxycytidine, augmented levels of NTSR1/2 in Caco2 and DLD1 cells, which have little or no transcripts for NTSR1/2 suggesting that DNA methylation suppresses NTSR1/2 expression. In addition, we demonstrated that knockdown of NTSR1 decreased cell growth and migration in HCT116 and HT29 cells. Finally, we showed that treatment with SR48692, an antagonist of NTSR1, also inhibited cell proliferation and migration in the CRC cells. Our findings identify promoter methylation as an important process regulating the differential expression or silencing of NTSR1/2 in CRC cells. Moreover, inhibition of NTSR1 repressed tumorigenic effects in CRC cells, suggesting that NTSR1 may be used as a therapeutic target for CRC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Fearon ER: Molecular genetics of colorectal cancer. Annu Rev Pathol. 6:479–507. 2011. View Article : Google Scholar
3	Ashktorab H and Brim H: DNA methylation and colorectal cancer. Curr Colorectal Cancer Rep. 10:425–430. 2014. View Article : Google Scholar
4	Evers BM: Neurotensin and growth of normal and neoplastic tissues. Peptides. 27:2424–2433. 2006. View Article : Google Scholar : PubMed/NCBI
5	Kalafatakis K and Triantafyllou K: Contribution of neurotensin in the immune and neuroendocrine modulation of normal and abnormal enteric function. Regul Pept. 170:7–17. 2011. View Article : Google Scholar : PubMed/NCBI
6	Li J, Song J, Zaytseva YY, Liu Y, Rychahou P, Jiang K, Starr ME, Kim JT, Harris JW, Yiannikouris FB, et al: An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature. 533:411–415. 2016. View Article : Google Scholar : PubMed/NCBI
7	Mustain WC, Rychahou PG and Evers BM: The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes. 18:75–82. 2011. View Article : Google Scholar
8	Wu Z, Martinez-Fong D, Trédaniel J and Forgez P: Neurotensin and its high affinity receptor 1 as a potential pharmacological target in cancer therapy. Front Endocrinol (Lausanne). 3:1842013.
9	Dupouy S, Mourra N, Doan VK, Gompel A, Alifano M and 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. 93:1369–1378. 2011. View Article : Google Scholar : PubMed/NCBI
10	Wang L, Friess H, Zhu Z, Graber H, Zimmermann A, Korc M, Reubi JC and Büchler MW: Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease. Clin Cancer Res. 6:566–571. 2000.PubMed/NCBI
11	Souazé F, Dupouy S, Viardot-Foucault V, Bruyneel E, Attoub S, Gespach C, Gompel A and Forgez P: Expression of neurotensin and NT1 receptor in human breast cancer: A potential role in tumor progression. Cancer Res. 66:6243–6249. 2006. View Article : Google Scholar : PubMed/NCBI
12	Gui X, Guzman G, Dobner PR and Kadkol SS: Increased neurotensin receptor-1 expression during progression of colonic adenocarcinoma. Peptides. 29:1609–1615. 2008. View Article : Google Scholar : PubMed/NCBI
13	Dupouy S, Viardot-Foucault V, Alifano M, Souazé F, Plu-Bureau G, Chaouat M, Lavaur A, Hugol D, Gespach C, Gompel A, et al: The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression. PLoS One. 4:e42232009. View Article : Google Scholar : PubMed/NCBI
14	Alifano M, Souazé F, Dupouy S, Camilleri-Broët S, Younes M, Ahmed-Zaïd SM, Takahashi T, Cancellieri A, Damiani S, Boaron M, et al: Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin Cancer Res. 16:4401–4410. 2010. View Article : Google Scholar : PubMed/NCBI
15	Valerie NC, Casarez EV, Dasilva JO, Dunlap-Brown ME, Parsons SJ, Amorino GP and Dziegielewski J: Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation. Cancer Res. 71:6817–6826. 2011. View Article : Google Scholar : PubMed/NCBI
16	Kim JT, Li J, Song J, Lee EY, Weiss HL, Townsend CM Jr and Evers BM: Differential expression and tumorigenic function of neurotensin receptor 1 in neuroendocrine tumor cells. Oncotarget. 6:26960–26970. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kim JT, Li J, Jang ER, Gulhati P, Rychahou PG, Napier DL, Wang C, Weiss HL, Lee EY, Anthony L, et al: Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors. Carcinogenesis. 34:953–961. 2013. View Article : Google Scholar : PubMed/NCBI
18	Kim JT, Liu C, Zaytseva YY, Weiss HL, Townsend CM Jr and Evers BM: Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells. Int J Cancer. 136:1475–1481. 2015. View Article : Google Scholar
19	Evers BM, Ishizuka J, Chung DH, Townsend CM Jr and Thompson JC: Neurotensin expression and release in human colon cancers. Ann Surg. 216:423–430; discussion 430–431. 1992. View Article : Google Scholar : PubMed/NCBI
20	Zhao D, Kuhnt-Moore S, Zeng H, Wu JS, Moyer MP and Pothoulakis C: Neurotensin stimulates IL-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF-kappa B pathways. Am J Physiol Cell Physiol. 284:C1397–C1404. 2003. View Article : Google Scholar : PubMed/NCBI
21	Ning Y, Manegold PC, Hong YK, Zhang W, Pohl A, Lurje G, Winder T, Yang D, LaBonte MJ, Wilson PM, et al: Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int J Cancer. 128:2038–2049. 2011. View Article : Google Scholar :
22	Kerkhoff E and Rapp UR: Cell cycle targets of Ras/Raf signalling. Oncogene. 17:1457–1462. 1998. View Article : Google Scholar : PubMed/NCBI
23	Servotte S, Camby I, Debeir O, Deroanne C, Lambert CA, Lapière CM, Kiss R, Nusgens B and Decaestecker C: The in vitro influences of neurotensin on the motility characteristics of human U373 glioblastoma cells. Neuropathol Appl Neurobiol. 32:575–584. 2006. View Article : Google Scholar : PubMed/NCBI
24	Shimizu S, Tsukada J, Sugimoto T, Kikkawa N, Sasaki K, Chazono H, Hanazawa T, Okamoto Y and Seki N: 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. 2008. View Article : Google Scholar : PubMed/NCBI
25	Souazé F, Viardot-Foucault V, Roullet N, Toy-Miou-Leong M, Gompel A, Bruyneel E, Comperat E, Faux MC, Mareel M, Rostène W, et al: Neurotensin receptor 1 gene activation by the Tcf/beta-catenin pathway is an early event in human colonic adenomas. Carcinogenesis. 27:708–716. 2006. View Article : Google Scholar
26	Dong Z, Wang X, Zhao Q, Townsend CM Jr and Evers BM: DNA méthylation contributes to expression of the human neurotensin/neuromedin N gene. Am J Physiol. 274:G535–G543. 1998.PubMed/NCBI
27	Dong Z, Wang X and Evers BM: Site-specific DNA méthylation contributes to neurotensin/neuromedin N expression in colon cancers. Am J Physiol Gastrointest Liver Physiol. 279:G1139–G1147. 2000.PubMed/NCBI
28	Hagihara A, Miyamoto K, Furuta J, Hiraoka N, Wakazono K, Seki S, Fukushima S, Tsao MS, Sugimura T and Ushijima T: Identification of 27 5′ CPG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers. Oncogene. 23:8705–8710. 2004. View Article : Google Scholar : PubMed/NCBI
29	Tan AC, Jimeno A, Lin SH, Wheelhouse J, Chan F, Solomon A, Rajeshkumar V, Rubio-Viqueira B and Hidalgo M: Characterizing DNA méthylation patterns in pancreatic cancer genome. Mol Oncol. 3:425–438. 2009. View Article : Google Scholar : PubMed/NCBI
30	Guo S, Yan F, Xu J, Bao Y, Zhu J, Wang X, Wu J, Li Y, Pu W, Liu Y, et al: Identification and validation of the methylation biomarkers of non-small cell lung cancer (NSCLC). Clin Epigenetics. 7:32015. View Article : Google Scholar : PubMed/NCBI