幽门螺杆菌感染和环氧化酶-2在胃癌发生中的作用研究进展
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摘要
胃恶性肿瘤是致死率极高的恶性肿瘤之一,大量流行病学调查,动物和实验研究均证明幽门螺杆菌(Hp)感染对于胃癌的发生发展至关重要,但其确切作用机制仍存在争议。现已证明,环氧化酶-2(COX-2)在胃黏膜癌变过程中表达上调,高表达的COX-2参与胃癌的发生,调控胃癌的浸润程度,影响胃癌的转移。文章主要对有关Hp感染及其诱导的COX-2表达在胃癌发生中作用的研究进展进行综述。
Gastric cancer is one of the most frequent neoplasms and a main cause of the death worldwide especially in China and Japan. Numerous epidemiological,animal and experimental studies support a positive association between chronic Helicobacter pylori(H. pylori)infection and the development of gastric cancer. However,the exact mechanism whereby H. pylori causes gastric carcinogenesis remains still unclear. It has been demonstrated that expression of cyclooxygenase-2(COX-2)is elevated in gastric carcinomas and in their precursor lesions. Overexpression of COX-2 plays an important role in the carcinogenesis,invasion and metastasis of gastric cancer. In this review,we present the latest clinical and experimental evidences showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.
Gastric cancer is one of the most frequent neoplasms and a main cause of the death worldwide especially in China and Japan. Numerous epidemiological,animal and experimental studies support a positive association between chronic Helicobacter pylori(H. pylori)infection and the development of gastric cancer. However,the exact mechanism whereby H. pylori causes gastric carcinogenesis remains still unclear. It has been demonstrated that expression of cyclooxygenase-2(COX-2)is elevated in gastric carcinomas and in their precursor lesions. Overexpression of COX-2 plays an important role in the carcinogenesis,invasion and metastasis of gastric cancer. In this review,we present the latest clinical and experimental evidences showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.
引文
[1]杨辛怡,季国忠.幽门螺杆菌感染的治疗方案[J].东南国防医药,2017,19(3):280-284.
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[3] Parsonnet J,Friedman GD,Vandersteen DP,et al. Helicobacter pylori infection and the risk of gastric carcinoma[J]. N Engl J Med,1991,325:1127-1131
[4] Nomura A,Stemmermann GN,Chyou PH,et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii[J]. N Engl J Med,1991,325:1132-1136.
[5] Eslick GD,Lim LL,Byles JE,et al. Association of Helicobacter pylori infection with gastric carcinoma:a meta-analysis[J]. Am J Gastroenterol,1999,94(9):2373-2379.
[6]胡洁,孙哲,梅林.幽门螺杆菌细胞毒导致胃癌发生的作用机制[J].中国药理学通报,2014,30(2):156-159.
[7] Huang JQ,Zheng GF,Sumanac K,et al. Meta-analysis of the relationship between cagA seropositivity and gastric cancer[J].Gastroenterology,2003,125(6):1636-1644.
[8]蒋利锋,王强,钮秋亚,等.胃癌病理特征改变与幽门螺旋杆菌感染的相关性分析[J].现代生物医学进展,2014,14(36):7087-7089,7129.
[9] Parsonnet J,Friedman GD,Orentreich N,et al. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection[J]. Gut,1997,40(3):297-301.
[10] Shimizu N,Ikehara Y,Inada K,et al. Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian gerbils[J]. Cancer Res,2000,60(6):1512-1514.
[11] Nozaki K,Shimizu N,Ikehara Y,et al. Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils[J]. Cancer Sci,2003,94(3):235-239.
[12] Correa P. Human gastric carcinogenesis:a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention[J]. Cancer Res,1992,52(24):6735-6740.
[13] Uemura N,Mukai T,Okamoto S,et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer[J]. Cancer Epidemiol Biomarkers Prev,1997,6(8):639-642.
[14] Fukase K,Kato M,Kikuchi S,et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer:an open-label,randomised controlled trial[J]. Lancet,2008,372(9636):392-397.
[15] Ford AC,Forman D,Hunt RH,et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals:systematic review and meta-analysis of randomised controlled trials[J]. BMJ,2014,348:g3174.
[16] Wong BC,Lam SK,Wong WM,et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China:a randomized controlled trial[J]. JAMA,2004,291(2):187-194.
[17] Wang J,Xu L,Shi R,et al. Gastric atrophy and intestinal metaplasia before and after Helicobacter pylori eradication:a metaanalysis[J]. Digestion,2011,83(4):253-260.
[18] Niwa T,Toyoda T,Tsukamoto T,et al. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent[J]. Cancer Prev Res(Phila),2013,6(4):263-270.
[19] Zhou J,Xie Y,Zhao Y,et al. Human gastrin mRNA expression up-regulated by Helicobacter pylori CagA through MEK/ERK and JAK2-signaling pathways in gastric cancer cells[J]. Gastric Cancer,2011,14(4):322-331.
[20] Beales I,Blaser MJ,Srinivasan S,et al. Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells[J]. Gastroenterology,1997,113(2):465-471.
[21] Beales IL,Calam J. Helicobacter pylori increases gastrin release from cultured canine antral G-cells[J]. Eur J Gastroenterol Hepatol,2000,12(6):641-644.
[22] Lehmann FS,Golodner EH,Wang J,et al. Mononuclear cells and cytokines stimulate gastrin release from canine antral cells in primary culture[J]. Am J Physiol,1996,270(5 Pt 1):G783-788.
[23]朱人敏,秦苏堤,金鑫鑫,等.幽门螺杆菌分型与上消化道疾病的关系[J].医学研究生学报,2005,18(10):911-917.
[24] De Francesco V,Zullo A,Rinaldi V,et al. Relationship between antral lymphocyte density and basal gastrin levels in patients with Helicobacter pylori infection[J]. Dig Liver Dis,2000,32(8):676-681.
[25] Romano M,Ricci V,Memoli A,et al. Helicobacter pylori upregulates cyclooxygenase-2 mRNA expression and prostaglandin E2 synthesis in MKN 28 gastric mucosal cells in vitro[J]. J Biol Chem,1998,273(44):28560-28563.
[26] Li Q,Liu N,Shen B,et al. Helicobacter pylori enhances cyclooxygenase 2 expression via p38MAPK/ATF-2 signaling pathway in MKN45 cells[J]. Cancer Lett,2009,278(1):97-103.
[27] Sun WH,Zhu F,Chen GS,et al. Blockade of cholecystokinin-2 receptor and cyclooxygenase-2 synergistically induces cell apoptosis,and inhibits the proliferation of human gastric cancer cells in vitro[J]. Cancer Lett,2008,263(2):302-311.
[28] Nardone G,Rocco A,Vaira D,et al. Expression of COX-2,mPGE-synthase1,MDR-1(P-gp),and Bcl-xL:a molecular pathway of H pylori-related gastric carcinogenesis[J]. J Pathol,2004,202(3):305-312.
[29] Xu W,Chen GS,Shao Y,et al. Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells[J]. Cancer Lett,2013,332(1):11-18.
[30] Konturek PC,Rembiasz K,Konturek SJ,et al. Gene expression of ornithine decarboxylase,cyclooxygenase-2,and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy[J]. Dig Dis Sci,2003,48(1):36-46.
[31] Gibbons AH,Legon S,Walker MM,et al. The effect of gastrinreleasing peptide on gastrin and somatostatin messenger RNAs in humans infected with Helicobacter pylori[J]. Gastroenterology,1997,112(6):1940-1947.
[32] Sumii M,Sumii K,Tari A,et al. Expression of antral gastrin and somatostatin mRNA in Helicobacter pylori-infected subjects[J]. Am J Gastroenterol,1994,89(9):1515-1519.
[33] Smith JT,Pounder RE,Nwokolo CU,et al. Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori[J]. Gut,1990,31(5):522-525.
[34] Levi S,Beardshall K,Swift I,et al. Antral Helicobacter pylori,hypergastrinaemia,and duodenal ulcers:effect of eradicating the organism[J]. BMJ,1989,299(6714):1504-1505.
[35] Moss SF,Legon S,Bishop AE,et al. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease[J]. Lancet,1992,340(8825):930-932.
[36] Chao C,Hellmich MR. Gastrin,inflammation,and carcinogenesis[J]. Curr Opin Endocrinol Diabetes Obes,2010,17(1):33-39.
[37] Xu W,Chen GS,Shao Y,et al. Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells[J]. Cancer Lett,2013,332(1):11-18.
[38] Semple G,Ryder H,Rooker DP,et al.(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzo diazepin-3-yl)-N'-(3-(methylamino)phenyl)urea(YF476):a potent and orally active gastrin/CCK-B antagonist[J]. J Med Chem,1997,40(3):331-341.
[39] Takaishi S,Cui G,Frederick DM,et al. Synergistic inhibitory effects of gastrin and histamine receptor antagonists on Helicobacter-induced gastric cancer[J]. Gastroenterology,2005,128(7):1965-1983.
[40] Matsushima K,Isomoto H,Inoue N,et al. MicroRNA signatures in Helicobacter pylori-infected gastric mucosa[J]. Int J Cancer,2011,128(2):361-370.
[41] Wang WH,Huang JQ,Zheng GF,et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer:a systematic review and meta-analysis[J]. J Natl Cancer Inst,2003,95(23):1784-1791.
[42] Hu PJ,Yu J,Zeng ZR,et al. Chemoprevention of gastric cancer by celecoxib in rats[J]. Gut,2004,53(2):195-200.
[43] Saukkonen K,Tomasetto C,Narko K,et al. Cyclooxygenase-2expression and effect of celecoxib in gastric adenomas of trefoil factor 1-deficient mice[J]. Cancer Res,2003,63(12):3032-3036.
[44] Futagami S,Suzuki K,Hiratsuka T,et al. Celecoxib inhibits Cdx2 expression and prevents gastric cancer in Helicobacter pylori-infected Mongolian gerbils[J]. Digestion,2006,74(3-4):187-198.
[45] Magari H,Shimizu Y,Inada K,et al. Inhibitory effect of etodolac,a selective cyclooxygenase-2 inhibitor,on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils[J].Biochem Biophys Res Commun,2005,334(2):606-612.
[2] Fox JG,Wang TC,Rogers AB,et al. Host and microbial constituents influence Helicobacter pylori-induced cancer in a murine model of hypergastrinemia[J]. Gastroenterology,2003,124(7):1879-1890.
[3] Parsonnet J,Friedman GD,Vandersteen DP,et al. Helicobacter pylori infection and the risk of gastric carcinoma[J]. N Engl J Med,1991,325:1127-1131
[4] Nomura A,Stemmermann GN,Chyou PH,et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii[J]. N Engl J Med,1991,325:1132-1136.
[5] Eslick GD,Lim LL,Byles JE,et al. Association of Helicobacter pylori infection with gastric carcinoma:a meta-analysis[J]. Am J Gastroenterol,1999,94(9):2373-2379.
[6]胡洁,孙哲,梅林.幽门螺杆菌细胞毒导致胃癌发生的作用机制[J].中国药理学通报,2014,30(2):156-159.
[7] Huang JQ,Zheng GF,Sumanac K,et al. Meta-analysis of the relationship between cagA seropositivity and gastric cancer[J].Gastroenterology,2003,125(6):1636-1644.
[8]蒋利锋,王强,钮秋亚,等.胃癌病理特征改变与幽门螺旋杆菌感染的相关性分析[J].现代生物医学进展,2014,14(36):7087-7089,7129.
[9] Parsonnet J,Friedman GD,Orentreich N,et al. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection[J]. Gut,1997,40(3):297-301.
[10] Shimizu N,Ikehara Y,Inada K,et al. Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian gerbils[J]. Cancer Res,2000,60(6):1512-1514.
[11] Nozaki K,Shimizu N,Ikehara Y,et al. Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils[J]. Cancer Sci,2003,94(3):235-239.
[12] Correa P. Human gastric carcinogenesis:a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention[J]. Cancer Res,1992,52(24):6735-6740.
[13] Uemura N,Mukai T,Okamoto S,et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer[J]. Cancer Epidemiol Biomarkers Prev,1997,6(8):639-642.
[14] Fukase K,Kato M,Kikuchi S,et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer:an open-label,randomised controlled trial[J]. Lancet,2008,372(9636):392-397.
[15] Ford AC,Forman D,Hunt RH,et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals:systematic review and meta-analysis of randomised controlled trials[J]. BMJ,2014,348:g3174.
[16] Wong BC,Lam SK,Wong WM,et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China:a randomized controlled trial[J]. JAMA,2004,291(2):187-194.
[17] Wang J,Xu L,Shi R,et al. Gastric atrophy and intestinal metaplasia before and after Helicobacter pylori eradication:a metaanalysis[J]. Digestion,2011,83(4):253-260.
[18] Niwa T,Toyoda T,Tsukamoto T,et al. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent[J]. Cancer Prev Res(Phila),2013,6(4):263-270.
[19] Zhou J,Xie Y,Zhao Y,et al. Human gastrin mRNA expression up-regulated by Helicobacter pylori CagA through MEK/ERK and JAK2-signaling pathways in gastric cancer cells[J]. Gastric Cancer,2011,14(4):322-331.
[20] Beales I,Blaser MJ,Srinivasan S,et al. Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells[J]. Gastroenterology,1997,113(2):465-471.
[21] Beales IL,Calam J. Helicobacter pylori increases gastrin release from cultured canine antral G-cells[J]. Eur J Gastroenterol Hepatol,2000,12(6):641-644.
[22] Lehmann FS,Golodner EH,Wang J,et al. Mononuclear cells and cytokines stimulate gastrin release from canine antral cells in primary culture[J]. Am J Physiol,1996,270(5 Pt 1):G783-788.
[23]朱人敏,秦苏堤,金鑫鑫,等.幽门螺杆菌分型与上消化道疾病的关系[J].医学研究生学报,2005,18(10):911-917.
[24] De Francesco V,Zullo A,Rinaldi V,et al. Relationship between antral lymphocyte density and basal gastrin levels in patients with Helicobacter pylori infection[J]. Dig Liver Dis,2000,32(8):676-681.
[25] Romano M,Ricci V,Memoli A,et al. Helicobacter pylori upregulates cyclooxygenase-2 mRNA expression and prostaglandin E2 synthesis in MKN 28 gastric mucosal cells in vitro[J]. J Biol Chem,1998,273(44):28560-28563.
[26] Li Q,Liu N,Shen B,et al. Helicobacter pylori enhances cyclooxygenase 2 expression via p38MAPK/ATF-2 signaling pathway in MKN45 cells[J]. Cancer Lett,2009,278(1):97-103.
[27] Sun WH,Zhu F,Chen GS,et al. Blockade of cholecystokinin-2 receptor and cyclooxygenase-2 synergistically induces cell apoptosis,and inhibits the proliferation of human gastric cancer cells in vitro[J]. Cancer Lett,2008,263(2):302-311.
[28] Nardone G,Rocco A,Vaira D,et al. Expression of COX-2,mPGE-synthase1,MDR-1(P-gp),and Bcl-xL:a molecular pathway of H pylori-related gastric carcinogenesis[J]. J Pathol,2004,202(3):305-312.
[29] Xu W,Chen GS,Shao Y,et al. Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells[J]. Cancer Lett,2013,332(1):11-18.
[30] Konturek PC,Rembiasz K,Konturek SJ,et al. Gene expression of ornithine decarboxylase,cyclooxygenase-2,and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy[J]. Dig Dis Sci,2003,48(1):36-46.
[31] Gibbons AH,Legon S,Walker MM,et al. The effect of gastrinreleasing peptide on gastrin and somatostatin messenger RNAs in humans infected with Helicobacter pylori[J]. Gastroenterology,1997,112(6):1940-1947.
[32] Sumii M,Sumii K,Tari A,et al. Expression of antral gastrin and somatostatin mRNA in Helicobacter pylori-infected subjects[J]. Am J Gastroenterol,1994,89(9):1515-1519.
[33] Smith JT,Pounder RE,Nwokolo CU,et al. Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori[J]. Gut,1990,31(5):522-525.
[34] Levi S,Beardshall K,Swift I,et al. Antral Helicobacter pylori,hypergastrinaemia,and duodenal ulcers:effect of eradicating the organism[J]. BMJ,1989,299(6714):1504-1505.
[35] Moss SF,Legon S,Bishop AE,et al. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease[J]. Lancet,1992,340(8825):930-932.
[36] Chao C,Hellmich MR. Gastrin,inflammation,and carcinogenesis[J]. Curr Opin Endocrinol Diabetes Obes,2010,17(1):33-39.
[37] Xu W,Chen GS,Shao Y,et al. Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells[J]. Cancer Lett,2013,332(1):11-18.
[38] Semple G,Ryder H,Rooker DP,et al.(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzo diazepin-3-yl)-N'-(3-(methylamino)phenyl)urea(YF476):a potent and orally active gastrin/CCK-B antagonist[J]. J Med Chem,1997,40(3):331-341.
[39] Takaishi S,Cui G,Frederick DM,et al. Synergistic inhibitory effects of gastrin and histamine receptor antagonists on Helicobacter-induced gastric cancer[J]. Gastroenterology,2005,128(7):1965-1983.
[40] Matsushima K,Isomoto H,Inoue N,et al. MicroRNA signatures in Helicobacter pylori-infected gastric mucosa[J]. Int J Cancer,2011,128(2):361-370.
[41] Wang WH,Huang JQ,Zheng GF,et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer:a systematic review and meta-analysis[J]. J Natl Cancer Inst,2003,95(23):1784-1791.
[42] Hu PJ,Yu J,Zeng ZR,et al. Chemoprevention of gastric cancer by celecoxib in rats[J]. Gut,2004,53(2):195-200.
[43] Saukkonen K,Tomasetto C,Narko K,et al. Cyclooxygenase-2expression and effect of celecoxib in gastric adenomas of trefoil factor 1-deficient mice[J]. Cancer Res,2003,63(12):3032-3036.
[44] Futagami S,Suzuki K,Hiratsuka T,et al. Celecoxib inhibits Cdx2 expression and prevents gastric cancer in Helicobacter pylori-infected Mongolian gerbils[J]. Digestion,2006,74(3-4):187-198.
[45] Magari H,Shimizu Y,Inada K,et al. Inhibitory effect of etodolac,a selective cyclooxygenase-2 inhibitor,on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils[J].Biochem Biophys Res Commun,2005,334(2):606-612.