TGR5和CDX2在胃黏膜肠化生及胃癌中的表达及意义
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摘要
目的:探讨G蛋白偶联受体(G protein-coupled receptor,TGR5)和尾型同源盒2(Caudal type homeobox 2,CDX2)在胃黏膜肠化生(Intestinal Metaplasia,IM)及胃癌中的表达和意义。方法:采用免疫组织化学染色法检测TGR5和CDX2在57例慢性胃炎、85例IM、98例胃癌组织中的表达。比较各组间TGR5和CDX2的表达差异,并分析其与胃癌临床病理参数的关系及与胃癌患者预后的关系。利用Spearman秩相关检验分析TGR5和CDX2表达的相关性。结果:IM和胃癌组织中TGR5的高表达率分别为54.1%和58.2%,二者比较无显著差异(P>0.05),但均显著高于慢性胃炎组织(P<0.01)。TGR5高表达与胃癌患者TNM分期(III+IV期)(P=0.004)、淋巴结转移(P=0.046)及预后较差(P=0.006)相关。胃癌组织中CDX2的高表达率(30.6%)较IM组织(48.2%)显著降低(P<0.05),但其均显著高于慢性胃炎组织(P<0.01)。CDX2高表达与胃癌患者TNM分期(I+II期)(P=0.008)、无淋巴结转移(P=0.014)、预后较好(P=0.023)相关。TGR5和CDX2表达在慢性胃炎和IM中无相关性(P>0.05),在胃癌中呈显著正相关(P=0.003)。结论:TGR5和CDX2在IM和胃癌组织中均显著上调,可能参与了IM和胃癌的发生发展。
Objective: To investigate the expression and significance of G protein-coupled receptor(TGR5)and Caudal type homeobox 2(CDX2) in the gastric mucosal intestinal metaplasia(IM) and gastric carcinoma. Methods: Immunohistochemical staining was used to detect the expression of TGR5 and CDX2 in 57 cases of chronic gastritis, 85 cases of IM and 98 cases of gastric cancer. The differences in expression of TGR5 and CDX2 between the groups were compared, and the relationship between the expression of TGR5 and CDX2 and the clinicpatholo-gical parameters and prognosis of gastric cancer patients were analyzed. Spearman rank correlation test was used to analyze the correlation between the TGR5 and CDX2 expression. Results: The high expression rates of TGR5 in the IM and gastric cancer tissue were 54.1% and 58.2%, respectively(P>0.05), but they were significantly higher than chronic gastritis tissue(P<0.01).High expression of TGR5 was associated with TNM stage(III+IV stage)(P=0.004), lymph node metastasis(P=0.046), and worse prognosis(P=0.006) of patients with gastric cancer. The high expression rate of CDX2 in the gastric cancer tissue(30.6%) was significantly lower than that in IM tissue(48.2%)(P<0.05), but both were significantly higher than those in the chronic gastritis tissue(P<0.01). High expression of CDX2 was associated with the TNM stage(I+II stage)(P=0.008), no lymph node metastasis(P=0.014), and better prognosis(P=0.023) in patients with gastric cancer. There was no correlation between TGR5 and CDX2 expression in the chronic gastritis and IM(P>0.05), but they were positively correlated in the gastric cancer(P=0.003). Conclusions: TGR5 and CDX2 are significantly up-regulated in both IM and gastric cancer tissues, and may be involved in the occurrence and development of IM and gastric cancer.
Objective: To investigate the expression and significance of G protein-coupled receptor(TGR5)and Caudal type homeobox 2(CDX2) in the gastric mucosal intestinal metaplasia(IM) and gastric carcinoma. Methods: Immunohistochemical staining was used to detect the expression of TGR5 and CDX2 in 57 cases of chronic gastritis, 85 cases of IM and 98 cases of gastric cancer. The differences in expression of TGR5 and CDX2 between the groups were compared, and the relationship between the expression of TGR5 and CDX2 and the clinicpatholo-gical parameters and prognosis of gastric cancer patients were analyzed. Spearman rank correlation test was used to analyze the correlation between the TGR5 and CDX2 expression. Results: The high expression rates of TGR5 in the IM and gastric cancer tissue were 54.1% and 58.2%, respectively(P>0.05), but they were significantly higher than chronic gastritis tissue(P<0.01).High expression of TGR5 was associated with TNM stage(III+IV stage)(P=0.004), lymph node metastasis(P=0.046), and worse prognosis(P=0.006) of patients with gastric cancer. The high expression rate of CDX2 in the gastric cancer tissue(30.6%) was significantly lower than that in IM tissue(48.2%)(P<0.05), but both were significantly higher than those in the chronic gastritis tissue(P<0.01). High expression of CDX2 was associated with the TNM stage(I+II stage)(P=0.008), no lymph node metastasis(P=0.014), and better prognosis(P=0.023) in patients with gastric cancer. There was no correlation between TGR5 and CDX2 expression in the chronic gastritis and IM(P>0.05), but they were positively correlated in the gastric cancer(P=0.003). Conclusions: TGR5 and CDX2 are significantly up-regulated in both IM and gastric cancer tissues, and may be involved in the occurrence and development of IM and gastric cancer.
引文
[1] Chen W, Sun K, Zheng R, et al. Cancer incidence and mortality in China, 2014[J]. Chin J Cancer Res, 2018, 30(1):1-12
[2] Yang L, Zheng R, Wang N, et al. Incidence and mortality of stomach cancer in China, 2014[J]. Chin J Cancer Res, 2018, 30(3):291-298
[3] Correa P. A human model of gastric carcinogenesis[J]. Cancer Res,1988, 48(13):3554-3560
[4] Giroux V, Rustgi A K. Metaplasia:tissue injury adaptation and a precursor to the dysplasia-cancer sequence[J]. Nat Rev Cancer, 2017, 17(10):594-604
[5] Oue N, Sentani K, Sakamoto N, et al. Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype[J]. Cancer Sci, 2015, 106(8):951-958
[6] Barros R, Freund J N, David L, et al. Gastric intestinal metaplasia revisited:function and regulation of CDX2[J]. Trends Mol Med, 2012,18(9):555-563
[7] Silberg D G, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice[J]. Gastroenterology, 2002, 122(3):689-696
[8] Mutoh H, Sakurai S, Satoh K, et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice[J]. Cancer Res,2004, 64(21):7740-7747
[9] Joo M K, Park J J, Chun H J. Impact of homeobox genes in gastrointestinal cancer[J]. World J Gastroenterol, 2016, 22(37):8247-8256
[10] Jiang J X, Liu Q, Zhao B, et al. Risk factors for intestinal metaplasia in a southeastern Chinese population:an analysis of 28,745 cases[J].J Cancer Res Clin Oncol, 2017, 143(3):409-418
[11] Karimi P, Islami F, Anandasabapathy S, et al. Gastric cancer:descriptive epidemiology, risk factors, screening, and prevention[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(5):700-713
[12] Li S, Chen X, Zhou L, et al. Farnesoid X receptor signal is involved in deoxycholic acid-induced intestinal metaplasia of normal human gastric epithelial cells[J]. Oncol Rep, 2015, 34(5):2674-2682
[13] Martinot E, Sèdes L, Baptissart M, et al. Bile acids and their receptors[J]. Mol Aspects Med, 2017, 56:2-9
[14] Duboc H, TachéY, Hofmann A F. The bile acid TGR5 membrane receptor:from basic research to clinical application[J]. Dig Liver Dis,2014, 46(4):302-312
[15]陈吉,徐征宇.胃黏膜病变过程中SOX9、CDX2基因的表达及相关性研究[J].国际消化病杂志, 2018, 38(05):340-343
[16]孙丹,武洋,辛彦,等. Sox2和Cdx2基因编码蛋白在胃癌及其癌前病变中的表达及意义[J].现代肿瘤医学, 2016, 24(10):1585-1591
[17] Liu Q, Teh M, Ito K, et al. CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer[J]. Mod Pathol, 2007, 20(12):1286-1297
[18]李玄,郅敏,何欢,等. CDX2表达水平与胃癌患者病理特征及预后的关系[J].新医学, 2017, 48(10):736-741
[19]王柏桦,孟加榕,唐忠辉,等. RRMI、CDX2在胃癌组织中的表达及临床意义[J].现代肿瘤医学, 2017, 48(05):475-478
[20] Zhang J F, Qu L S, Qian X F, et al. Nuclear transcription factor CDX2 inhibits gastric cancer cell growth and reverses epithelial to mesenchymal transition in vitro and in vivo[J]. Mol Med Rep, 2015,12(4):5231-5238
[21] Masood M A, Loya A, Yusuf M A. CDX2 as a prognostic marker in gastric cancer[J]. Acta Gastroenterol Belg, 2016, 79(2):197-200
[22] Nakayama C, Yamamichi N, Tomida S, et al. Transduced caudal type homeobox(CDX)2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation[J]. Cancer Sci,2018, 109(12):3853-3864
[23] Donkers J M, Roscam A RLP, van de Graaf SFJ. Developments in bile salt based therapies:a critical overview[J]. Biochem Pharmacol,2018, 161:1-13
[24] ani M, Stanimirov B, Pavlovi N, et al. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome[J]. Front Pharmacol, 2018, 9:1382
[25] Cao W, Tian W, Hong J, et al. Expression of bile acid receptor TGR5in gastric adenocarcinoma[J]. Am J Physiol. Gastrointest. Liver Physiol, 2013, 304(4):G322-327
[26] Carino A, Graziosi L, D'Amore C, et al. The bile acid receptor GPBAR1(TGR5)is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines[J]. Oncotarget, 2016, 7(38):61021-61035
[27] Chen M C, Chen Y L, Wang T W, et al. Membrane bile acid receptor TGR5 predicts good prognosis in ampullary adenocarcinoma patients with hyperbilirubinemia[J]. Oncol Rep, 2016, 36(4):1997-2008
[28] Matsuhisa T, Arakawa T, Watanabe T, et al. Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia:a multicenter study of 2283 cases[J]. Dig Endosc,2013, 25(5):519-525
[29] Zhou H, Ni Z, Li T, et al. Activation of FXR promotes intestinal metaplasia of gastric cells via SHP-dependent upregulation of the expression of CDX2[J]. Oncol Lett, 2018, 15(5):7617-7624
[30] Miwa K, Hasegawa H, Fujimura T, et al. Duodenal reflux through the pylorus induces gastric adenocarcinoma in the rat[J]. Carcinogenesis,1992, 13(12):2313-2316
[31] Tatsugami M, Ito M, Tanaka S, et al. Bile acid promotes intestinal metaplasia and gastric carcinogenesis[J]. Cancer Epidemiol Biomarkers Prev, 2012, 21(11):2101-2107
[2] Yang L, Zheng R, Wang N, et al. Incidence and mortality of stomach cancer in China, 2014[J]. Chin J Cancer Res, 2018, 30(3):291-298
[3] Correa P. A human model of gastric carcinogenesis[J]. Cancer Res,1988, 48(13):3554-3560
[4] Giroux V, Rustgi A K. Metaplasia:tissue injury adaptation and a precursor to the dysplasia-cancer sequence[J]. Nat Rev Cancer, 2017, 17(10):594-604
[5] Oue N, Sentani K, Sakamoto N, et al. Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype[J]. Cancer Sci, 2015, 106(8):951-958
[6] Barros R, Freund J N, David L, et al. Gastric intestinal metaplasia revisited:function and regulation of CDX2[J]. Trends Mol Med, 2012,18(9):555-563
[7] Silberg D G, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice[J]. Gastroenterology, 2002, 122(3):689-696
[8] Mutoh H, Sakurai S, Satoh K, et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice[J]. Cancer Res,2004, 64(21):7740-7747
[9] Joo M K, Park J J, Chun H J. Impact of homeobox genes in gastrointestinal cancer[J]. World J Gastroenterol, 2016, 22(37):8247-8256
[10] Jiang J X, Liu Q, Zhao B, et al. Risk factors for intestinal metaplasia in a southeastern Chinese population:an analysis of 28,745 cases[J].J Cancer Res Clin Oncol, 2017, 143(3):409-418
[11] Karimi P, Islami F, Anandasabapathy S, et al. Gastric cancer:descriptive epidemiology, risk factors, screening, and prevention[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(5):700-713
[12] Li S, Chen X, Zhou L, et al. Farnesoid X receptor signal is involved in deoxycholic acid-induced intestinal metaplasia of normal human gastric epithelial cells[J]. Oncol Rep, 2015, 34(5):2674-2682
[13] Martinot E, Sèdes L, Baptissart M, et al. Bile acids and their receptors[J]. Mol Aspects Med, 2017, 56:2-9
[14] Duboc H, TachéY, Hofmann A F. The bile acid TGR5 membrane receptor:from basic research to clinical application[J]. Dig Liver Dis,2014, 46(4):302-312
[15]陈吉,徐征宇.胃黏膜病变过程中SOX9、CDX2基因的表达及相关性研究[J].国际消化病杂志, 2018, 38(05):340-343
[16]孙丹,武洋,辛彦,等. Sox2和Cdx2基因编码蛋白在胃癌及其癌前病变中的表达及意义[J].现代肿瘤医学, 2016, 24(10):1585-1591
[17] Liu Q, Teh M, Ito K, et al. CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer[J]. Mod Pathol, 2007, 20(12):1286-1297
[18]李玄,郅敏,何欢,等. CDX2表达水平与胃癌患者病理特征及预后的关系[J].新医学, 2017, 48(10):736-741
[19]王柏桦,孟加榕,唐忠辉,等. RRMI、CDX2在胃癌组织中的表达及临床意义[J].现代肿瘤医学, 2017, 48(05):475-478
[20] Zhang J F, Qu L S, Qian X F, et al. Nuclear transcription factor CDX2 inhibits gastric cancer cell growth and reverses epithelial to mesenchymal transition in vitro and in vivo[J]. Mol Med Rep, 2015,12(4):5231-5238
[21] Masood M A, Loya A, Yusuf M A. CDX2 as a prognostic marker in gastric cancer[J]. Acta Gastroenterol Belg, 2016, 79(2):197-200
[22] Nakayama C, Yamamichi N, Tomida S, et al. Transduced caudal type homeobox(CDX)2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation[J]. Cancer Sci,2018, 109(12):3853-3864
[23] Donkers J M, Roscam A RLP, van de Graaf SFJ. Developments in bile salt based therapies:a critical overview[J]. Biochem Pharmacol,2018, 161:1-13
[24] ani M, Stanimirov B, Pavlovi N, et al. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome[J]. Front Pharmacol, 2018, 9:1382
[25] Cao W, Tian W, Hong J, et al. Expression of bile acid receptor TGR5in gastric adenocarcinoma[J]. Am J Physiol. Gastrointest. Liver Physiol, 2013, 304(4):G322-327
[26] Carino A, Graziosi L, D'Amore C, et al. The bile acid receptor GPBAR1(TGR5)is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines[J]. Oncotarget, 2016, 7(38):61021-61035
[27] Chen M C, Chen Y L, Wang T W, et al. Membrane bile acid receptor TGR5 predicts good prognosis in ampullary adenocarcinoma patients with hyperbilirubinemia[J]. Oncol Rep, 2016, 36(4):1997-2008
[28] Matsuhisa T, Arakawa T, Watanabe T, et al. Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia:a multicenter study of 2283 cases[J]. Dig Endosc,2013, 25(5):519-525
[29] Zhou H, Ni Z, Li T, et al. Activation of FXR promotes intestinal metaplasia of gastric cells via SHP-dependent upregulation of the expression of CDX2[J]. Oncol Lett, 2018, 15(5):7617-7624
[30] Miwa K, Hasegawa H, Fujimura T, et al. Duodenal reflux through the pylorus induces gastric adenocarcinoma in the rat[J]. Carcinogenesis,1992, 13(12):2313-2316
[31] Tatsugami M, Ito M, Tanaka S, et al. Bile acid promotes intestinal metaplasia and gastric carcinogenesis[J]. Cancer Epidemiol Biomarkers Prev, 2012, 21(11):2101-2107