CLDN18表达在胃癌进展中的意义
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摘要
目的:探讨CLDN18表达与胃癌临床病理特征之间的关系。方法:组织芯片免疫组化染色法检测胃癌claudin-18蛋白表达,Real-time PCR法检测胃癌CLDN18 mRNA的表达。结果:胃癌组织claudin-18表达显著降低,并与组织学类型和浸润相关,肠型胃癌和浸润在肌层以内者其黏膜层claudin-18的下调表达率明显高于弥漫型胃癌或浸润程度超过肌层者。从黏膜层进展至侵袭前缘区,claudin-18的下调表达率逐渐升高,黏膜层claudin-18表达水平明显高于侵袭前沿区。进展期胃癌黏膜层癌组织claudin-18表达未下调者34例进展至侵袭前沿区28例转变为表达下调,其中弥漫型胃癌、浸润程度超过肌层者、有淋巴结转移者以及非贲门胃癌者发生率均高于肠型胃癌、浸润程度在肌层内者、无淋巴结转移者以及贲门胃癌者。52例胃癌黏膜层胃癌组织CLDN18 mRNA表达下调者20例,其相对表达量与浸润程度及肿瘤大小有关。结论:胃癌的进展中claudin-18表达降低,组织学类型的维持与其密切相关。
Objective:To study relationship between CLDN18 gene expression and the clinicopathologic features of gastric cancer (GC).Methods:A tissue microarray was made and immunohistochemistry was performed to detect the expression of claudin-18 protein.Real-time polymerase chain reaction was conducted to examine mRNA expression of CLDN18 gene.Results:Expression of claudin-18 protein in GC was significantly downregulated and was correlated with histologic types and extent of invasion,which was greatly decreased in the intestinal-type and intramuscular infiltration of GC than in the diffuse-type and the extramuscular extension,respectively. There was a gradual downregulation of claudin-18 expression from the mucosa to the front of the invasion.Claudin-18 expression was higher in the mucosa than at the front of invasion.Of the 34 cases with advanced GC without downregulation of claudin -18 expression in mucosa,28 had claudin-18 downregulation as GC developed to the front of the invasion.In the 28 cases,the incidences of the diffuse-type GC,extramuscular infiltration,lymph node metastasis,and non-cardiac GC were higher compared with the intestinal-type,intramuscular,non-metastatic,and cardiac GC.CLDN18 mRNA expression was downregulated in 20 of the 52 GC cases. The relative expression was associated with the infiltration and size of the tumors.Conclusion:Downregulation of claudin-18 expression is involved in the progression of disease,and in maintaining the phenotype of gastric adenocarcinoma.
Objective:To study relationship between CLDN18 gene expression and the clinicopathologic features of gastric cancer (GC).Methods:A tissue microarray was made and immunohistochemistry was performed to detect the expression of claudin-18 protein.Real-time polymerase chain reaction was conducted to examine mRNA expression of CLDN18 gene.Results:Expression of claudin-18 protein in GC was significantly downregulated and was correlated with histologic types and extent of invasion,which was greatly decreased in the intestinal-type and intramuscular infiltration of GC than in the diffuse-type and the extramuscular extension,respectively. There was a gradual downregulation of claudin-18 expression from the mucosa to the front of the invasion.Claudin-18 expression was higher in the mucosa than at the front of invasion.Of the 34 cases with advanced GC without downregulation of claudin -18 expression in mucosa,28 had claudin-18 downregulation as GC developed to the front of the invasion.In the 28 cases,the incidences of the diffuse-type GC,extramuscular infiltration,lymph node metastasis,and non-cardiac GC were higher compared with the intestinal-type,intramuscular,non-metastatic,and cardiac GC.CLDN18 mRNA expression was downregulated in 20 of the 52 GC cases. The relative expression was associated with the infiltration and size of the tumors.Conclusion:Downregulation of claudin-18 expression is involved in the progression of disease,and in maintaining the phenotype of gastric adenocarcinoma.
引文
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7 Jovov B,Van Itallie CM,Shaheen NT,et al.Claudin-18:a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance[J].Am J Physiol Gastrointest Liver Physiol,2007,293 (6) :G1106-G1113．
8 Hewitt KJ,Agarwal R,Morin PJ.The claudin gene family:expression in normal and neoplastic tissues[J].BMC Cancer,2006,6:186．
9 Matsuda Y,Semba S,Ueda J,et al.Gastric and intestinal claudin expression at the invasive front of gastric carcinoma[J].Cancer Sci,2007,98(7) :1014-1019．
10 Arabzadeh A,Troy TC,Turksen K.Changes in the distribution pattern of Claudin right junction proteins during the progression of mouse skin tumorigenesis[J].BMC Cancer,2007,7:196．
11 Katoh M.Epithelial-mesenchymal transition in gastric cancer (Review) [J].Int J Oncol,2005,27(6) :1677-1683．
12 Dhawan P,Singh AB,Deane NG,et al.Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer[J].J Clin Invest,2005,115(7) :1765-1776．
13 Yano K,Imaeda T,Niimi T.Transcriptional activation of the human claudin-18 gene promoter through two AP-1 motifs in PMA-stimulated MKN45 gastric cancer cells[J].Am J Physiol Gastrointest Liver Physiol,2008,294(1) :G336-G343．
14 Boitano S,Safdar Z,Welsh DG,et al.Cell-cell interactions in regulating lung function[J].Am J Physiol Lung Cell Mol Physiol,2004,287(3) :L455-L459．
2 Niimi T,Nagashima K,WardJM,et al.claudin-18,a novel downstream target gene for the T/EBP/NKX2． 1 homeodomain transcription factor,encodes lung-and stomach-specific isoforms through alternative splicing[J].Mo1 Cell Biol,2001,21(21) :7380-7390．
3 Sanada Y,Oue N,Mitani Y,et al.Down-regulation of the claudin-18 gene,identified through serial analysis of gene expression data analysis,in gastric cancer with an intestinal phenotype[J].J Pathol,2006,208(5) :633-642．
4 Koval M.Claudins-key pieces in the tight junction puzzle[J].Cell Commun Adhes,2006,13(3) :127-138．
5 Furuse M,Tsukita S.Claudins in occluding junctions of humans and flies[J].Trends Cell Biol,2006,16(4) :181-188．
6 Kitajiri SI,Furuse M,Morita K,et al.Expression patterns of claudins,tight junction adhesion molecules,in the inner ear[J].Hear Res,2004,187(1-2) :25-34．
7 Jovov B,Van Itallie CM,Shaheen NT,et al.Claudin-18:a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance[J].Am J Physiol Gastrointest Liver Physiol,2007,293 (6) :G1106-G1113．
8 Hewitt KJ,Agarwal R,Morin PJ.The claudin gene family:expression in normal and neoplastic tissues[J].BMC Cancer,2006,6:186．
9 Matsuda Y,Semba S,Ueda J,et al.Gastric and intestinal claudin expression at the invasive front of gastric carcinoma[J].Cancer Sci,2007,98(7) :1014-1019．
10 Arabzadeh A,Troy TC,Turksen K.Changes in the distribution pattern of Claudin right junction proteins during the progression of mouse skin tumorigenesis[J].BMC Cancer,2007,7:196．
11 Katoh M.Epithelial-mesenchymal transition in gastric cancer (Review) [J].Int J Oncol,2005,27(6) :1677-1683．
12 Dhawan P,Singh AB,Deane NG,et al.Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer[J].J Clin Invest,2005,115(7) :1765-1776．
13 Yano K,Imaeda T,Niimi T.Transcriptional activation of the human claudin-18 gene promoter through two AP-1 motifs in PMA-stimulated MKN45 gastric cancer cells[J].Am J Physiol Gastrointest Liver Physiol,2008,294(1) :G336-G343．
14 Boitano S,Safdar Z,Welsh DG,et al.Cell-cell interactions in regulating lung function[J].Am J Physiol Lung Cell Mol Physiol,2004,287(3) :L455-L459．