CXCR1 promotes malignant behavior of gastric cancer cells in vitro and in vivo in AKT and ERK1/2 phosphorylation Corrigendum in /10.3892/ijo.2023.5520

Wang,Junpu; Hu,Wanming; Wu,Xiaoying; Wang,Kuansong; Yu,Jun; Luo,Baihua; Luo,Gengqiu; Wang,Weiyuan; Wang,Huiling; Li,Jinghe; Wen,Jifang

doi:10.3892/ijo.2016.3428

CXCR1 promotes malignant behavior of gastric cancer cells in vitro and in vivo in AKT and ERK1/2 phosphorylation

Corrigendum in: /10.3892/ijo.2023.5520

Authors:
- Junpu Wang
- Wanming Hu
- Xiaoying Wu
- Kuansong Wang
- Jun Yu
- Baihua Luo
- Gengqiu Luo
- Weiyuan Wang
- Huiling Wang
- Jinghe Li
- Jifang Wen
View Affiliations

Affiliations: Department of Pathology, Xiang-ya Hospital, Central South University, Changsha, Hunan 410083, P.R. China, Department of Pathology, School of Basic Medicine, Central South University, Changsha, Hunan 410083, P.R. China, Department of Neurology, Third Xiang-ya Hospital, Central South University, Changsha, Hunan 410083, P.R. China
Published online on: March 9, 2016 https://doi.org/10.3892/ijo.2016.3428
Pages: 2184-2196

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

CXCR1 is a member of the chemokine receptor family, which was reported to play an important role in several cancers. The present study investigated the influence of CXCR1 stable knockdown or overexpression on the malignant behavior of gastric cancer cells in vitro and in vivo and the potential mechanisms. MKN45 and BGC823 cells were stably transfected with plasmid pYr-1.1-CXCR1-shRNA (knockdown) and pIRES2-ZsGreen1-CXCR1 (overexpression), respectively. Malignant behavior was evaluated in vitro for changes in proliferation by MTT and colony forming assays; cell cycle and apoptosis by flow cytometry; and migration and invasion using transwell and wound-healing assays. Proliferation, cell cycle, apoptosis, migration and invasion-related signaling molecule expression were measured by real-time RT-PCR and western blot analysis. CXCR1 knockdown and overexpressing xenografts were monitored for in vivo tumor growth. Stable knockdown of CXCR1 inhibited MKN45 cell proliferation, migration and invasion, but were reversed in BGC823 cells stably overexpressing CXCR1. In addition, MKN45 cells stably transfected with CXCR1 shRNA inhibited AKT and ERK1/2 phosphorylation, protein expression of cyclin D1, EGFR, VEGF, MMP-9, MMP-2 and Bcl-2, and increased protein expression of Bax and E-cadherin (all P<0.05). In vivo CXCR1-shRNA-MKN45 cells transplanted into nude mice formed smaller tumors than non-transfected or scrambled-shRNA cells (both P<0.05). In contrast BGC823 cells overexpressing CXCR1 formed larger tumors in mice than cells carrying an empty expression plasmid or non-transfected cells (both P<0.05). CXCR1 promoted gastric cancer cell proliferation, migration and invasion. The present study provides preclinical data to support CXCR1 as a novel therapeutic target for gastric cancer.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Herszényi L and Tulassay Z: Epidemiology of gastrointestinal and liver tumors. Eur Rev Med Pharmacol Sci. 14:249–258. 2010.PubMed/NCBI
3	Brenner H, Rothenbacher D and Arndt V: Epidemiology of stomach cancer. Methods Mol Biol. 472:467–477. 2009. View Article : Google Scholar
4	Kusano T, Shiraishi N, Shiroshita H, Etoh T, Inomata M and Kitano S: Poor prognosis of advanced gastric cancer with metastatic suprapancreatic lymph nodes. Ann Surg Oncol. 20:2290–2295. 2013. View Article : Google Scholar : PubMed/NCBI
5	Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ and Power CA: International Union of Pharmacology. XXII Nomenclature for chemokine receptors. Pharmacol Rev. 52:145–176. 2000.PubMed/NCBI
6	Zlotnik A and Yoshie O: Chemokines: A new classification system and their role in immunity. Immunity. 12:121–127. 2000. View Article : Google Scholar : PubMed/NCBI
7	Balkwill F: Cancer and the chemokine network. Nat Rev Cancer. 4:540–550. 2004. View Article : Google Scholar : PubMed/NCBI
8	Wells TN, Lusti-Narasimhan M, Chung CW, Cooke R, Power CA, Peitsch MC and Proudfoot AE: The molecular basis of selectivity between CC and CXC chemokines: The possibility of chemokine antagonists as anti-inflammatory agents. Ann NY Acad Sci. 796:1 Cytokines. 245–256. 1996. View Article : Google Scholar : PubMed/NCBI
9	Vandercappellen J, Van Damme J and Struyf S: The role of CXC chemokines and their receptors in cancer. Cancer Lett. 267:226–244. 2008. View Article : Google Scholar : PubMed/NCBI
10	Waugh DJ and Wilson C: The interleukin-8 pathway in cancer. Clin Cancer Res. 14:6735–6741. 2008. View Article : Google Scholar : PubMed/NCBI
11	Singh S, Nannuru KC, Sadanandam A, Varney ML and Singh RK: CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. Br J Cancer. 100:1638–1646. 2009. View Article : Google Scholar : PubMed/NCBI
12	Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, et al: CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest. 120:485–497. 2010. View Article : Google Scholar : PubMed/NCBI
13	Chen Y, Shi M, Yu GZ, Qin XR, Jin G, Chen P and Zhu MH: Interleukin-8, a promising predictor for prognosis of pancreatic cancer. World J Gastroenterol. 18:1123–1129. 2012. View Article : Google Scholar : PubMed/NCBI
14	Li A, Varney ML and Singh RK: Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials. Clin Cancer Res. 7:3298–3304. 2001.PubMed/NCBI
15	Yang G, Rosen DG, Liu G, Yang F, Guo X, Xiao X, Xue F, Mercado-Uribe I, Huang J, Lin SH, et al: CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis. Clin Cancer Res. 16:3875–3886. 2010. View Article : Google Scholar : PubMed/NCBI
16	Leonard DA, Merhige ME, Williams BA and Greene RS: Elevated expression of the interleukin-8 receptors CXCR1 and CXCR2 in peripheral blood cells in obstructive coronary artery disease. Coron Artery Dis. 22:491–496. 2011.PubMed/NCBI
17	Singh S, Wu S, Varney M, Singh AP and Singh RK: CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation. Microvasc Res. 82:318–325. 2011. View Article : Google Scholar : PubMed/NCBI
18	Wang JP, Hu WM, Wang KS, Yu J, Luo BH, Wu C, Chen ZH, Luo GQ, Liu YW, Liu QL, et al: Expression of C-X-C chemokine receptor types 1/2 in patients with gastric carcinoma: Clinicopathological correlations and significance. Oncol Lett. 5:574–582. 2013.PubMed/NCBI
19	Park SH, Das BB, Casagrande F, Tian Y, Nothnagel HJ, Chu M, Kiefer H, Maier K, De Angelis AA, Marassi FM, et al: Structure of the chemokine receptor CXCR1 in phospholipid bilayers. Nature. 491:779–783. 2012.PubMed/NCBI
20	Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G and Linsley PS: Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol. 21:635–637. 2003. View Article : Google Scholar : PubMed/NCBI
21	Fedorov Y, Anderson EM, Birmingham A, Reynolds A, Karpilow J, Robinson K, Leake D, Marshall WS and Khvorova A: Off-target effects by siRNA can induce toxic phenotype. RNA. 12:1188–1196. 2006. View Article : Google Scholar : PubMed/NCBI
22	Li Z, Wang Y, Dong S, Ge C, Xiao Y, Li R, Ma X, Xue Y, Zhang Q, Lv J, et al: Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro. Cytokine. 69:6–13. 2014. View Article : Google Scholar : PubMed/NCBI
23	Almhanna K, Strosberg J and Malafa M: Targeting AKT protein kinase in gastric cancer. Anticancer Res. 31:4387–4392. 2011.PubMed/NCBI
24	Sasaki T and Kuniyasu H: Significance of AKT in gastric cancer (Review). Int J Oncol. 45:2187–2192. 2014.PubMed/NCBI
25	Zhang Y, Wang L, Zhang M, Jin M, Bai C and Wang X: Potential mechanism of interleukin-8 production from lung cancer cells: An involvement of EGF-EGFR-PI3K-Akt-Erk pathway. J Cell Physiol. 227:35–43. 2012. View Article : Google Scholar
26	Knall C, Worthen GS and Johnson GL: Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc Natl Acad Sci USA. 94:3052–3057. 1997. View Article : Google Scholar : PubMed/NCBI
27	Correia C, Lee SH, Meng XW, Vincelette ND, Knorr KL, Ding H, Nowakowski GS, Dai H and Kaufmann SH: Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment. Biochim Biophys Acta. 1853:1658–1671. 2015. View Article : Google Scholar : PubMed/NCBI
28	Ye X, Guo Y, Zhang Q, Chen W, Hua X, Liu W, Yang Y and Chen G: βKlotho suppresses tumor growth in hepatocellular carcinoma by regulating Akt/GSK-3β/cyclin D1 signaling pathway. PLoS One. 8:e556152013. View Article : Google Scholar
29	Tsai HL, Yeh YS, Chang YT, Yang IP, Lin CH, Kuo CH, Juo SH and Wang JY: Co-existence of cyclin D1 and vascular endothe-lial growth factor protein expression is a poor prognostic factor for UICC stage I-III colorectal cancer patients after curative resection. J Surg Oncol. 107:148–154. 2013. View Article : Google Scholar
30	Venkatakrishnan G, Salgia R and Groopman JE: 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. 2000. View Article : Google Scholar : PubMed/NCBI
31	Luppi F, Longo AM, de Boer WI, Rabe KF and Hiemstra PS: Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer. 56:25–33. 2007. View Article : Google Scholar
32	Roomi MW, Monterrey JC, Kalinovsky T, Rath M and Niedzwiecki A: Comparative effects of EGCG, green tea and a nutrient mixture on the patterns of MMP-2 and MMP-9 expression in cancer cell lines. Oncol Rep. 24:747–757. 2010.PubMed/NCBI
33	Roomi MW, Monterrey JC, Kalinovsky T, Rath M and Niedzwiecki A: Patterns of MMP-2 and MMP-9 expression in human cancer cell lines. Oncol Rep. 21:1323–1333. 2009.PubMed/NCBI
34	Sancéau J, Truchet S and Bauvois B: Matrix metalloproteinase-9 silencing by RNA interference triggers the migratory-adhesive switch in Ewing's sarcoma cells. J Biol Chem. 278:36537–36546. 2003. View Article : Google Scholar : PubMed/NCBI
35	Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, et al: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2:737–744. 2000. View Article : Google Scholar : PubMed/NCBI
36	Liu X and Chu KM: E-cadherin and gastric cancer: Cause, consequence, and applications. Biomed Res Int. 2014:6373082014.PubMed/NCBI
37	Carneiro P, Figueiredo J, Bordeira-Carriço R, Fernandes MS, Carvalho J, Oliveira C and Seruca R: Therapeutic targets associated to E-cadherin dysfunction in gastric cancer. Expert Opin Ther Targets. 17:1187–1201. 2013. View Article : Google Scholar : PubMed/NCBI
38	Kitadai Y: Cancer-stromal cell interaction and tumor angiogenesis in gastric cancer. Cancer Microenviron. 3:109–116. 2010. View Article : Google Scholar
39	Bădescu A, Georgescu CV, Vere CC, Crăiţoiu S and Grigore D: Correlations between Her2 oncoprotein, VEGF expression, MVD and clinicopathological parameters in gastric cancer. Rom J Morphol Embryol. 53:997–1005. 2012.