Cdx2在胃黏膜肠上皮化生中作用机制的研究
摘要
胃黏膜肠上皮化生(IM)是胃癌的癌前病变，与肠型胃癌密切相关。在从胃炎到肠化乃至肠型胃癌的发病过程中，出现了一系列细胞表型的变化，主要是由于相关转录因子及其所调控基因的表达变化所致。肠转录因子Cdx2的过度表达在IM的发生、发展过程中起着至关重要的作用。Cdx2是肠化生的重要调节因子，甚至可能是始动因子；并可能通过对肠化生的另一重要标志物肝肠钙粘连蛋白(LI-CD)的调节来传递由胃向肠表型转化的信号。
实验目的：
探讨在不同胃黏膜IM病理情况下Cdx2、Sox2及LI-CD的表达变化；Cdx2与LI-CD及Sox2是否存在表达相关性。转染Cdx2基因，体外构建Cdx2基因过表达胃上皮肠化模型，研究Cdx2过表达是否可以导致胃上皮向肠上皮表型的转变及其对LI-CD的表达是否具有调控作用。
方法：
1．Real-time PCR方法检测病理学诊断为胃炎、轻度IM、中-重度IM组各12例胃镜活检标本中Sox2、Cdx2和LI-CD基因的转录水平。使用免疫组化方法检测80例病理学诊断为胃炎、轻、中、重度肠化的石蜡包埋胃黏膜标本中Cdx2和LI-CD蛋白的表达情况。
2．构建含野生型人Cdx2基因读码框的重组真核表达载体pcDNA3．1／wtCdx2，转染体外培养的人胃上皮细胞系GES-1。经Western Blot(WB)证实外源Cdx2基因的表达后，检测被转染细胞中Sox2和villin的表达情况。
3．以点突变的方法构建Cdx2 DNA结合结构域(DNA binding domain)编码区突变型重组质粒pcDNA3．1／mutCdx2，转染人胃上皮细胞系GES-1，WB方法检测Cdx2、Sox2和villin的表达情况。
结果：
1．临床活检标本的Real-time PCR结果显示：Cdx2，Sox2，LI-CD基因cDNA的水平在慢炎组、轻度肠化组、中-重度肠化各组之间两两比较均存在统计学差异(P＜0．05)。随着肠化程度加重，Cdx2和LI-CD的表达逐渐增高，而Sox2的表达则明显下调。Cdx2和LI-CD cDNA在各组中的表达呈正相关，并以在轻度肠化组的相关性最高(r=0．910，P＜0．01)。
2．临床活检标本的免疫组化结果显示：Cdx2和LI-CD在胃炎组、轻、中、重??度IM组的表达阳性率及表达水平逐渐增高，各组间均有显著性差异(P＜0．001)。Cdx2和LI-CD在各组间的总相关系数r=0．827(P＜0．01)，呈显著正相关。
3．较空pcDNA3．1质粒转染的对照组相比，在不同剂量pcDNA3．1／wtCdx2质粒转染的人胃黏膜上皮细胞中以Western Blot证实Cdx2和villin的表达成正相关；Sox2的表达则与Cdx2负相关。在pcDNA3．1／mutCdx2质粒转染的细胞系中，仅可检测到突变型Cdx2蛋白的表达，villin及Sox2的表达均与对照组无明显区别。
结论：
1．在人胃黏膜肠化组织中，随着肠化的进展，出现Cdx2和LI-CD的异位表达及Sox2的下调；在肠化组织中Cdx2和LI-CD具有显著正相关性，提示两者可能处于同一信号调节通路中。同时从转录水平证实了在肠化生组织中Sox2和Cdx2的表达负相关。
2．体外细胞试验证实了野生型Cdx2基因可以上调villin的表达和下调Sox2的表达，使细胞向肠化生表型转化，而突变型Cdx2基因则无此功能。证实了Cdx2在肠化生中的重要作用，证明Cdx2在肠化的信号通路中至少有一条路径处于Sox2的上游。
3．以野生型Cdx2基因过表达的方式，成功建立了胃上皮体外肠化模型。
Intestinal metaplasia(IM) of the gastric mucosa was regarded as theprecancerosis of gastric cancer.Varied expressions of some transcriptional factors andtheir controlled genes were intensively involved in the process of intestinalmetaplasia and further carcinogenesis of the gastric mucosa.Cdx2 is a specificintestinal transcription factor and plays a critical role in IM.Overexpressed Cdx2could cause intestinal metaplasia in vitro,and its function was reported largelymediated by LI-CD,another key regulator of IM.
Objectives:
To investigate the expression variation of Sox2,Cdx2 and LI-CD and investigatetheir relationships in the process of intestinal metaplasia.To verify whether Cdx2 isthe upstream regulator of LI-CD in IM and to elucidate the possible mechanism ofCdx2 induced intestinal metaplasia.
Methods:
1.Determined the relative level of Sox2、Cdx2 and LI-CD transcript by real-timequantitative PCR in grouped gastric mucosa samples which were collected bybiopsy with the pathological diagnosis.Immunohistochemically (IHC) evaluatedthe expression and distribution of Cdx2 and LI-CD protein in slided gastric mucosasamples with chronic gastritis,mild,moderate and severe IM.
2.Constucted the recombinant eukaryotic expression plasmid of pcDNA3.1/wtCdx2which contains wild type human Cdx2 gene in plasmid pcDNA3.1.In vitro culturedgastric epithelial cell line GES-1 was transfected by pcDNA3.1/wtCdx2 in differentdose.The effect of wtCdx2 tranfection was determined by detecting the expressionof Sox2 and villin by Western Blot.
3.Recombinant plasmid pcDNA3.1/mutCdx2 was also constructed by site directedmutagenensis,which contains a DNA binding domain mutated Cdx2 gene.GES-1celline was transfected by plasmid pcDNA3.1/mutCdx2,then the expressions ofCdx2,Sox2 and villin were also determined.
Results
1.Compared to gastritis group,elevated expressions of Cdx2 and LI-CD in IMgroups were confirmed by Real-time PCR (P＜0.05).The expressions of Cdx2significant related with LI-CD and they are all in consistance with the progress ofIM.
2.IHC assays of the clinical samples also showed Cdx2 and LI-CD expression wereup-regulated in different IM groups (P＜0.001).Their expressions were in positiverelationship with the status of IM (r=0.827,P＜0.01).
3.Over expressed wtCdx2 could increase villin expression and decrease Sox2expression in transfected GES-1 cell line,while mutCdx2 did not have this kind offunction although increased expression of mutated Cdx2 protein was detected.
Conclusions
1.Cdx2,Sox2 and LI-CD are all intensively involved in the process of IM,whereCdx2 and LI-CD stimulate IM while Sox2,inhibits IM.There is good correlationbetween the expression of Cdx2 and LI-CD,they might exert their functionsthrough the same signaling pathway.On the contrary,it is showed inversecorrelation between Cdx2 and Sox2 in transcriptional level.
2.Over-expressed Cdx2 by pcDNA3.1/wtCdx2 transfection in in vitro culturedGES-1 cell line cause increasing expression of villin implying intestinal phenotypeformed,and decreasing expression of Sox2 implying gastric phenotype disappeared.Cdx2 over-expression is critical to IM generation,and Sox2 should be adownstream target gene of Cdx2 at least in one pathway.
3.IM cell model is successfully constructed by over-expression of wtCdx2.
实验目的：
探讨在不同胃黏膜IM病理情况下Cdx2、Sox2及LI-CD的表达变化；Cdx2与LI-CD及Sox2是否存在表达相关性。转染Cdx2基因，体外构建Cdx2基因过表达胃上皮肠化模型，研究Cdx2过表达是否可以导致胃上皮向肠上皮表型的转变及其对LI-CD的表达是否具有调控作用。
方法：
1．Real-time PCR方法检测病理学诊断为胃炎、轻度IM、中-重度IM组各12例胃镜活检标本中Sox2、Cdx2和LI-CD基因的转录水平。使用免疫组化方法检测80例病理学诊断为胃炎、轻、中、重度肠化的石蜡包埋胃黏膜标本中Cdx2和LI-CD蛋白的表达情况。
2．构建含野生型人Cdx2基因读码框的重组真核表达载体pcDNA3．1／wtCdx2，转染体外培养的人胃上皮细胞系GES-1。经Western Blot(WB)证实外源Cdx2基因的表达后，检测被转染细胞中Sox2和villin的表达情况。
3．以点突变的方法构建Cdx2 DNA结合结构域(DNA binding domain)编码区突变型重组质粒pcDNA3．1／mutCdx2，转染人胃上皮细胞系GES-1，WB方法检测Cdx2、Sox2和villin的表达情况。
结果：
1．临床活检标本的Real-time PCR结果显示：Cdx2，Sox2，LI-CD基因cDNA的水平在慢炎组、轻度肠化组、中-重度肠化各组之间两两比较均存在统计学差异(P＜0．05)。随着肠化程度加重，Cdx2和LI-CD的表达逐渐增高，而Sox2的表达则明显下调。Cdx2和LI-CD cDNA在各组中的表达呈正相关，并以在轻度肠化组的相关性最高(r=0．910，P＜0．01)。
2．临床活检标本的免疫组化结果显示：Cdx2和LI-CD在胃炎组、轻、中、重??度IM组的表达阳性率及表达水平逐渐增高，各组间均有显著性差异(P＜0．001)。Cdx2和LI-CD在各组间的总相关系数r=0．827(P＜0．01)，呈显著正相关。
3．较空pcDNA3．1质粒转染的对照组相比，在不同剂量pcDNA3．1／wtCdx2质粒转染的人胃黏膜上皮细胞中以Western Blot证实Cdx2和villin的表达成正相关；Sox2的表达则与Cdx2负相关。在pcDNA3．1／mutCdx2质粒转染的细胞系中，仅可检测到突变型Cdx2蛋白的表达，villin及Sox2的表达均与对照组无明显区别。
结论：
1．在人胃黏膜肠化组织中，随着肠化的进展，出现Cdx2和LI-CD的异位表达及Sox2的下调；在肠化组织中Cdx2和LI-CD具有显著正相关性，提示两者可能处于同一信号调节通路中。同时从转录水平证实了在肠化生组织中Sox2和Cdx2的表达负相关。
2．体外细胞试验证实了野生型Cdx2基因可以上调villin的表达和下调Sox2的表达，使细胞向肠化生表型转化，而突变型Cdx2基因则无此功能。证实了Cdx2在肠化生中的重要作用，证明Cdx2在肠化的信号通路中至少有一条路径处于Sox2的上游。
3．以野生型Cdx2基因过表达的方式，成功建立了胃上皮体外肠化模型。
Intestinal metaplasia(IM) of the gastric mucosa was regarded as theprecancerosis of gastric cancer.Varied expressions of some transcriptional factors andtheir controlled genes were intensively involved in the process of intestinalmetaplasia and further carcinogenesis of the gastric mucosa.Cdx2 is a specificintestinal transcription factor and plays a critical role in IM.Overexpressed Cdx2could cause intestinal metaplasia in vitro,and its function was reported largelymediated by LI-CD,another key regulator of IM.
Objectives:
To investigate the expression variation of Sox2,Cdx2 and LI-CD and investigatetheir relationships in the process of intestinal metaplasia.To verify whether Cdx2 isthe upstream regulator of LI-CD in IM and to elucidate the possible mechanism ofCdx2 induced intestinal metaplasia.
Methods:
1.Determined the relative level of Sox2、Cdx2 and LI-CD transcript by real-timequantitative PCR in grouped gastric mucosa samples which were collected bybiopsy with the pathological diagnosis.Immunohistochemically (IHC) evaluatedthe expression and distribution of Cdx2 and LI-CD protein in slided gastric mucosasamples with chronic gastritis,mild,moderate and severe IM.
2.Constucted the recombinant eukaryotic expression plasmid of pcDNA3.1/wtCdx2which contains wild type human Cdx2 gene in plasmid pcDNA3.1.In vitro culturedgastric epithelial cell line GES-1 was transfected by pcDNA3.1/wtCdx2 in differentdose.The effect of wtCdx2 tranfection was determined by detecting the expressionof Sox2 and villin by Western Blot.
3.Recombinant plasmid pcDNA3.1/mutCdx2 was also constructed by site directedmutagenensis,which contains a DNA binding domain mutated Cdx2 gene.GES-1celline was transfected by plasmid pcDNA3.1/mutCdx2,then the expressions ofCdx2,Sox2 and villin were also determined.
Results
1.Compared to gastritis group,elevated expressions of Cdx2 and LI-CD in IMgroups were confirmed by Real-time PCR (P＜0.05).The expressions of Cdx2significant related with LI-CD and they are all in consistance with the progress ofIM.
2.IHC assays of the clinical samples also showed Cdx2 and LI-CD expression wereup-regulated in different IM groups (P＜0.001).Their expressions were in positiverelationship with the status of IM (r=0.827,P＜0.01).
3.Over expressed wtCdx2 could increase villin expression and decrease Sox2expression in transfected GES-1 cell line,while mutCdx2 did not have this kind offunction although increased expression of mutated Cdx2 protein was detected.
Conclusions
1.Cdx2,Sox2 and LI-CD are all intensively involved in the process of IM,whereCdx2 and LI-CD stimulate IM while Sox2,inhibits IM.There is good correlationbetween the expression of Cdx2 and LI-CD,they might exert their functionsthrough the same signaling pathway.On the contrary,it is showed inversecorrelation between Cdx2 and Sox2 in transcriptional level.
2.Over-expressed Cdx2 by pcDNA3.1/wtCdx2 transfection in in vitro culturedGES-1 cell line cause increasing expression of villin implying intestinal phenotypeformed,and decreasing expression of Sox2 implying gastric phenotype disappeared.Cdx2 over-expression is critical to IM generation,and Sox2 should be adownstream target gene of Cdx2 at least in one pathway.
3.IM cell model is successfully constructed by over-expression of wtCdx2.
引文
[1]管仁珍，刘文天，王邦茂等．胃黏膜不典型增生和肠化生的内镜监测评价[J]．胃肠病学和肝病学杂志，2008，17(2)：136-138．
[2]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.
[3]Liu YQ,Zhao H,Ning T,et al.Expression of 1A6 gene and its correlation with intestinal gastric carcinoma[J].World J Gastroenterol,2003,9(2):238-241.
[4]WalkerM M.Is intestinal metaplasia of the stomach reversible[J].Gut,2003,52(1):1-4.
[5]Kang JY,Finlayson C,Maxwell JD et al.Risk of gastric carcinoma in patients with atrophic gastritis and intestinal metaplasia[J].Gut,2002,51 (6):899.
[6]Whiting JL,Sigurdsson A,Rowlands DC,et al.The long term results of endoscopic surveillance of premalignant gastric lesions[J].Gut,2002,50(3):378-381.
[7]Jaffee IM,Rahmani M,Singhal MG,et al.Expression of the intestinal transcription factor CDX2 in carcinoid tumors is a marker of midgut origin[J].Arch Pathol Lab Med,2006,130(10):1522-1526.
[8]Drummond F,Putt W,Fox M,et al.Cloning and chromosome assignment of the human CDX2 gene[J].Ann Hum Genet,1997,61(5):393-400.
[9]Chawengsaksophak K,James R,Hammond VE,et al.Homeosis and intestinal tumours in Cdx2 mutant mice[J].Nature,1997,386(6620):84-87.
[10]Beck F.Homeobox genes in gut development[J].Gut.2002,51:450-454.
[11]许海泉，王邦茂，章明放，等．Cdx2和PTEN在胃黏膜肠上皮化生及肠型胃癌组织中的表达[J]．天津医科大学学报，2004，10(4)：510-513．
[12]李姝，王邦茂，张洁，等．Cdx2和MUC2在反流性食管炎、Barrer食管和食管腺癌中的表达[J]．中华消化内镜杂志，2006，23(5)：355-357．
[13]Guti(?)rrez-Gonz(?)lez L,Wright NA.Biology of intestinal metaplasia in 2008:more than a simple phenotypic alteration[J].Dig Liver Dis,2008,40(7):510-522.
[14]Ko S,Chu KM,Luk JM,et al.CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach[J]. J Pathol, 2005,205(5): 615-622.
[15] Groisman GM, Amar M, Meir A.Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia[J].Mod Pathol, 2004,17(10):1282-1288.
[16] Seno H, Oshima M, Taniguchi MA, et al. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer:Prognostic implications [J]. Int J Oncol, 2002, 21(4):769-774.
[17] Phillips RW, Frierson Jr HF, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus[J]. Am J Surg Pathol, 2003, 27(11):1442- 1447.
[18] Eda A, Osawa H, Yanaka I, et al. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia[J]. J Gastroenterol,2002, 37(2):94-100.
[19] Kim HS, Lee JS, Freund JN, et al.CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions[J]. J Gastroenterol Hepatol, 2006, 21(2):438-442.
[20] Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice[J]. Biochem Biophys Res Commun, 2002,294(2):470-479.
[21] Mutoh H, Satoh K, Kita H, et al. Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine[J]. Int J Dev Biol, 2005, 49(7):867-871.
[22]Mizoshita T , Inada K, Tsukamoto T , et al. Expression of the intestine-specific t ranscription factor s , Cdxl and Cdx2 , correlates shift to an intestinal phenotype in gast ric cancer cells[J]. J Cancer Res Clin Oncol, 2004 , 130 : 29-36.
[23]Bai YQ , Yamamoto H , Akiyama Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of t he stomach[J]. Cancer Lett,2002, 176:47-55.
[24] Dong W, Yu Q, Xu Y. Altered expression of a LI-cadherin in gastric cancer and intestinal metaplasia[J]. Dig Dsi Sci, 2007, 52(2): 536-542.
[25]Gr(o|¨)tzinger C,Kneifel J,Patschan D,et al.LI-cadherin:a marker of gastric metaplasia and neoplasia[J].Gut,2001,49(1):73-81.
[26]Motoshita J,Nakayama H,Taniyama K,et al.Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype:LI-cadherin is associated with intestinal phenotype[J].Pathol Int,2006,56(4):200-205.
[27]余琼芳，董卫国，程春生，等．肝肠钙粘连蛋白在胃癌组织中的表达及临床意义[J]．临床内科杂志，2005，22(9)：616-618．
[28]Hinoi T,Lucas PC,Kuick R,et al.CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia[J].Gastroenterology,2002,123(5):1565-1577.
[29]Ge J,Chen Z,Wu S,et al.A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma[J].Clin Oncol,2008,20(4):275-283.
[30]Gibson UE,Heid CA,Williams PM.A novel method for real time quantitative RT-PCR [J].Genome Res,1996,6:995-1001.
[31]Schmittgen TD.Real time quantitative PCR [J].Methods,2001;25:383-385.
[32]Giraud AS.Metaplasia as a premalignant pathology in the stomach [J].Gastroenterology,2007,132:2053-2056.
[33]Fitzgerald RC.Genetics and prevention of oesophageal adenocarcinoma[J].Recent Results Cancer Res,2005,66:35-46.
[34]Barros R,Pereira B,Duluc I,et al.Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines[J].J Pathol,2008,215(4):411-420.
[35]Guarner J,Mohar A,Parsonnet J,et al.The association ofHelicobacter pylori with gastric cancer and preneoplastic gastric lesions in chiapas[J].Mexico Cancer,1993,71:297-301.
[36]任刚，蔡嵘，陈强，等．幽门螺杆菌与肠化生相关性的初步研究[J]．临床消化病杂志，2000，12(3)：102-103
[37]兰春慧，张渊智，房殿春．幽门螺杆菌感染诱发蒙古沙鼠胃黏膜肠上皮化生和异型增生[J]．解放军医学杂志，2003，28(11)：985-986．
[38]Maruta F,Ota H,Genta RM,et al.Role of N-methyl-N-nitrosourea in the induction of intestinal metaplasia and gastric adenocarcinoma in Mongolian gerbils infected with Helicobacter pylori[J].Scand J Gastroenterol,2001,36(3):283-290.
[39]Kawazoe T,Sakagami T,Nakajima K,et al.Role of bacterial strain diversity of Helicobacter pylori in gastric carcinogenesis induced by N-methyl-N-nitrosourea in Mongolian gerbils [J].Helicobacter,2007,12(3):213-223.
[40]兰春慧，房殿春，邹全明．HP感染内蒙古沙鼠致Barrett食管及胃癌的实验研究[J]．重庆医学，2007，36(15)：1491-1493．
[41]秦玉峨，单国栋，季峰．肠化生和肠型胃癌内镜及病理特点分析[J]．浙江预防医学，2005：17(8)：6-8．
[42]周丽雅，林三仁，丁士刚，等．根除幽门螺杆菌对胃癌患病率及胃黏膜组织学变化的八年随访研究[J]．中华消化杂志，2005，25(6)：324-327．
[43]Tosh D,Slack JM.How cells change their phenotype[J].Nat Rev Mol Cell Biol,2002,3:187-194.
[44]Que J,Choi M,Ziel JW,et al.Morphogenesis of the trachea and esophagus:current players and new roles for noggin and Bmps[J].Differentiation,2006,74:422-437.
[45]Mizoshita T,Inada K,Tsukamoto T,et al.Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa--with special emphasis on participation in intestinal metaplasia of the human stomach [J].Gastric Cancer,2001,4(4):185-191.
[46]Werling RW,Yaziji H,Bacchi CE,et al.CDX2,a Highly sensitive and specific marker of adenocarcinomas of intestinal origin:An immunohistochemical survey of 476 primary and metastatic carcinomas [J].Am J Surg Pathol,2003,27:303-310.
[47]Houle M,Prinos P,Iulianella A,et al.Retinoic acid regulation of Cdx1:an indirect mechanism for retinoids and vertebral specification [J].Mol Cell Biol,2000,20:6579-6586.
[48]Shi XY,Bhagwandeen B,Leong AS.CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus [J].Am J Clin Pathol,2008,129(4):571-577.
[49]Souza RF, Krishnan K, Spechler SJ. Acid, bile, and CDX: the ABCs of making Barrett's metaplasia [J]. Am J Physiol Gastrointest Liver Physiol, 2008, 295(2):G 211-218.
[50] Moons LM, Bax DA, Kuipers EJ, et al. The homeodomain protein CDX2 is an early marker of Barrett's oesophagus [J]. J Clin Pathol, 2004,57(10):1063-1068.
[51]Tannapfel A. Molecular Findings in Barrett's Epithelium [J]. Dig Dis, 2004,22:126-133.
[52]Lynch JP, Silberg DG. To differentiate or proliferate? The interaction between PI3K/PTEN and Cdx2 [J]. Gastroenterology, 2002,123:1395-1397.
[53]Yamamoto H, Bai YQ, Yuasa Y. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression[J]. Biochem Biophys Res Commun, 2003,300(4): 813-818.
[54]Silberg DG, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice[J]. Gastroenterology, 2002, 122(3):689-696.
[55]Geiger B, Ayalon O, Cadherins[J]. Annu Rev Cell Biol, 1992, 8:307-332.
[56]Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion [J]. Trends Genet, 1993, 9:317-321.
[57]Takeichi, M. Morphogenetic roles of classical cadherins [J]. Curr Opin Cell Biol, 1995,7:619-627.
[58]Thomson RB, Igarashi P, Biemesderfer D, et al. Isolation and cDNA cloning of Ksp-cadherin,a novel kidney-specific member of the cadherin multigene family [J].J Biol Chem, 1995, 270:17594-17601.
[59]Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness[J]. Biochem Biophys Acta, 1994,1198:11-26.
[60]Berndorff D R. Gessner BK, Schnoy N, et al. Liver-intestine cadherin: molecular cloning and characterization of a novel Ca~(2+)-dependent cell adhesion molecule expressed in liver and intestine[J]. J Cell Biol,1994, 125:1353-1369.
[61]Wang XQ, Luk JM, Leung PP, et al. Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma [J].Clin Cancer Res, 2005, 11(2 Pt 1):483-489.
[62]Takamura M, Sakamoto M, Ino Y, et al. Expression of liver-intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas[J].Cancer Sci, 2003, 94(5):425-430.
[63]Takamura M, Ichida T, Matsuda Y, et al.Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma[J].Cancer Lett, 2004, 212(2):253-259.
[64]Ko S, Chu KM, Luk JM,et al.Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis[XJ.Biochem Biophys Res Commun,2004, 319(2):562-568.
[65]Que J, Okubo T, Goldenring JR, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm [J]. Development,2007, 134(13):2521-2531.
[66]Williamson KA, Hever AM, Rainger J, et al. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome[J]. Hum Mol Genet. 2006,15,1413-1422.
[67] Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gast ric carcinoma[J]. Int J Oncol, 2004, 24(2):257-263.
[68] Tsukamoto T, Inada K, Tanaka H,et al. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes,Cdxl and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia[J]. J Cancer Res Clin Oncol, 2004, 130(3):135-145.
[69] Tsukamoto T, Mizoshita T, Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization[J]. Gastric Cancer, 2006, 9(3): 156-166.
[70] Tsukamoto T, Mizoshita T, Mihara M, et al.Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes[J].Histopathology, 2005, 46(6):649-658.
[71] Bornschein J, Wex T, Peitz U, et al. The combined presence of H pylori infection and gastro-oesophageal reflux disease leads to an up-regulation of CDX2 gene expression in antrum and cardia [J]. J Clin Pathol, 2009 ,62(3):254-259.
[72] Manzo BA, Crabtree JE, Fiona Campbell M, et al. Helicobacter pylori regulates the expression of inhibitors of DNA binding (Id) proteins by gastric epithelial cells[J]. Microbes Infect, 2006, 8(4):1064-1074.
[73] Barros R, Marcos N, Reis CA, et al. CDX2 expression is induced by Helicobacter pylori in AGS cells[J]. Scand J Gastroenterol, 2009,4(1):124-125.
[74] Satoh K, Mutoh H, Eda A, et al. Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori [J]. Helicobacter, 2002, 7(3):192-198.
[75] Vauhkonen M, Vauhkonen H, Sipponen P. Helicobacter pylori infection induces a reversible expression of the CDX2 transcription factor protein in human gastric epithelium [J]. Scand J Gastroenterol, 2008,43: 915-921.
[76] Shiotani A, Uedo N, Iishi H, et al. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia [J]. Int J Cancer, 2007,121(6):1182-1189.
[77] Guo RJ, Suh ER, Lynch JP.The Role of Cdx Proteins in Intestinal Development and Cancer [J]. Cancer Biol Ther, 2004, 3(7):593-601.
[78 Beck F, Chawengsaksophak K, Luckett J, et al. A study of regional gut endoderm potency by analysis of Cdx2 null mutant chimaeric mice[J]. Devel Biol, 2003, 255:399-406.
[79] Chawengsaksophak K, de Graaff W, Rossant J, et al.Cdx2 is essential for axial elongation in mouse development. Proc Natl Acad Sci USA, 2004, 101(20):7641-7645.
[80] Beck F, Chawengsaksophak K, Waring P, et al. Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice [J]. Proc Natl Acad Sci USA, 1999, 96(13): 7318-7323.
[81] Jobert, A S, Zhang P, Couvineau A, et al. Absence of functional receptors parathyroid hormone and parathyroid hormone related peptide in Blomstrand chondrodysplasia [J]. Clin Invest, 1998,102: 34-40.
[82] Yang L, Yan D, Bruggeman M, et al.Mutation of a lysine residue in a homeodomain generates dominant negative thyroid transcription factor 1 [J].Biochemistry, 2004, 43(39): 12489-12497.
[83] Assenberg R, Webb M, Connolly E, Stott K, Watson M, Hobbs J, Thomas JO.A critical role in structure-specific DNA binding for the acetylatable lysine residues in HMGB1 [J]. Biochem J, 2008,411(3):553-561.
[1]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.
[2]Liu YQ,Zhao H,Ning T et al.Expression of 1A6 gene and its correlation with intestinal gastric carcinoma[J].World J Gastroenterol,2003,9(2):238-241.
[3]Walker MM.Is intestinal metaplasia of the stomach reversible[J].Gut,2003,52(1):1-4.
[4]Kang JY,Finlayson C,Maxwell JD et al.Risk of gastric carcinoma in patients with atrophic gastritis and intestinal metaplasia[J].Gut,2002,51 (6):899.
[5]Whiting JL,Sigurdsson A,Rowlands DC et al.The long term results of endoscopic surveillance of premalignant gastric lesions[J].Gut,2002,50(3):378-381.
[6]管仁珍，刘文天，王邦茂等．胃黏膜不典型增生和肠化生的内镜监测评价[J]．胃肠病学和肝病学杂志，2008，17(2)：136-138．
[7]Que J,Choi M,Ziel JW et al.Morphogenesis of the trachea and esophagus:current players and new roles for noggin and Bmps[J].Differentiation,2006,74(7):422-437.
[8]Guamer J,Mohar A,Parsonnet Jet al.The association of helicobacter pylori with gastric cancer and preneoplastic gastric lesions in chiapas[J].Mexico Cancer,1993,71(2):297-301.
[9]任刚，蔡嵘，陈强等．幽门螺杆菌与肠化生相关性的初步研究[J]．临床消化病杂志，2000，12(3)：102-103．
[10]兰春慧，张渊智，房殿春．幽门螺杆菌感染诱发蒙古沙鼠胃黏膜肠上皮化生和异型增生[J]．解放军医学杂志，2003，28(11)：985-986．
[11]Maruta F,Ota H,Genta RM et al.Role of N-methyl-N-nitrosourea in the induction of intestinal metaplasia and gastric adenocarcinoma in Mongolian gerbils infected with Helicobacter pylori[J].Scand J Gastroenterol,2001,36(3):283-290.
[12]Kawazoe T,Sakagami T,Nakajima K et al.Role of bacterial strain diversity of Helicobacter pylori in gastric carcinogenesis induced by N-methyl-N-nitrosourea in Mongolian gerbils [J].Helicobacter,2007,12(3):213-223.
[13]兰春慧，房殿春，邹全明．HP感染内蒙古沙鼠致Barrett食管及胃癌的实验研究[J]．重庆医学，2007，36(15)：1491-1493．
[14]秦玉峨，单国栋，季峰．肠化生和肠型胃癌内镜及病理特点分析[J]．浙江预防医学，2005，17(8)：6-8．
[15]Sung JJ,Lin SR,Ching JY et al.Atrophy and intestinal metaplasia one year after cure of H.pylori infection:a prospective,randomized study[J].Gastroenterology,2000,119(1):7-14.
[16]Leung WK,Sung JJ.Review article:intestinal metaplasia and gastric carcinogenesis [J].Aliment Pharmacol Ther,2002,16(7):1209-1216.
[17]Leung WK,Lin SR,Ching JY et al.Factors predicting progression of gastric intestinal metaplasia:results of a randomised trial on Helicobacter pylori eradication[J].Gut,2004,53(9):1244-1249.
[18]马雪芹，胡敏．根除反复幽门螺杆菌感染对胃黏膜炎症和肠上皮化生的临 床意义[J]．青海医学院学报，2007，28(2)：131-133．
[19]范国明，丁秀婷，杜若红．根除幽门螺杆菌对胃黏膜病变影响的观察[J]．中国医师杂志，2003，增刊：60-62．
[20]Tucci A,Poli L,Tosetti C et al.Reversal of fundic atrophy after eradication of Helicobacter pylori[J].Am J Gastroenterolgy,1998,93(9):1425-1431.
[21]周丽雅，林三仁，丁士刚等．根除幽门螺杆菌对胃癌患病率及胃黏膜组织学变化的八年随访研究[J]．中华消化杂志，2005，25(6)：324-327．
[22]王佳林，刘星群，赵贵军．根除幽门螺杆菌对胃粘膜病变的影响[J]．胃肠病学，2007，12(11)：691-692．
[23]Sobala GM,O'Connor HJ,Dewar EP,et al.Bile reflux and intestinal metaplasia in gastric mucosa[J].J Clin Pathol,1993,46(3):235-240.
[24]张卓群．原发性胆汁反流对胃粘膜病变的影响[J]．中华腹部疾病杂志，2003，3(4)：261-262．
[25]Ebert MP,Leodolter A,Malfertheiner P.Novel strategies in the prevention of gastric cancer[J].Hepatogastroentemlogy,2001,48(42):1569-1571.
[26]Guti(?)rrez-Gonz(?)lez L,Wright NA.Biology of intestinal metaplasia in 2008:more than a simple phenotypic alteration[J].Dig Liver Dis,2008,40(7):510-522.
[27]周心明，梁杏云．胆汁反流性胃炎临床分析[J]．武汉大学学报(医学版)，2007，287(5)：680-682．
[28]Nehra D,Howell P,Williams CP et al.Toxic bile acids in gastro-oesophageal reflux disease:influence of gastric acidity[J].Gut,1999,44(5):598-602.
[29]Berk F.Homeobox genes in gut development[J].Gut,2002,51 (3):450-454.
[30]Guo RJ,Suh ER,Lynch JP.The Role of Cdx Proteins in Intestinal Development and Cancer[J].Cancer Biol Ther,2004,3(7):593-601.
[31]Souza RF,Krishnan K,Spechler SJ.Acid,bile,and CDX:the ABCs of making Barrett's metaplasia[J].Am J Physiol Gastrointest Liver Physiol,2008,295(2):211-218.
[32]Beck F,Chawengsaksophak K,Luckett J,et al.A study of regional gut endoderm potency by analysis of Cdx2 null mutant chimaeric mice[J].Devel Biol,2003,255(2):399-406.
[33]Mizoshita T,Inada K,Tsukamoto T,et al.Expression of Cdxl and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa-with special emphasis on participation in intestinal metaplasia of the human stomach[J].Gastric Cancer,2001,4(4):185-191.
[34]Werling RW,Yaziji H,Bacchi CE,et al.CDX2,a Highly sensitive and specific marker of adenocarcinomas of intestinal origin:An immunohistochemical survey of 476 primary and metastatic carcinomas[J].Am J Surg Pathol,2003,27(3):303-310.
[35]Scoville DH,Sato T,He XC et al.Current view:intestinal stem cells and signaling[J].Gastroenterology,2008,134(3):849-864.
[36]Houde M,Laprise P,Jean D et al.Intestinal epithelial cell differentiation involves activation of p38 mitogen-activated protein kinase that regulates the homeobox transcription factor CDX2[J].J Biol Chem,2001,276(38):21885-21894.
[37]Houle M,Prinos P,Iulianella A et al.Retinoic acid regulation of Cdx1.an indirect mechanism for retinoids and vertebral specification[J].Mol.Cell.Biol.,2000,20(17):6579 - 6586.
[38]Jaffee IM,Rahrnani M,Singhal MG,et al.Expression of the intestinal transcription factor CDX2 in carcinoid tumors is a marker of midgut origin[J].Arch Pathol Lab Med,2006,130(10):1522-1526.
[39]Drummond F,Putt W,Fox M,et al.Cloning and chromosome assignment of the human CDX2 gene[J].Ann Hum Genet,1997,61(5):393-400.
[40]Chawengsaksophak K,de Graaff W,Rossant J,et al.Cdx2 is essential for axial elongation in mouse development[J].Proc Natl Acad Sci U S A,2004,18,101(20):7641-7645.
[41]Beck F,Chawengsaksophak K,Waring P,et al.Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice[J].Proc Natl Acad Sci U S A,1999,22,96(13):7318-7323.
[42]许海泉，王邦茂，章明放等．Cdx2和PTEN在胃粘膜肠上皮化生及肠型胃癌组织中的表达[J]．天津医科大学学报，2004，10(4)：510-513．
[43]李姝，王邦茂，张洁等．Cdx2和MUC2在反流性食管炎、Barrett食管和食管腺癌中的表达[J]．到中华消化内镜杂志，2006，23(5)：355-357．
[44]Shi XY,Bhagwandeen B,Leong AS.CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus[J].Am J Clin Pathol, 2008, 129(4):571-577.
[45] Moons LM, Bax DA, Kuipers EJ, et al. The homeodomain protein CDX2 is an early marker of Barrett's oesophagus[J]. J Clin Pathol, 2004, 57(10):1063-1068.
[46] Tannapfel A. Molecular Findings in Barrett's Epithelium [J]. Dig Dis, 2004, 22(2): 126-133.
[47] Ko S, Chu KM, Luk JM, et al. CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach[J]. J Pathol, 2005,205(5): 615-622.
[48] Groisman GM, Amar M, Meir A.Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia[J]. Mod Pathol, 2004, 17(10):1282-1288.
[49] Seno H, Oshima M, Taniguchi MA, et al. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer:Prognostic implications [J]. Int J Oncol, 2002, 21(4):769-774.
[50] Phillips RW, Frierson Jr HF, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus[J].Am J Surg Pathol, 2003,27:1442-1447.
[51] Eda A, Osawa H, Yanaka I, et al. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia[J]. J Gastroenterol,2002, 37(2):94-100.
[52] Lynch JP, Silberg DG. To differentiate or proliferate? The interaction between PI3K/PTEN and Cdx2[J]. Gastroenterology, 2002, 123(4):1395-1397.
[53] Yamamoto H, Bai YQ, Yuasa Y. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression[J]. Biochem Biophys Res Commun, 2003, 24,300(4):813-818.
[54] Silberg DG, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice[J]. Gastroenterology, 2002, 122(3):689-696.
[55] Kim HS, Lee JS, Freund JN, et al.CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions[J]. J Gastroenterol Hepatol, 2006, 21(2):438-442.
[56] Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice[J]. Biochem Biophys Res Commun, 2002, 294(2):470-479.
[57] Mutoh H, Satoh K, Kita H, et al. Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine[J]. Int J Dev Biol, 2005, 49(7):867-871.
[58] Mizoshita T , Inada K, Tsukamoto T , et al. Expression of the intestine-specific transcription factors , Cdx1 and Cdx2 , correlates shift to an intestinal phenotype in gast ric cancer cells [J]. J Cancer Res Clin Oncol, 2004 ,130 : 29-36.
[59] Bai YQ , Yamamoto H , Akiyama Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach[J]. Cancer Lett,2002,176: 47-55.
[60] Chawengsaksophak K, James R, Hammond VE, et al. Homeosis and intestinal tumours in Cdx2 mutant mice[J]. Nature, 1997, 386(6620):84-87.
[61] Marchetti M, Caliot E, Pringault E. Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes[J]. J Cell Sci, 2003,116(8): 1429-1436.
[62] Liu T, Zhang X, So CK, et al. Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells[J]. Carcinogenesis, 2007,28(2):488-496.
[63] Dettmar PW, Strugala V, Tselepis C, et al. The effect of alginates on deoxycholic-acid-induced changes in oesophageal mucosal biology at pH 4[J]. J Biomater Sci Polym Ed, 2007,18:317-333.
[64] Burnat G, Rau T, Elshimi E, et al. Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett's esophageal mucosa and adenocarcinoma cell line[J]. Scandinavian Journal of Gastroenterology, 42(12): 1460 - 1465.
[65] Avissar NE, Toia L, Hu Y, et al. Bile acid alone, or in combination with acid,induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR)[J]. J Gastrointest Surg, 2009, 13(2):212-222.
[66] Chen X, Qin R, Liu B, et al. Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers[J]. Gastroenterology, 2008, 8:1-9.
[67] Barros R, Pereira B, Duluc I, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines[J]. J Pathol, 2008, 215(4):411-420.
[68] Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell[J]. Anat Rec, 1993, 236(2):259-279.
[69] Hattori T, Fujita S. Tritiated thymidine autoradiographic study of cell migration and renewal in the pyloric mucosa of golden hamsters[J]. Cell Tissue Res, 1976,175(l):49-57.
[70] Kim S, Domon-Dell C, Wang Q, et al. PTEN and TNF-a regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-KB-dependentpathway[J]. Gastroenterology, 2002,123(4):1163-1178.
[71] Jin T, Li H. Pou homeodomain protein OCT1 is implicated in the expression of the caudal-related homeobox gene Cdx-2 [J]. J Biol Chem, 2001,276:14752-14758.
[72] Xu F, Li H, Jin T. Cell type-specific autoregulation of the Caudal-related homeobox gene Cdx-2/3[J]. J Biol Chem, 1999, 274:34310-34316.
[73] Drummond F, Sowden J, Morrison K, et al. The caudaltype homeobox protein Cdx2 binds to the colon promoter of the carbonic anhydrase 1 gene[J]. Eur J Biochem, 1996, 236:670 - 681.
[74] Silberg DG, Swain GP, Suh ER, et al. Cdxl and Cdx2 expression during intestinal development [J]. Gastroenterology, 2000, 119:961-971.
[75] Lorentz O, Duluc I, Arcangelis AD, et al. Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation[J]. J Cell Biol, 1997,139:1553-1565.
[76] Troelsen JT, Mitchelmore C, Spodsberg N, et al. Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homeodomain protein Cdx-2 [J].Biochem J, 1997, 322:833-888.
[77] Taylor JK, Boll W, Levy T, et al. Comparison of intestinal phospholipase A/lysophospholipase and sucrase-isomaltase genes suggests a common structure for enterocyte-specific promoters[J]. DNA Cell Biol, 1997, 16:1419-1428.
[78] Lambert M, Colnot S, Suh E, et al. cis-Acting elements and transcription factors involved in the intestinal specific expression of the rat calbindin-D9k gene Binding of the intestine-specific transcription factor Cdx-2 to the TATA box[J].Eur J Biochem,1996,236:778-780.
[79]Yamamoto H,Miyamoto K,Li B,et al.The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine[J].J Bone Miner Res,1999,14:240-247.
[80]Drummond F J,Sowden J,Morrison K,et al.Colon carbonic anhydrase 1:transactivation of gene expression by the homeodomain protein Cdx2[J].FEBS Lett,1998,423:218-222.
[81]Geiger B,Ayalon O.Cadherins[J].Annu Rev Cell Biol,1992,8:307-332.
[82]Kemler R.From cadherins to catenins:cytoplasmic protein interactions and regulation of cell adhesion[J].Trends Genet,1993,9:317-321.
[83]Takeichi M.Morphogenetic roles of classical cadherins[J].Curr Opin Cell Biol,1995,7:619-627.
[84]Thomson,RB,Igarashi P,Biemesderfer D,et al.Isolation and cDNA cloning of Ksp-cadherin,a novel kidney-specific member of the cadherin multigene family[J].J Biol Chem,1995,270:17594-17601.
[85]Birchmeier W,Behrens J.Cadherin expression in carcinomas:role in the formation of cell junctions and the prevention of invasiveness[J].Biochem Biophys Acta,1994,1198:11-26.
[86]Bemdorff D,Gessner R,Kreft B,et al.Liver-intestine cadherin:molecular cloning and characterization of a novel Ca2+-dependent cell adhesion molecule expressed in liver and intestine[J].J Cell Biol,1994,125:1353-1369.
[87]Gessner R,Taubef R.Intestinal cell adhesion molecules,liver-intestine cadherin[J].Ann N Y Acad Sci,2000,915:136-143.
[88]Kreft B,Berndorff D,B(o|¨)ttinger A,et al.LI-cadherin-mediated cell-cell adhesion does not require cytoplasmic interactions[J].J Cell Biol,1997,136(5):1109-1121.
[89]刘仕琪，牛建华．肝肠-钙黏蛋白——一种新的胃腺癌标记物[J]．中国普通外科杂志，2008，17(10)：1010-1012．
[90]Wang XQ,Luk JM,Leung PP,et al.Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma[J].Clin Cancer Res,2005,11(2): 483-489.
[91]Takamura M,Sakamoto M,Ino Y,et al.Expression of liver-intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas[J].Cancer Sci,2003,94(5):425-430.
[92]Takamura M,Ichida T,Matsuda Y,et al.Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma[J].Cancer Lett,2004,212(2):253-259.
[93]Dong W,Yu Q,Xu Y.Altered expression of a LI-cadherin in gastric cancer and intestinal metaplasia[J].Dig Dsi Sci,2007,52(2):536-542.
[94]Gr(o|¨)tzinger C,Kneifel J,Patschan D,et al.LI-cadherin:a marker of gastric metaplasia and neoplasia[J].Gut,2001,49(1):73-81.
[95]Ko S,Chu KM,Luk JM,et al.Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis[J].Biochem Biophys Res Commun,2004,319(2):562-568.
[96]余琼芳，董卫国，程春生等．肝肠钙粘连蛋白在胃癌组织中的表达及临床意义[J]．临床内科杂志，2005，22(9)：616-618．
[97]Nakamura E,Sugihara H,Bamba M,et al.Dynamic alteration of the E-cadherin/catenin complex during cell differentiation and invasion of undifferentiated-type gastric carcinomas[J].J Pathol,2005,205(3):349-358.
[98]Motoshita J,Nakayama H,Taniyama K,et al.Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype:LI-cadherin is associated with intestinal phenotype[J].Pathol Int,2006,56(4):200-205.
[99]Hinoi T,Lucas PC,Kuick R,et al.CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia[J].Gastroenterology,2002,123(5):1565-1577.
[100]Ito R,Oue N,Yoshida K,et al.Clinicopathological significant and prognostic influence of cadherin-17 expression in gastric cancer[J].Virchows Arch,2005,447:717-722.
[101]Mizoshita T,Tsukamoto T,Nakanishi H,et al.Expression of Cdx2 and the phenotype of advanced gastric cancers:relationship with prognosis[J].J Cancer Res Clin Oncol,2003,129:727-734.
[102] Fan Z, Li J, Dong B, et al. Expression of Cdx2 and hepatocyte antigen in gastric carcinoma: association with histologic type and implications for prognosis [J].Clin Cancer Res, 2005,11: 6162-6170.
[103] Ge J, Chen Z, Wu S, et al. A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma[J]. Clin Oncol, 2008,20(4):275-283.
[104] Bai YQ, Miyake S, Iwai T, et al. CDX2, a homeobox transcription factor, upregulates transcription of the p21/WAFl/CIPl gene[J]. Oncogene, 2003, 22:7942-7949.
[105] Que J, Okubo T, Goldenring JR, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm[J]. Development,2007, 134(13):2521-2531.
[106]Williamson, K. A., Hever, A. M, Rainger, J., et al. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome[J]. Hum. Mol. Genet, 2006, 15:1413-1422.
[107] Okubo T, Pevny L H, Hogan, B L. Sox2 is required for development of taste bud sensory cells[J]. Genes Dev, 2006,20: 2654-2659.
[108] Ishii Y, Rex M, Scotting P J, et al. Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial- mesenchymal interactions[J]. Dev Dyn, 1998,213:464-475.
[109] Fukuda K, Yasugi S.The molecular mechanisms of stomach development in vertebrates[J]. Dev. Growth Differ, 2005, 47:375-382.
[110] Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gast ric carcinoma[J], Int J Oncol, 2004, 24(2):257-263.
[111] Tsukamoto T, Mizoshita T, Mihara M, et al.Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes[J].Histopathology, 2005, 46(6):649-658.
[112] Tsukamoto T, Inada K, Tanaka H,et al. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes,Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia[J]. J Cancer Res Clin Oncol, 2004, 130(3): 135-145.
[113] Tsukamoto T, Mizoshita T, Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization[J]. Gastric Cancer, 2006, 9(3):156-166.
[114] Kim BM, Buchner G, Miletich I, et al.The stomach mesenchymal transcription factor Barxl specifies gastric epithelial identity through inhibition of transient Wnt signaling[J]. Dev Cell, 2005, 8(4):611-622.
[115] Sakamoto N, Fukuda K, Watanuki K, et al.Role for cGATA-5 in transcriptional regulation of the embryonic chicken pepsinogen gene by epithelial-mesenchymal interactions in the developing chicken stomach[J]. Dev Biol, 2000,223(1):103-113.
[116] Park HS, Goodlad RA, Wright NA. Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens[J]. Am J Pathol, 1995 ,147(5):1416-1427.
[117] van den Brink GR, Hardwick JC, Tytgat GN, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse[J]. Gastroenterology, 2001, 121:317-328.
[118] van den Brink GR, Hardwick JC, Nielsen C, et al. Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract[J]. Gut,2002,51:628-633.
[119] Shiotani A, Iishi H, Uedo N,et al. Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer[J]. Am J Gastroenterol, 2005,100:581-587.
[120] Shiotani A, Iishi H, Uedo N,et al. Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression[J]. Aliment Pharmacol Ther, 2006,24(Suppl 4):71-80.
[121]Rountree MR, Bachman KE, Baylin SB.DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci[J]. Nat Genet, 2000,25(3):269-277.
[122] Yuasa Y, Nagasaki H, Akiyama Y, et al.Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients[J]. Carcinogenesis. 2005,26(l):193-200.
[2]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.
[3]Liu YQ,Zhao H,Ning T,et al.Expression of 1A6 gene and its correlation with intestinal gastric carcinoma[J].World J Gastroenterol,2003,9(2):238-241.
[4]WalkerM M.Is intestinal metaplasia of the stomach reversible[J].Gut,2003,52(1):1-4.
[5]Kang JY,Finlayson C,Maxwell JD et al.Risk of gastric carcinoma in patients with atrophic gastritis and intestinal metaplasia[J].Gut,2002,51 (6):899.
[6]Whiting JL,Sigurdsson A,Rowlands DC,et al.The long term results of endoscopic surveillance of premalignant gastric lesions[J].Gut,2002,50(3):378-381.
[7]Jaffee IM,Rahmani M,Singhal MG,et al.Expression of the intestinal transcription factor CDX2 in carcinoid tumors is a marker of midgut origin[J].Arch Pathol Lab Med,2006,130(10):1522-1526.
[8]Drummond F,Putt W,Fox M,et al.Cloning and chromosome assignment of the human CDX2 gene[J].Ann Hum Genet,1997,61(5):393-400.
[9]Chawengsaksophak K,James R,Hammond VE,et al.Homeosis and intestinal tumours in Cdx2 mutant mice[J].Nature,1997,386(6620):84-87.
[10]Beck F.Homeobox genes in gut development[J].Gut.2002,51:450-454.
[11]许海泉，王邦茂，章明放，等．Cdx2和PTEN在胃黏膜肠上皮化生及肠型胃癌组织中的表达[J]．天津医科大学学报，2004，10(4)：510-513．
[12]李姝，王邦茂，张洁，等．Cdx2和MUC2在反流性食管炎、Barrer食管和食管腺癌中的表达[J]．中华消化内镜杂志，2006，23(5)：355-357．
[13]Guti(?)rrez-Gonz(?)lez L,Wright NA.Biology of intestinal metaplasia in 2008:more than a simple phenotypic alteration[J].Dig Liver Dis,2008,40(7):510-522.
[14]Ko S,Chu KM,Luk JM,et al.CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach[J]. J Pathol, 2005,205(5): 615-622.
[15] Groisman GM, Amar M, Meir A.Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia[J].Mod Pathol, 2004,17(10):1282-1288.
[16] Seno H, Oshima M, Taniguchi MA, et al. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer:Prognostic implications [J]. Int J Oncol, 2002, 21(4):769-774.
[17] Phillips RW, Frierson Jr HF, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus[J]. Am J Surg Pathol, 2003, 27(11):1442- 1447.
[18] Eda A, Osawa H, Yanaka I, et al. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia[J]. J Gastroenterol,2002, 37(2):94-100.
[19] Kim HS, Lee JS, Freund JN, et al.CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions[J]. J Gastroenterol Hepatol, 2006, 21(2):438-442.
[20] Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice[J]. Biochem Biophys Res Commun, 2002,294(2):470-479.
[21] Mutoh H, Satoh K, Kita H, et al. Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine[J]. Int J Dev Biol, 2005, 49(7):867-871.
[22]Mizoshita T , Inada K, Tsukamoto T , et al. Expression of the intestine-specific t ranscription factor s , Cdxl and Cdx2 , correlates shift to an intestinal phenotype in gast ric cancer cells[J]. J Cancer Res Clin Oncol, 2004 , 130 : 29-36.
[23]Bai YQ , Yamamoto H , Akiyama Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of t he stomach[J]. Cancer Lett,2002, 176:47-55.
[24] Dong W, Yu Q, Xu Y. Altered expression of a LI-cadherin in gastric cancer and intestinal metaplasia[J]. Dig Dsi Sci, 2007, 52(2): 536-542.
[25]Gr(o|¨)tzinger C,Kneifel J,Patschan D,et al.LI-cadherin:a marker of gastric metaplasia and neoplasia[J].Gut,2001,49(1):73-81.
[26]Motoshita J,Nakayama H,Taniyama K,et al.Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype:LI-cadherin is associated with intestinal phenotype[J].Pathol Int,2006,56(4):200-205.
[27]余琼芳，董卫国，程春生，等．肝肠钙粘连蛋白在胃癌组织中的表达及临床意义[J]．临床内科杂志，2005，22(9)：616-618．
[28]Hinoi T,Lucas PC,Kuick R,et al.CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia[J].Gastroenterology,2002,123(5):1565-1577.
[29]Ge J,Chen Z,Wu S,et al.A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma[J].Clin Oncol,2008,20(4):275-283.
[30]Gibson UE,Heid CA,Williams PM.A novel method for real time quantitative RT-PCR [J].Genome Res,1996,6:995-1001.
[31]Schmittgen TD.Real time quantitative PCR [J].Methods,2001;25:383-385.
[32]Giraud AS.Metaplasia as a premalignant pathology in the stomach [J].Gastroenterology,2007,132:2053-2056.
[33]Fitzgerald RC.Genetics and prevention of oesophageal adenocarcinoma[J].Recent Results Cancer Res,2005,66:35-46.
[34]Barros R,Pereira B,Duluc I,et al.Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines[J].J Pathol,2008,215(4):411-420.
[35]Guarner J,Mohar A,Parsonnet J,et al.The association ofHelicobacter pylori with gastric cancer and preneoplastic gastric lesions in chiapas[J].Mexico Cancer,1993,71:297-301.
[36]任刚，蔡嵘，陈强，等．幽门螺杆菌与肠化生相关性的初步研究[J]．临床消化病杂志，2000，12(3)：102-103
[37]兰春慧，张渊智，房殿春．幽门螺杆菌感染诱发蒙古沙鼠胃黏膜肠上皮化生和异型增生[J]．解放军医学杂志，2003，28(11)：985-986．
[38]Maruta F,Ota H,Genta RM,et al.Role of N-methyl-N-nitrosourea in the induction of intestinal metaplasia and gastric adenocarcinoma in Mongolian gerbils infected with Helicobacter pylori[J].Scand J Gastroenterol,2001,36(3):283-290.
[39]Kawazoe T,Sakagami T,Nakajima K,et al.Role of bacterial strain diversity of Helicobacter pylori in gastric carcinogenesis induced by N-methyl-N-nitrosourea in Mongolian gerbils [J].Helicobacter,2007,12(3):213-223.
[40]兰春慧，房殿春，邹全明．HP感染内蒙古沙鼠致Barrett食管及胃癌的实验研究[J]．重庆医学，2007，36(15)：1491-1493．
[41]秦玉峨，单国栋，季峰．肠化生和肠型胃癌内镜及病理特点分析[J]．浙江预防医学，2005：17(8)：6-8．
[42]周丽雅，林三仁，丁士刚，等．根除幽门螺杆菌对胃癌患病率及胃黏膜组织学变化的八年随访研究[J]．中华消化杂志，2005，25(6)：324-327．
[43]Tosh D,Slack JM.How cells change their phenotype[J].Nat Rev Mol Cell Biol,2002,3:187-194.
[44]Que J,Choi M,Ziel JW,et al.Morphogenesis of the trachea and esophagus:current players and new roles for noggin and Bmps[J].Differentiation,2006,74:422-437.
[45]Mizoshita T,Inada K,Tsukamoto T,et al.Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa--with special emphasis on participation in intestinal metaplasia of the human stomach [J].Gastric Cancer,2001,4(4):185-191.
[46]Werling RW,Yaziji H,Bacchi CE,et al.CDX2,a Highly sensitive and specific marker of adenocarcinomas of intestinal origin:An immunohistochemical survey of 476 primary and metastatic carcinomas [J].Am J Surg Pathol,2003,27:303-310.
[47]Houle M,Prinos P,Iulianella A,et al.Retinoic acid regulation of Cdx1:an indirect mechanism for retinoids and vertebral specification [J].Mol Cell Biol,2000,20:6579-6586.
[48]Shi XY,Bhagwandeen B,Leong AS.CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus [J].Am J Clin Pathol,2008,129(4):571-577.
[49]Souza RF, Krishnan K, Spechler SJ. Acid, bile, and CDX: the ABCs of making Barrett's metaplasia [J]. Am J Physiol Gastrointest Liver Physiol, 2008, 295(2):G 211-218.
[50] Moons LM, Bax DA, Kuipers EJ, et al. The homeodomain protein CDX2 is an early marker of Barrett's oesophagus [J]. J Clin Pathol, 2004,57(10):1063-1068.
[51]Tannapfel A. Molecular Findings in Barrett's Epithelium [J]. Dig Dis, 2004,22:126-133.
[52]Lynch JP, Silberg DG. To differentiate or proliferate? The interaction between PI3K/PTEN and Cdx2 [J]. Gastroenterology, 2002,123:1395-1397.
[53]Yamamoto H, Bai YQ, Yuasa Y. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression[J]. Biochem Biophys Res Commun, 2003,300(4): 813-818.
[54]Silberg DG, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice[J]. Gastroenterology, 2002, 122(3):689-696.
[55]Geiger B, Ayalon O, Cadherins[J]. Annu Rev Cell Biol, 1992, 8:307-332.
[56]Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion [J]. Trends Genet, 1993, 9:317-321.
[57]Takeichi, M. Morphogenetic roles of classical cadherins [J]. Curr Opin Cell Biol, 1995,7:619-627.
[58]Thomson RB, Igarashi P, Biemesderfer D, et al. Isolation and cDNA cloning of Ksp-cadherin,a novel kidney-specific member of the cadherin multigene family [J].J Biol Chem, 1995, 270:17594-17601.
[59]Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness[J]. Biochem Biophys Acta, 1994,1198:11-26.
[60]Berndorff D R. Gessner BK, Schnoy N, et al. Liver-intestine cadherin: molecular cloning and characterization of a novel Ca~(2+)-dependent cell adhesion molecule expressed in liver and intestine[J]. J Cell Biol,1994, 125:1353-1369.
[61]Wang XQ, Luk JM, Leung PP, et al. Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma [J].Clin Cancer Res, 2005, 11(2 Pt 1):483-489.
[62]Takamura M, Sakamoto M, Ino Y, et al. Expression of liver-intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas[J].Cancer Sci, 2003, 94(5):425-430.
[63]Takamura M, Ichida T, Matsuda Y, et al.Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma[J].Cancer Lett, 2004, 212(2):253-259.
[64]Ko S, Chu KM, Luk JM,et al.Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis[XJ.Biochem Biophys Res Commun,2004, 319(2):562-568.
[65]Que J, Okubo T, Goldenring JR, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm [J]. Development,2007, 134(13):2521-2531.
[66]Williamson KA, Hever AM, Rainger J, et al. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome[J]. Hum Mol Genet. 2006,15,1413-1422.
[67] Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gast ric carcinoma[J]. Int J Oncol, 2004, 24(2):257-263.
[68] Tsukamoto T, Inada K, Tanaka H,et al. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes,Cdxl and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia[J]. J Cancer Res Clin Oncol, 2004, 130(3):135-145.
[69] Tsukamoto T, Mizoshita T, Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization[J]. Gastric Cancer, 2006, 9(3): 156-166.
[70] Tsukamoto T, Mizoshita T, Mihara M, et al.Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes[J].Histopathology, 2005, 46(6):649-658.
[71] Bornschein J, Wex T, Peitz U, et al. The combined presence of H pylori infection and gastro-oesophageal reflux disease leads to an up-regulation of CDX2 gene expression in antrum and cardia [J]. J Clin Pathol, 2009 ,62(3):254-259.
[72] Manzo BA, Crabtree JE, Fiona Campbell M, et al. Helicobacter pylori regulates the expression of inhibitors of DNA binding (Id) proteins by gastric epithelial cells[J]. Microbes Infect, 2006, 8(4):1064-1074.
[73] Barros R, Marcos N, Reis CA, et al. CDX2 expression is induced by Helicobacter pylori in AGS cells[J]. Scand J Gastroenterol, 2009,4(1):124-125.
[74] Satoh K, Mutoh H, Eda A, et al. Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori [J]. Helicobacter, 2002, 7(3):192-198.
[75] Vauhkonen M, Vauhkonen H, Sipponen P. Helicobacter pylori infection induces a reversible expression of the CDX2 transcription factor protein in human gastric epithelium [J]. Scand J Gastroenterol, 2008,43: 915-921.
[76] Shiotani A, Uedo N, Iishi H, et al. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia [J]. Int J Cancer, 2007,121(6):1182-1189.
[77] Guo RJ, Suh ER, Lynch JP.The Role of Cdx Proteins in Intestinal Development and Cancer [J]. Cancer Biol Ther, 2004, 3(7):593-601.
[78 Beck F, Chawengsaksophak K, Luckett J, et al. A study of regional gut endoderm potency by analysis of Cdx2 null mutant chimaeric mice[J]. Devel Biol, 2003, 255:399-406.
[79] Chawengsaksophak K, de Graaff W, Rossant J, et al.Cdx2 is essential for axial elongation in mouse development. Proc Natl Acad Sci USA, 2004, 101(20):7641-7645.
[80] Beck F, Chawengsaksophak K, Waring P, et al. Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice [J]. Proc Natl Acad Sci USA, 1999, 96(13): 7318-7323.
[81] Jobert, A S, Zhang P, Couvineau A, et al. Absence of functional receptors parathyroid hormone and parathyroid hormone related peptide in Blomstrand chondrodysplasia [J]. Clin Invest, 1998,102: 34-40.
[82] Yang L, Yan D, Bruggeman M, et al.Mutation of a lysine residue in a homeodomain generates dominant negative thyroid transcription factor 1 [J].Biochemistry, 2004, 43(39): 12489-12497.
[83] Assenberg R, Webb M, Connolly E, Stott K, Watson M, Hobbs J, Thomas JO.A critical role in structure-specific DNA binding for the acetylatable lysine residues in HMGB1 [J]. Biochem J, 2008,411(3):553-561.
[1]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.
[2]Liu YQ,Zhao H,Ning T et al.Expression of 1A6 gene and its correlation with intestinal gastric carcinoma[J].World J Gastroenterol,2003,9(2):238-241.
[3]Walker MM.Is intestinal metaplasia of the stomach reversible[J].Gut,2003,52(1):1-4.
[4]Kang JY,Finlayson C,Maxwell JD et al.Risk of gastric carcinoma in patients with atrophic gastritis and intestinal metaplasia[J].Gut,2002,51 (6):899.
[5]Whiting JL,Sigurdsson A,Rowlands DC et al.The long term results of endoscopic surveillance of premalignant gastric lesions[J].Gut,2002,50(3):378-381.
[6]管仁珍，刘文天，王邦茂等．胃黏膜不典型增生和肠化生的内镜监测评价[J]．胃肠病学和肝病学杂志，2008，17(2)：136-138．
[7]Que J,Choi M,Ziel JW et al.Morphogenesis of the trachea and esophagus:current players and new roles for noggin and Bmps[J].Differentiation,2006,74(7):422-437.
[8]Guamer J,Mohar A,Parsonnet Jet al.The association of helicobacter pylori with gastric cancer and preneoplastic gastric lesions in chiapas[J].Mexico Cancer,1993,71(2):297-301.
[9]任刚，蔡嵘，陈强等．幽门螺杆菌与肠化生相关性的初步研究[J]．临床消化病杂志，2000，12(3)：102-103．
[10]兰春慧，张渊智，房殿春．幽门螺杆菌感染诱发蒙古沙鼠胃黏膜肠上皮化生和异型增生[J]．解放军医学杂志，2003，28(11)：985-986．
[11]Maruta F,Ota H,Genta RM et al.Role of N-methyl-N-nitrosourea in the induction of intestinal metaplasia and gastric adenocarcinoma in Mongolian gerbils infected with Helicobacter pylori[J].Scand J Gastroenterol,2001,36(3):283-290.
[12]Kawazoe T,Sakagami T,Nakajima K et al.Role of bacterial strain diversity of Helicobacter pylori in gastric carcinogenesis induced by N-methyl-N-nitrosourea in Mongolian gerbils [J].Helicobacter,2007,12(3):213-223.
[13]兰春慧，房殿春，邹全明．HP感染内蒙古沙鼠致Barrett食管及胃癌的实验研究[J]．重庆医学，2007，36(15)：1491-1493．
[14]秦玉峨，单国栋，季峰．肠化生和肠型胃癌内镜及病理特点分析[J]．浙江预防医学，2005，17(8)：6-8．
[15]Sung JJ,Lin SR,Ching JY et al.Atrophy and intestinal metaplasia one year after cure of H.pylori infection:a prospective,randomized study[J].Gastroenterology,2000,119(1):7-14.
[16]Leung WK,Sung JJ.Review article:intestinal metaplasia and gastric carcinogenesis [J].Aliment Pharmacol Ther,2002,16(7):1209-1216.
[17]Leung WK,Lin SR,Ching JY et al.Factors predicting progression of gastric intestinal metaplasia:results of a randomised trial on Helicobacter pylori eradication[J].Gut,2004,53(9):1244-1249.
[18]马雪芹，胡敏．根除反复幽门螺杆菌感染对胃黏膜炎症和肠上皮化生的临 床意义[J]．青海医学院学报，2007，28(2)：131-133．
[19]范国明，丁秀婷，杜若红．根除幽门螺杆菌对胃黏膜病变影响的观察[J]．中国医师杂志，2003，增刊：60-62．
[20]Tucci A,Poli L,Tosetti C et al.Reversal of fundic atrophy after eradication of Helicobacter pylori[J].Am J Gastroenterolgy,1998,93(9):1425-1431.
[21]周丽雅，林三仁，丁士刚等．根除幽门螺杆菌对胃癌患病率及胃黏膜组织学变化的八年随访研究[J]．中华消化杂志，2005，25(6)：324-327．
[22]王佳林，刘星群，赵贵军．根除幽门螺杆菌对胃粘膜病变的影响[J]．胃肠病学，2007，12(11)：691-692．
[23]Sobala GM,O'Connor HJ,Dewar EP,et al.Bile reflux and intestinal metaplasia in gastric mucosa[J].J Clin Pathol,1993,46(3):235-240.
[24]张卓群．原发性胆汁反流对胃粘膜病变的影响[J]．中华腹部疾病杂志，2003，3(4)：261-262．
[25]Ebert MP,Leodolter A,Malfertheiner P.Novel strategies in the prevention of gastric cancer[J].Hepatogastroentemlogy,2001,48(42):1569-1571.
[26]Guti(?)rrez-Gonz(?)lez L,Wright NA.Biology of intestinal metaplasia in 2008:more than a simple phenotypic alteration[J].Dig Liver Dis,2008,40(7):510-522.
[27]周心明，梁杏云．胆汁反流性胃炎临床分析[J]．武汉大学学报(医学版)，2007，287(5)：680-682．
[28]Nehra D,Howell P,Williams CP et al.Toxic bile acids in gastro-oesophageal reflux disease:influence of gastric acidity[J].Gut,1999,44(5):598-602.
[29]Berk F.Homeobox genes in gut development[J].Gut,2002,51 (3):450-454.
[30]Guo RJ,Suh ER,Lynch JP.The Role of Cdx Proteins in Intestinal Development and Cancer[J].Cancer Biol Ther,2004,3(7):593-601.
[31]Souza RF,Krishnan K,Spechler SJ.Acid,bile,and CDX:the ABCs of making Barrett's metaplasia[J].Am J Physiol Gastrointest Liver Physiol,2008,295(2):211-218.
[32]Beck F,Chawengsaksophak K,Luckett J,et al.A study of regional gut endoderm potency by analysis of Cdx2 null mutant chimaeric mice[J].Devel Biol,2003,255(2):399-406.
[33]Mizoshita T,Inada K,Tsukamoto T,et al.Expression of Cdxl and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa-with special emphasis on participation in intestinal metaplasia of the human stomach[J].Gastric Cancer,2001,4(4):185-191.
[34]Werling RW,Yaziji H,Bacchi CE,et al.CDX2,a Highly sensitive and specific marker of adenocarcinomas of intestinal origin:An immunohistochemical survey of 476 primary and metastatic carcinomas[J].Am J Surg Pathol,2003,27(3):303-310.
[35]Scoville DH,Sato T,He XC et al.Current view:intestinal stem cells and signaling[J].Gastroenterology,2008,134(3):849-864.
[36]Houde M,Laprise P,Jean D et al.Intestinal epithelial cell differentiation involves activation of p38 mitogen-activated protein kinase that regulates the homeobox transcription factor CDX2[J].J Biol Chem,2001,276(38):21885-21894.
[37]Houle M,Prinos P,Iulianella A et al.Retinoic acid regulation of Cdx1.an indirect mechanism for retinoids and vertebral specification[J].Mol.Cell.Biol.,2000,20(17):6579 - 6586.
[38]Jaffee IM,Rahrnani M,Singhal MG,et al.Expression of the intestinal transcription factor CDX2 in carcinoid tumors is a marker of midgut origin[J].Arch Pathol Lab Med,2006,130(10):1522-1526.
[39]Drummond F,Putt W,Fox M,et al.Cloning and chromosome assignment of the human CDX2 gene[J].Ann Hum Genet,1997,61(5):393-400.
[40]Chawengsaksophak K,de Graaff W,Rossant J,et al.Cdx2 is essential for axial elongation in mouse development[J].Proc Natl Acad Sci U S A,2004,18,101(20):7641-7645.
[41]Beck F,Chawengsaksophak K,Waring P,et al.Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice[J].Proc Natl Acad Sci U S A,1999,22,96(13):7318-7323.
[42]许海泉，王邦茂，章明放等．Cdx2和PTEN在胃粘膜肠上皮化生及肠型胃癌组织中的表达[J]．天津医科大学学报，2004，10(4)：510-513．
[43]李姝，王邦茂，张洁等．Cdx2和MUC2在反流性食管炎、Barrett食管和食管腺癌中的表达[J]．到中华消化内镜杂志，2006，23(5)：355-357．
[44]Shi XY,Bhagwandeen B,Leong AS.CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus[J].Am J Clin Pathol, 2008, 129(4):571-577.
[45] Moons LM, Bax DA, Kuipers EJ, et al. The homeodomain protein CDX2 is an early marker of Barrett's oesophagus[J]. J Clin Pathol, 2004, 57(10):1063-1068.
[46] Tannapfel A. Molecular Findings in Barrett's Epithelium [J]. Dig Dis, 2004, 22(2): 126-133.
[47] Ko S, Chu KM, Luk JM, et al. CDX2 co-localizes with liver-intestine cadherin in intestinal metaplasia and adenocarcinoma of the stomach[J]. J Pathol, 2005,205(5): 615-622.
[48] Groisman GM, Amar M, Meir A.Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia[J]. Mod Pathol, 2004, 17(10):1282-1288.
[49] Seno H, Oshima M, Taniguchi MA, et al. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer:Prognostic implications [J]. Int J Oncol, 2002, 21(4):769-774.
[50] Phillips RW, Frierson Jr HF, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus[J].Am J Surg Pathol, 2003,27:1442-1447.
[51] Eda A, Osawa H, Yanaka I, et al. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia[J]. J Gastroenterol,2002, 37(2):94-100.
[52] Lynch JP, Silberg DG. To differentiate or proliferate? The interaction between PI3K/PTEN and Cdx2[J]. Gastroenterology, 2002, 123(4):1395-1397.
[53] Yamamoto H, Bai YQ, Yuasa Y. Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression[J]. Biochem Biophys Res Commun, 2003, 24,300(4):813-818.
[54] Silberg DG, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice[J]. Gastroenterology, 2002, 122(3):689-696.
[55] Kim HS, Lee JS, Freund JN, et al.CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions[J]. J Gastroenterol Hepatol, 2006, 21(2):438-442.
[56] Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice[J]. Biochem Biophys Res Commun, 2002, 294(2):470-479.
[57] Mutoh H, Satoh K, Kita H, et al. Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine[J]. Int J Dev Biol, 2005, 49(7):867-871.
[58] Mizoshita T , Inada K, Tsukamoto T , et al. Expression of the intestine-specific transcription factors , Cdx1 and Cdx2 , correlates shift to an intestinal phenotype in gast ric cancer cells [J]. J Cancer Res Clin Oncol, 2004 ,130 : 29-36.
[59] Bai YQ , Yamamoto H , Akiyama Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach[J]. Cancer Lett,2002,176: 47-55.
[60] Chawengsaksophak K, James R, Hammond VE, et al. Homeosis and intestinal tumours in Cdx2 mutant mice[J]. Nature, 1997, 386(6620):84-87.
[61] Marchetti M, Caliot E, Pringault E. Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes[J]. J Cell Sci, 2003,116(8): 1429-1436.
[62] Liu T, Zhang X, So CK, et al. Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells[J]. Carcinogenesis, 2007,28(2):488-496.
[63] Dettmar PW, Strugala V, Tselepis C, et al. The effect of alginates on deoxycholic-acid-induced changes in oesophageal mucosal biology at pH 4[J]. J Biomater Sci Polym Ed, 2007,18:317-333.
[64] Burnat G, Rau T, Elshimi E, et al. Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett's esophageal mucosa and adenocarcinoma cell line[J]. Scandinavian Journal of Gastroenterology, 42(12): 1460 - 1465.
[65] Avissar NE, Toia L, Hu Y, et al. Bile acid alone, or in combination with acid,induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR)[J]. J Gastrointest Surg, 2009, 13(2):212-222.
[66] Chen X, Qin R, Liu B, et al. Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers[J]. Gastroenterology, 2008, 8:1-9.
[67] Barros R, Pereira B, Duluc I, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines[J]. J Pathol, 2008, 215(4):411-420.
[68] Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell[J]. Anat Rec, 1993, 236(2):259-279.
[69] Hattori T, Fujita S. Tritiated thymidine autoradiographic study of cell migration and renewal in the pyloric mucosa of golden hamsters[J]. Cell Tissue Res, 1976,175(l):49-57.
[70] Kim S, Domon-Dell C, Wang Q, et al. PTEN and TNF-a regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-KB-dependentpathway[J]. Gastroenterology, 2002,123(4):1163-1178.
[71] Jin T, Li H. Pou homeodomain protein OCT1 is implicated in the expression of the caudal-related homeobox gene Cdx-2 [J]. J Biol Chem, 2001,276:14752-14758.
[72] Xu F, Li H, Jin T. Cell type-specific autoregulation of the Caudal-related homeobox gene Cdx-2/3[J]. J Biol Chem, 1999, 274:34310-34316.
[73] Drummond F, Sowden J, Morrison K, et al. The caudaltype homeobox protein Cdx2 binds to the colon promoter of the carbonic anhydrase 1 gene[J]. Eur J Biochem, 1996, 236:670 - 681.
[74] Silberg DG, Swain GP, Suh ER, et al. Cdxl and Cdx2 expression during intestinal development [J]. Gastroenterology, 2000, 119:961-971.
[75] Lorentz O, Duluc I, Arcangelis AD, et al. Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation[J]. J Cell Biol, 1997,139:1553-1565.
[76] Troelsen JT, Mitchelmore C, Spodsberg N, et al. Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homeodomain protein Cdx-2 [J].Biochem J, 1997, 322:833-888.
[77] Taylor JK, Boll W, Levy T, et al. Comparison of intestinal phospholipase A/lysophospholipase and sucrase-isomaltase genes suggests a common structure for enterocyte-specific promoters[J]. DNA Cell Biol, 1997, 16:1419-1428.
[78] Lambert M, Colnot S, Suh E, et al. cis-Acting elements and transcription factors involved in the intestinal specific expression of the rat calbindin-D9k gene Binding of the intestine-specific transcription factor Cdx-2 to the TATA box[J].Eur J Biochem,1996,236:778-780.
[79]Yamamoto H,Miyamoto K,Li B,et al.The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine[J].J Bone Miner Res,1999,14:240-247.
[80]Drummond F J,Sowden J,Morrison K,et al.Colon carbonic anhydrase 1:transactivation of gene expression by the homeodomain protein Cdx2[J].FEBS Lett,1998,423:218-222.
[81]Geiger B,Ayalon O.Cadherins[J].Annu Rev Cell Biol,1992,8:307-332.
[82]Kemler R.From cadherins to catenins:cytoplasmic protein interactions and regulation of cell adhesion[J].Trends Genet,1993,9:317-321.
[83]Takeichi M.Morphogenetic roles of classical cadherins[J].Curr Opin Cell Biol,1995,7:619-627.
[84]Thomson,RB,Igarashi P,Biemesderfer D,et al.Isolation and cDNA cloning of Ksp-cadherin,a novel kidney-specific member of the cadherin multigene family[J].J Biol Chem,1995,270:17594-17601.
[85]Birchmeier W,Behrens J.Cadherin expression in carcinomas:role in the formation of cell junctions and the prevention of invasiveness[J].Biochem Biophys Acta,1994,1198:11-26.
[86]Bemdorff D,Gessner R,Kreft B,et al.Liver-intestine cadherin:molecular cloning and characterization of a novel Ca2+-dependent cell adhesion molecule expressed in liver and intestine[J].J Cell Biol,1994,125:1353-1369.
[87]Gessner R,Taubef R.Intestinal cell adhesion molecules,liver-intestine cadherin[J].Ann N Y Acad Sci,2000,915:136-143.
[88]Kreft B,Berndorff D,B(o|¨)ttinger A,et al.LI-cadherin-mediated cell-cell adhesion does not require cytoplasmic interactions[J].J Cell Biol,1997,136(5):1109-1121.
[89]刘仕琪，牛建华．肝肠-钙黏蛋白——一种新的胃腺癌标记物[J]．中国普通外科杂志，2008，17(10)：1010-1012．
[90]Wang XQ,Luk JM,Leung PP,et al.Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma[J].Clin Cancer Res,2005,11(2): 483-489.
[91]Takamura M,Sakamoto M,Ino Y,et al.Expression of liver-intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas[J].Cancer Sci,2003,94(5):425-430.
[92]Takamura M,Ichida T,Matsuda Y,et al.Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma[J].Cancer Lett,2004,212(2):253-259.
[93]Dong W,Yu Q,Xu Y.Altered expression of a LI-cadherin in gastric cancer and intestinal metaplasia[J].Dig Dsi Sci,2007,52(2):536-542.
[94]Gr(o|¨)tzinger C,Kneifel J,Patschan D,et al.LI-cadherin:a marker of gastric metaplasia and neoplasia[J].Gut,2001,49(1):73-81.
[95]Ko S,Chu KM,Luk JM,et al.Overexpression of LI-cadherin in gastric cancer is associated with lymph node metastasis[J].Biochem Biophys Res Commun,2004,319(2):562-568.
[96]余琼芳，董卫国，程春生等．肝肠钙粘连蛋白在胃癌组织中的表达及临床意义[J]．临床内科杂志，2005，22(9)：616-618．
[97]Nakamura E,Sugihara H,Bamba M,et al.Dynamic alteration of the E-cadherin/catenin complex during cell differentiation and invasion of undifferentiated-type gastric carcinomas[J].J Pathol,2005,205(3):349-358.
[98]Motoshita J,Nakayama H,Taniyama K,et al.Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype:LI-cadherin is associated with intestinal phenotype[J].Pathol Int,2006,56(4):200-205.
[99]Hinoi T,Lucas PC,Kuick R,et al.CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia[J].Gastroenterology,2002,123(5):1565-1577.
[100]Ito R,Oue N,Yoshida K,et al.Clinicopathological significant and prognostic influence of cadherin-17 expression in gastric cancer[J].Virchows Arch,2005,447:717-722.
[101]Mizoshita T,Tsukamoto T,Nakanishi H,et al.Expression of Cdx2 and the phenotype of advanced gastric cancers:relationship with prognosis[J].J Cancer Res Clin Oncol,2003,129:727-734.
[102] Fan Z, Li J, Dong B, et al. Expression of Cdx2 and hepatocyte antigen in gastric carcinoma: association with histologic type and implications for prognosis [J].Clin Cancer Res, 2005,11: 6162-6170.
[103] Ge J, Chen Z, Wu S, et al. A clinicopathological study on the expression of cadherin-17 and caudal-related homeobox transcription factor (CDX2) in human gastric carcinoma[J]. Clin Oncol, 2008,20(4):275-283.
[104] Bai YQ, Miyake S, Iwai T, et al. CDX2, a homeobox transcription factor, upregulates transcription of the p21/WAFl/CIPl gene[J]. Oncogene, 2003, 22:7942-7949.
[105] Que J, Okubo T, Goldenring JR, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm[J]. Development,2007, 134(13):2521-2531.
[106]Williamson, K. A., Hever, A. M, Rainger, J., et al. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome[J]. Hum. Mol. Genet, 2006, 15:1413-1422.
[107] Okubo T, Pevny L H, Hogan, B L. Sox2 is required for development of taste bud sensory cells[J]. Genes Dev, 2006,20: 2654-2659.
[108] Ishii Y, Rex M, Scotting P J, et al. Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial- mesenchymal interactions[J]. Dev Dyn, 1998,213:464-475.
[109] Fukuda K, Yasugi S.The molecular mechanisms of stomach development in vertebrates[J]. Dev. Growth Differ, 2005, 47:375-382.
[110] Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gast ric carcinoma[J], Int J Oncol, 2004, 24(2):257-263.
[111] Tsukamoto T, Mizoshita T, Mihara M, et al.Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes[J].Histopathology, 2005, 46(6):649-658.
[112] Tsukamoto T, Inada K, Tanaka H,et al. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes,Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia[J]. J Cancer Res Clin Oncol, 2004, 130(3): 135-145.
[113] Tsukamoto T, Mizoshita T, Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization[J]. Gastric Cancer, 2006, 9(3):156-166.
[114] Kim BM, Buchner G, Miletich I, et al.The stomach mesenchymal transcription factor Barxl specifies gastric epithelial identity through inhibition of transient Wnt signaling[J]. Dev Cell, 2005, 8(4):611-622.
[115] Sakamoto N, Fukuda K, Watanuki K, et al.Role for cGATA-5 in transcriptional regulation of the embryonic chicken pepsinogen gene by epithelial-mesenchymal interactions in the developing chicken stomach[J]. Dev Biol, 2000,223(1):103-113.
[116] Park HS, Goodlad RA, Wright NA. Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens[J]. Am J Pathol, 1995 ,147(5):1416-1427.
[117] van den Brink GR, Hardwick JC, Tytgat GN, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse[J]. Gastroenterology, 2001, 121:317-328.
[118] van den Brink GR, Hardwick JC, Nielsen C, et al. Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract[J]. Gut,2002,51:628-633.
[119] Shiotani A, Iishi H, Uedo N,et al. Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer[J]. Am J Gastroenterol, 2005,100:581-587.
[120] Shiotani A, Iishi H, Uedo N,et al. Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression[J]. Aliment Pharmacol Ther, 2006,24(Suppl 4):71-80.
[121]Rountree MR, Bachman KE, Baylin SB.DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci[J]. Nat Genet, 2000,25(3):269-277.
[122] Yuasa Y, Nagasaki H, Akiyama Y, et al.Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients[J]. Carcinogenesis. 2005,26(l):193-200.