N‑methyl‑N‑nitro‑N'‑nitrosoguanidine induces the expression of CCR2 in human gastric epithelial cells promoting CCL2‑mediated migration

Cai,Jie; Wang,Mei; Zhu,Mengchu; Zhang,Qiang; Zhang,Xu; Yan,Yongmin; Qian,Hui; Xu,Wenrong

doi:10.3892/mmr.2015.4650

N‑methyl‑N‑nitro‑N'‑nitrosoguanidine induces the expression of CCR2 in human gastric epithelial cells promoting CCL2‑mediated migration

Authors:
- Jie Cai
- Mei Wang
- Mengchu Zhu
- Qiang Zhang
- Xu Zhang
- Yongmin Yan
- Hui Qian
- Wenrong Xu
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Affiliations: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, The Affiliated Hospital, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
Published online on: December 7, 2015 https://doi.org/10.3892/mmr.2015.4650
Pages: 1083-1090
Copyright: © Cai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chronic inflammation has a decisive role in tumorigenesis, particularly in gastric carcinogenesis. The CC chemokine ligand 2 (CCL2), an important inflammatory cytokine, is involved in the initiation, development and progression of various types of cancer. However, the role of CCL2 in gastric cancer remains to be elucidated. The present study demonstrated that recombinant CCL2 stimulation caused no effect on the morphology, proliferation and migration of human GES‑1 gastric mucosa epithelial cells, in which the protein expression of CC‑chemokine receptor 2 (CCR2) was markedly low. However, the expression of CCR2 was significantly upregulated in the GES‑1 cells following pretreatment with the chemical carcinogen, N‑methyl‑N‑nitro‑N'‑nitrosoguanidine (MNNG), for 12 h or transformed with MNNG (MC cells). The present study used CCL2 to stimulate MNNG pretreated GES‑1 cells and MC cells, and demonstrated that CCL2 clearly promoted their migration and the epithelial‑mesenchymal transition (EMT). However, no effect was observed on the proliferative ability of the cells. Taken together, these findings suggested that the CCL2/CCR2 chemokine signaling may regulate the EMT in gastric epithelial cells and resulted in gastric carcinogenesis in response to the intake of the carcinogen, MNNG.

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1	Hussain SP and Harris CC: Inflammation and cancer: An ancient link with novel potentials. Int J Cancer. 121:2373–2380. 2007. View Article : Google Scholar : PubMed/NCBI
2	Landskron G, De la Fuente M, Thuwajit P, Thuwajit C and Hermoso MA: Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014(149185)2014. View Article : Google Scholar : PubMed/NCBI
3	Grivennikov SI, Greten FR and Karin M: Immunity, inflammation and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI
4	Schetter AJ, Heegaard NH and Harris CC: Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis. 31:37–49. 2010. View Article : Google Scholar :
5	Schauer IG, Zhang J, Xing Z, Guo X, Mercado-Uribe I, Sood AK, Huang P and Liu J: Interleukin-1β promotes ovarian tumorigenesis through a p53/NF-κB-mediated inflammatory response in stromal fibroblasts. Neoplasia. 15:409–420. 2013. View Article : Google Scholar : PubMed/NCBI
6	Lin JT, Wang JY, Chen MK, Chen HC, Chang TH, Su BW and Chang PJ: Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6. Exp Cell Res. 319:2216–2229. 2013. View Article : Google Scholar : PubMed/NCBI
7	Anton K, Banerjee D and Glod J: Macrophage-associated mesenchymal stem cells assume an activated, migratory, pro-Inflammatory phenotype with increased IL-6 and CXCL10 secretion. PLoS One. 7:e350362012. View Article : Google Scholar : PubMed/NCBI
8	Huang F, Wang M, Yang T, Cai J, Zhang Q, Sun Z, Wu X, Zhang X, Zhu W, Qian H and Xu W: Gastric cancer-derived MSC-secreted PDGF-DD promotes gastric cancer progression. J Cancer Res Clin Oncol. 140:1835–1848. 2014. View Article : Google Scholar : PubMed/NCBI
9	Deshmane SL, Kremlev S, Amini S and Sawaya BE: Monocyte chemoattractant protein-1 (MCP-1): An overview. J Interferon Cytokine Res. 29:313–326. 2009. View Article : Google Scholar : PubMed/NCBI
10	Zhang J, Patel L and Pienta KJ: CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 21:41–48. 2010. View Article : Google Scholar :
11	Li X, Xu Q, Wu Y, Li J, Tang D, Han L and Fan Q: A CCL2/ROS autoregulation loop is critical for cancer-associated fibroblasts-enhanced tumor growth of oral squamous cell carcinoma. Carcinogenesis. 35:1362–1370. 2014. View Article : Google Scholar : PubMed/NCBI
12	Chen C, Duckworth CA, Fu B, Pritchard DM, Rhodes JM and Yu LG: Circulating galectins -2, -4 and -8 in cancer patients make important contributions to the increased circulation of several cytokines and chemokines that promote angiogenesis and metastasis. Br J Cancer. 110:741–752. 2014. View Article : Google Scholar : PubMed/NCBI
13	Rokavec M, Wu W and Luo JL: IL6-mediated suppression of miR-200c directs constitutive activation of inflammatory signaling circuit driving transformation and tumorigenesis. Mol Cell. 45:777–789. 2012. View Article : Google Scholar : PubMed/NCBI
14	Wu J, Liu X and Wang Y: Predictive value of preoperative serum CCL2, CCL18 and VEGF for the patients with gastric cancer. BMC Clin Pathol. 13(15)2013. View Article : Google Scholar
15	Tao LL, Shi SJ, Chen LB and Huang GC: Expression of Monocyte chemotactic protein-1/CCL2 in gastric cancer and its relationship with tumor hypoxia. World J Gastroenterol. 20:4421–4427. 2014. View Article : Google Scholar : PubMed/NCBI
16	Crew KD and Neugut AI: Epidemiology of gastric cancer. World J Gastroenterol. 12:354–362. 2006.PubMed/NCBI
17	Aggarwal BB and Gehlot P: Inflammation and cancer: How friendly is the relationship for cancer patients? Curr Opin Pharmacol. 9:351–369. 2009. View Article : Google Scholar : PubMed/NCBI
18	Abe M, Yamashita S, Kuramoto T, Hirayama Y, Tsukamoto T, Ohta T, Tatematsu M, Ohki M, Takato T, Sugimura T and Ushijima T: Global expression analysis of N-methyl-N′-nitro-N-nitrosoguanidine-induced rat stomach carcinomas using oligonucleotide microarrays. Carcinogenesis. 24:861–867. 2003. View Article : Google Scholar : PubMed/NCBI
19	Raphael KR, Sabu M, Kumar KH and Kuttan R: Inhibition of N-Methyl-N′-nitro-N-nitrosoguanidine (MNNG) induced gastric carcinogenesis by Phyllanthus amarus extract. Asian Pac J Cancer Prev. 7:299–302. 2006.PubMed/NCBI
20	Li JX, Wang ZB, Zhu LQ, Niu FL and Cui W: Effects of Radix notoginseng extracts drug-containing serum on expressions of bcl-2, Bax and p21WAF1 proteins in MNNG transformed GES-1 cells. Zhong Xi Yi Jie He Xue Bao. 6:817–820. 2008.PubMed/NCBI
21	Kundu JK and Surh YJ: Inflammation: Gearing the journey to cancer. Mutat Res. 659:15–30. 2008. View Article : Google Scholar : PubMed/NCBI
22	Xu Y, Zhao Y, Xu W, Luo F, Wang B, Li Y, Pang Y and Liu Q: Involvement of HIF-2α-mediated inflammation in arsenite-induced transformation of human bronchial epithelial cells. Toxicol Appl Pharmacol. 272:542–550. 2013. View Article : Google Scholar : PubMed/NCBI
23	Luo F, Xu Y, Ling M, Zhao Y, Xu W, Liang X, Jiang R, Wang B, Bian Q and Liu Q: Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells. Toxicol Appl Pharmacol. 273:27–34. 2013. View Article : Google Scholar : PubMed/NCBI
24	Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M and Ochiai A: Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 125:1276–1284. 2009. View Article : Google Scholar : PubMed/NCBI
25	Lu Y, Cai Z, Galson DL, Xiao G, Liu Y, George DE, Melhem MF, Yao Z and Zhang J: Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate. 66:1311–1318. 2006. View Article : Google Scholar : PubMed/NCBI
26	Li M, Knight DA, A Snyder L, Smyth MJ and Stewart TJ: A role for CCL2 in both tumor progression and immunosurveillance. Oncoimmunology. 2:e254742013. View Article : Google Scholar : PubMed/NCBI
27	Fang WB, Jokar I, Zou A, Lambert D, Dendukuri P and Cheng N: CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 287:36593–36608. 2012. View Article : Google Scholar : PubMed/NCBI
28	Ma Y, Adjemian S, Galluzzi L, Zitvogel L and Kroemer G: Chemokines and chemokine receptors required for optimal responses to anticancer chemotherapy. Oncoimmunology. 3:e276632014. View Article : Google Scholar : PubMed/NCBI
29	Wolf MJ, Hoos A, Bauer J, Boettcher S, Knust M, Weber A, Simonavicius N, Schneider C, Lang M, Stürzl M, et al: Endothelial CCR2 signaling Induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK Pathway. Cancer Cell. 22:91–105. 2012. View Article : Google Scholar : PubMed/NCBI
30	Gao J, Wang A, Zhang M, Li H, Wang K, Han Y, Wang Z, Shi C and Wang W: RNAi targeting of CCR2 gene expression induces apoptosis and inhibits the proliferation, migration and invasion of PC-3M cells. Oncol Res. 21:73–82. 2013. View Article : Google Scholar
31	Lu Y, Chen Q, Corey E, Xie W, Fan J, Mizokami A and Zhang J: Activation of MCP-1/CCR2 axis promotes prostate cancer growth in bone. Clin Exp Metastasis. 26:161–169. 2009. View Article : Google Scholar
32	Furukawa S, Soeda S, Kiko Y, Suzuki O, Hashimoto Y, Watanabe T, Nishiyama H, Tasaki K, Hojo H, Abe M and Fujimori K: MCP-1 promotes invasion and adhesion of human ovarian cancer cells. Anticancer Res. 33:4785–4790. 2013.PubMed/NCBI
33	Voulgari A and Pintzas A: Epithelial-mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta. 1796:75–90. 2009.PubMed/NCBI
34	Zhang H, Liu L, Wang Y, Zhao G, Xie R, Liu C, Xiao X, Wu K, Nie Y, Zhang H and Fan D: KLF8 involves in TGF-beta-induced EMT and promotes invasion and migration in gastric cancer cells. J Cancer Res Clin Oncol. 139:1033–1042. 2013. View Article : Google Scholar : PubMed/NCBI
35	Peng Z, Wang CX, Fang EH, Wang GB and Tong Q: Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 20:5403–5410. 2014. View Article : Google Scholar : PubMed/NCBI