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Published in: Digestive Diseases and Sciences 4/2010

01-04-2010 | Original Article

Involvement of Ras and AP-1 in Helicobacter pylori-Induced Expression of COX-2 and iNOS in Gastric Epithelial AGS Cells

Authors: Soon Ok Cho, Joo Weon Lim, Kyung Hwan Kim, Hyeyoung Kim

Published in: Digestive Diseases and Sciences | Issue 4/2010

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Abstract

Helicobacter pylori (H. pylori) is an important risk factor for chronic gastritis, peptic ulcer, and gastric cancer. The genetic differences of H. pylori isolates play a role in the clinical outcome of the infection. Inflammatory genes including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are involved in H. pylori gastritis. Transcription factor AP-1 is composed of c-Fos and c-Jun and mediates inflammation and carcinogenesis. Ras acts as a regulator for AP-1 activation in various cells. We investigated whether H. pylori in a Korean isolate (HP99), a cagA + , vacA + strain, induces the expression of c-Fos and c-Jun for AP-1 activation to induce COX-2 and iNOS and whether HP99-induced expressions of COX-2 and iNOS are mediated by Ras and AP-1, determined by the expressions of c-Fos and c-Jun, in gastric epithelial AGS cells, using transfection with mutant genes for Ras (ras N-17) and c-Jun (TAM-67). As a result, HP99 induced the expression of c-Fos and c-Jun and the expressions of COX-2 and iNOS in AGS cells. Transfection with mutant genes for Ras or c-Jun suppressed HP99-induced expressions of COX-2 and iNOS in AGS cells. In conclusion, H. pylori in a Korean isolate induces the expression of COX-2 and iNOS via AP-1 activation, which may be mediated by Ras and the expression of c-Fos and c-Jun in gastric epithelial cells.
Literature
1.
go back to reference Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991;325:1127–1131.PubMed Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991;325:1127–1131.PubMed
2.
3.
4.
7.
go back to reference Boolbol SK, Dannenberg AJ, Chadburn A, et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996;56:2556–2560.PubMed Boolbol SK, Dannenberg AJ, Chadburn A, et al. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996;56:2556–2560.PubMed
9.
go back to reference Lechner M, Rieder J, Tilg H. Helicobacter pylori infection, iNOS, and gastric cancer: the impact of another possible link. J Surg Oncol. 2006;94:226–233. doi:10.1002/jso.20372.CrossRef Lechner M, Rieder J, Tilg H. Helicobacter pylori infection, iNOS, and gastric cancer: the impact of another possible link. J Surg Oncol. 2006;94:226–233. doi:10.​1002/​jso.​20372.CrossRef
12.
go back to reference Seo JH, Kim H, Kim KH. Cyclooxygenase-2 expression by transcription factors in Helicobacter pylori–infected gastric epithelial cells: Comparison between HP99 and NCTC 11637. Ann N Y Acad Sci. 2002;937:477–480.CrossRef Seo JH, Kim H, Kim KH. Cyclooxygenase-2 expression by transcription factors in Helicobacter pylori–infected gastric epithelial cells: Comparison between HP99 and NCTC 11637. Ann N Y Acad Sci. 2002;937:477–480.CrossRef
13.
go back to reference Kim H, Seo JY, Kim KH. Effects of mannitol and dimethylthiourea on Helicobacter pylori -induced IL-8 production in gastric epithelial cells. Pharmacology. 1999;59:201–211. doi:10.1159/000028321.CrossRefPubMed Kim H, Seo JY, Kim KH. Effects of mannitol and dimethylthiourea on Helicobacter pylori -induced IL-8 production in gastric epithelial cells. Pharmacology. 1999;59:201–211. doi:10.​1159/​000028321.CrossRefPubMed
14.
go back to reference Seo JY, Kim H, Kim KH. Transcriptional regulation by thiol compounds in Helicobacter pylori -induced interleukin-8 production in human gastric epithelial cells. Ann N Y Acad Sci. 2002;973:541–545.CrossRefPubMed Seo JY, Kim H, Kim KH. Transcriptional regulation by thiol compounds in Helicobacter pylori -induced interleukin-8 production in human gastric epithelial cells. Ann N Y Acad Sci. 2002;973:541–545.CrossRefPubMed
15.
17.
go back to reference Seo JH, Lim JW, Kim H, Kim KH. Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-κB and induces chemokine expression in gastric epithelial AGS cells. Lab Invest. 2004;84:49–62. doi:10.1038/labinvest.3700010.CrossRefPubMed Seo JH, Lim JW, Kim H, Kim KH. Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-κB and induces chemokine expression in gastric epithelial AGS cells. Lab Invest. 2004;84:49–62. doi:10.​1038/​labinvest.​3700010.CrossRefPubMed
18.
go back to reference Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochim Biophys Acta. 1991;1072:129–139.PubMed Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochim Biophys Acta. 1991;1072:129–139.PubMed
19.
go back to reference Wasylyk C, Imler JL, Wasylyk B. Transforming but not immortalizing oncogenes activate the transcription factor PEA1. EMBO J. 1988;7:2475–2483.PubMed Wasylyk C, Imler JL, Wasylyk B. Transforming but not immortalizing oncogenes activate the transcription factor PEA1. EMBO J. 1988;7:2475–2483.PubMed
22.
go back to reference Sistomen L, Hotta E, Makella TP. Keski Oja, Alitalo K: The cellular response to induction of the p21 c-Ha-ras oncoprotein includes stimulation of jun gene expression. EMBO J. 1989;8:815–822. Sistomen L, Hotta E, Makella TP. Keski Oja, Alitalo K: The cellular response to induction of the p21 c-Ha-ras oncoprotein includes stimulation of jun gene expression. EMBO J. 1989;8:815–822.
23.
go back to reference Keates S, Sougioultzis S, Keates AC, et al. Cag+ Helicobacter pylori induces transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem. 2001;276:48127–48134. doi:10.1074/jbc.M107838200.CrossRefPubMed Keates S, Sougioultzis S, Keates AC, et al. Cag+ Helicobacter pylori induces transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem. 2001;276:48127–48134. doi:10.​1074/​jbc.​M107838200.CrossRefPubMed
24.
26.
go back to reference Snider JL, Allison C, Bellaire BH, Ferrero RL, Cardelli JA. The beta1 integrin activates JNK independent of CgA, and JNK activation is required for Helicobacter pylori CagA+-induced motility of gastric cancer cells. J Biol Chem. 2008;283:13952–13963. doi:10.1074/jbc.M800289200.CrossRefPubMed Snider JL, Allison C, Bellaire BH, Ferrero RL, Cardelli JA. The beta1 integrin activates JNK independent of CgA, and JNK activation is required for Helicobacter pylori CagA+-induced motility of gastric cancer cells. J Biol Chem. 2008;283:13952–13963. doi:10.​1074/​jbc.​M800289200.CrossRefPubMed
27.
go back to reference Pillinger MH, Marjanovic N, Kim SY, et al. Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and–independent ERK activation. J Biol Chem. 2007;282:18722–18731. doi:10.1074/jbc.M703022200.CrossRefPubMed Pillinger MH, Marjanovic N, Kim SY, et al. Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and–independent ERK activation. J Biol Chem. 2007;282:18722–18731. doi:10.​1074/​jbc.​M703022200.CrossRefPubMed
28.
go back to reference Brown PH, Chen TK, Birrer MJ. Mechanism of action of a dominant-negative mutant of c-Jun. Oncogene. 1994;9:791–799.PubMed Brown PH, Chen TK, Birrer MJ. Mechanism of action of a dominant-negative mutant of c-Jun. Oncogene. 1994;9:791–799.PubMed
29.
go back to reference Cai H, Szeberenyi J, Cooper GM. Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells. Mol Cell Biol. 1990;10:5314–5323.PubMed Cai H, Szeberenyi J, Cooper GM. Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells. Mol Cell Biol. 1990;10:5314–5323.PubMed
32.
go back to reference Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffman EP. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem. 1994;269:6765–6772.PubMed Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffman EP. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem. 1994;269:6765–6772.PubMed
35.
go back to reference Zar BH. Biostatistical Analysis. 2nd ed. Englewood Cliffs, New Jersey: Prentice-Hall; 1984. Zar BH. Biostatistical Analysis. 2nd ed. Englewood Cliffs, New Jersey: Prentice-Hall; 1984.
36.
go back to reference Zinck R, Cahill MA, Kracht M. Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and streaa-activated protein kinase pathways that converge on Elk-1. Mol Cell Biol. 1995;15:4930–4938.PubMed Zinck R, Cahill MA, Kracht M. Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and streaa-activated protein kinase pathways that converge on Elk-1. Mol Cell Biol. 1995;15:4930–4938.PubMed
37.
go back to reference Rinegaud J, Whitmarsh AJ, Barrett T. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996;16:1247–1255. Rinegaud J, Whitmarsh AJ, Barrett T. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996;16:1247–1255.
40.
go back to reference Cichocki M, Paluszczak J, Szaefer H, Piechowiak A, Rimando AM, Baer-Dubowska W. Pterostibene is equally potent as reseveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activate NF-kappa B, AP-1, COX-2, and iNOS in mouse epidermis. Mol Nutr Food Res. 2008;52(Suppl 1):S62–S70. doi:10.1002/mnfr.200700395.PubMed Cichocki M, Paluszczak J, Szaefer H, Piechowiak A, Rimando AM, Baer-Dubowska W. Pterostibene is equally potent as reseveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activate NF-kappa B, AP-1, COX-2, and iNOS in mouse epidermis. Mol Nutr Food Res. 2008;52(Suppl 1):S62–S70. doi:10.​1002/​mnfr.​200700395.PubMed
41.
go back to reference Chittezhath M, Deep G, Singh RP, Agarwal C, Agarwal R. Sillibinin inhibits cytokine-induced signaling cascade and down-regulates inducibe nitric oxide synthase in human lung carcinoma A549 cells. Mol Cancer Ther. 2008;7:1817826. doi:10.1158/1535-7163.MCT-08-0256.CrossRef Chittezhath M, Deep G, Singh RP, Agarwal C, Agarwal R. Sillibinin inhibits cytokine-induced signaling cascade and down-regulates inducibe nitric oxide synthase in human lung carcinoma A549 cells. Mol Cancer Ther. 2008;7:1817826. doi:10.​1158/​1535-7163.​MCT-08-0256.CrossRef
42.
go back to reference Chang YJ, Wu MS, Lin JT, Chen CC. Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TKR9 and promoter regulation. J Immunol. 2005;175:8242–8252.PubMed Chang YJ, Wu MS, Lin JT, Chen CC. Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TKR9 and promoter regulation. J Immunol. 2005;175:8242–8252.PubMed
45.
go back to reference Brandt S, Shafikhani S, Balachandran P, et al. Use of a novel coinfection system reveals a role for Rac1, H-Ras, and CrkII phosphorylation in Helicobacter pylori-induced host cell actin cytoskeletal rearrangements. FEMS Immunol Med Microbiol. 2007;50:190–205. doi:10.1111/j.1574-695X.2007.00234.x.CrossRefPubMed Brandt S, Shafikhani S, Balachandran P, et al. Use of a novel coinfection system reveals a role for Rac1, H-Ras, and CrkII phosphorylation in Helicobacter pylori-induced host cell actin cytoskeletal rearrangements. FEMS Immunol Med Microbiol. 2007;50:190–205. doi:10.​1111/​j.​1574-695X.​2007.​00234.​x.CrossRefPubMed
46.
47.
48.
go back to reference Zhu Y, Zhong X, Zheng S, Du Q, Xu W. Transformed immortalized gastric epithelial cells by virulence factor CagA of Helicobacter pylori through Erk mitogen-activated protein kinase pathway. Oncogene. 2005;24:3886–3895. doi:10.1038/sj.onc.1208551.CrossRefPubMed Zhu Y, Zhong X, Zheng S, Du Q, Xu W. Transformed immortalized gastric epithelial cells by virulence factor CagA of Helicobacter pylori through Erk mitogen-activated protein kinase pathway. Oncogene. 2005;24:3886–3895. doi:10.​1038/​sj.​onc.​1208551.CrossRefPubMed
52.
go back to reference Cao X, Tsukamoto T, Seki T, et al. 4-Vinyl-2, 6-dimethoxyphenol (canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter pylori-infected carcinogen-treated Mongolian gerbils. Int J Cancer. 2008;122:1445–1454. doi:10.1002/ijc.23245.CrossRefPubMed Cao X, Tsukamoto T, Seki T, et al. 4-Vinyl-2, 6-dimethoxyphenol (canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter pylori-infected carcinogen-treated Mongolian gerbils. Int J Cancer. 2008;122:1445–1454. doi:10.​1002/​ijc.​23245.CrossRefPubMed
55.
go back to reference Toyoda T, Tsukamoto T, Hirano N, et al. Synergistic upregulation of inducible nitric oxide synthase and cyclooxygenase-2 in gastric mucosa of Mongoliaan gerbils by a high-salt diet and Helicobacter pylori infection. Histol Histopathol. 2008;23:593–599.PubMed Toyoda T, Tsukamoto T, Hirano N, et al. Synergistic upregulation of inducible nitric oxide synthase and cyclooxygenase-2 in gastric mucosa of Mongoliaan gerbils by a high-salt diet and Helicobacter pylori infection. Histol Histopathol. 2008;23:593–599.PubMed
Metadata
Title
Involvement of Ras and AP-1 in Helicobacter pylori-Induced Expression of COX-2 and iNOS in Gastric Epithelial AGS Cells
Authors
Soon Ok Cho
Joo Weon Lim
Kyung Hwan Kim
Hyeyoung Kim
Publication date
01-04-2010
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 4/2010
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-009-0828-y

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