CDX2 MUC2在胃黏膜肠上皮化生组织中的表达情况及其临床意义研究

目的 探讨尾型同源盒转录因子2(CDX2)、黏蛋白2(MUC2)在胃黏膜肠上皮化生组织中的表达情况及其临床意义.方法 选择2011年1月至2014年5月于宁夏医科大学总医院消化内科就诊并行内镜活检的152例患者,根据病理检查结果将其分为非萎缩性胃炎组(32例)、萎缩性胃炎组(31例)、低级别上皮内瘤变组(24例)、高级...     

Expression of homeodomain protein CDX2 in gallbladder carcinomas

Purpose Caudal-related homeobox protein CDX2 plays an important role in the regulation of cell proliferation and differentiation of the intestinal epithelium. CDX2 is associated with intestinal metaplasia and carcinomas of the stomach, but the role of CDX2 in gallbladder carcinogenesis remains unknown.Methods We analyzed the expression of CDX2 and intestinal apomucin MUC2 in gallbladder cancer cell lines at the mRNA level by the RT-PCR method. We also investigated the expression of CDX2 and MUC2 in 68 primary gallbladder carcinomas by the immunohistochemical staining method and compared the expression of CDX2 with the clinicopathological factors in the gallbladder carcinoma cases.Results Expression of CDX2 and MUC2 was found in three of four gallbladder cancer cell lines at the mRNA level. In addition, we found that CDX2 was absent in the normal gallbladder epithelium, but the CDX2 protein was expressed in 25 of the 68 (36.8%) gallbladder carcinomas. Interestingly, in the tubular type gallbladder carcinomas, the frequency of CDX2 expression was much higher in the well-differentiated type than the moderately and poorly differentiated types, the difference being statistically significant (P<0.01). CDX2 expression showed a relationship with expression of MUC2 (P<0.04) in the gallbladder carcinomas. CDX2 was expressed in intestinal metaplasia and dysplasia, which are hypothesized to be premalignant conditions.Conclusion These results imply that CDX2 plays an important role in gallbladder carcinogenesis with intestinal differentiation.     

Barrett食管黏膜微细形态改变和CDX2蛋白的表达

目的 研究食管黏膜微细形态的改变和CDX2蛋白表达在Barrett食管（BE）诊断中的意义。方法 采用高清晰内镜观察BE及非BE的胃食管反流疾病（GERD）患者的齿状线附近黏膜的小凹及微细血管形态变化，并采用免疫组化方法检测CDX2蛋白的表达。结果 48例BE中，40例可观察到食管下段的栅状血管末端有不同程度的下移现象，而60例非BE的GERD患者均未发现有血管下移现象；放大内镜下BE黏膜可分为绒毛型、条纹型和小点型，绒毛型肠上皮化生（肠化）检出率显著高于条纹型及点状（P〈0.01）；CDX2蛋白不但在肠化的杯状细胞表达，而且在BE和非BE的柱状上皮中亦有表达，绒毛状上皮CDX2表达的阳性率显著高于条纹状（P〈0.01）和点状上皮（P〈0．05）。结论 观察食管黏膜微细形态有助于对BE的诊断、分型及了解其相关病理背景，CDX2蛋白是一种具有较高敏感性的肠上皮特异标志物，有助于判断早期肠化的发生，对BE的早期诊断可能有重要价值。     

Premalignant conditions of gastric cancer

Premalignant lesions of gastric cancer encompass a variety of conditions such as chronic gastritis, intestinal metaplasia and dysplasia, in which elevated risk of developing gastric cancer have been documented. Among them, intestinal metaplasia is frequently encountered in our daily endoscopic examination, yet its clinical significance is often underestimated despite of a number of reports demonstrating genetic and epigenetic alterations in the intestinal metaplastic mucosa. In this review, I will describe the molecular mechanisms of phenotypic changes from gastric mucosa to intestinal metaplasia based on our analysis of mouse model of intestinal metaplasia generated by ectopic expression of CDX2 in conjunction with the studies with human intestinal metaplasia.     

Helicobacter pylori infection induces a reversible expression of the CDX2 transcription factor protein in human gastric epithelium

Objective. The homeobox gene CDX2 is implicated in the appearance of intestinal metaplasia in Helicobacter pylori gastritis. The aim of this study was to investigate whether CDX2 expression in gastric mucosa occurs before the appearance of overt intestinal metaplasia in H. pylori gastritis, and whether or not this expression is reversible. Material and methods. CDX2 was studied by immunohistochemistry in a cohort of 38 patients with H. pylori gastritis before and after eradication (mean follow-up 6.3 years) of H. pylori. A cohort of 49 individuals with healthy stomachs was analysed as a control. Results. In the control group no immunostaining of CDX2 in the epithelial cells of the gastric body was found, while in 57% of the cases a mild, aberrant nuclear immunostaining of CDX2 in the non-metaplastic epithelial cells in antrum, designated as “positive staining of single cells” (PSSC), was found. In H. pylori gastritis, the PSSC was seen in antrum and corpus in 100% and 26% of the cases, respectively. The prevalence of antral PSSC was significantly increased (on average by 4-fold) in H. pylori gastritis as compared with controls. After eradication of H. pylori, the prevalence of PSSC decreased significantly in antrum but not in corpus. Conclusions. Expression of CDX2 at low intensity is common in the epithelium of normal antrum, and this expression is enhanced in H. pylori gastritis. Expression of CDX2 is reversible at least in antrum after eradication of H. pylori infection.     

PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas

BACKGROUND AND AIMS: Although it has been reported that intestinal metaplasia implicated in gastric carcinogenesis is induced by the ParaHox gene CDX2, it is unclear which genes are responsible for the formation of pseudopyloric glands and whether they play a role in gastric carcinogenesis. Pancreatic-duodenal homeobox 1 (PDX1) is also a ParaHox gene which contributes to the genesis and development of the pancreas, duodenum, and antrum. To clarify its significance for the formation of pseudopyloric glands and gastric carcinogenesis, we investigated expression of PDX1 and mucin in gastric carcinomas and surrounding mucosa. METHODS: Gastric carcinoma tissues from 95 patients were used for immunohistochemical analyses of PDX1, and mucins MUC6 and MUC5AC. RESULTS: PDX1 was found to be frequently expressed in pseudopyloric glands and intestinal metaplasia. MUC6 was more abundant than MUC5AC in pseudopyloric glands while higher levels of MUC5AC than MUC6 were evident in intestinal metaplasia. The frequency of PDX1 positive reactivity was higher in differentiated type carcinomas (39/43, 90.7%) and T1 carcinomas (42/43, 97.7%) than in undifferentiated type (33/52, 63.5%) and T2-4 (30/52, 57.7%) carcinomas. PDX1 and MUC6 double positive expression was observed in carcinomas, respectively, including the corpus, and also correlated with histological type and depth of invasion. In contrast, no link was apparent between PDX1 and MUC5AC double positive reactivity and histological type. CONCLUSION: Our study suggests that PDX1 plays an important role in the development of pseudopyloric glands, and that pseudopyloric glands may reflect a condition associated with gastric carcinogenesis.     

Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma

Purpose The extracellular signal-regulated kinase (ERK) 1/2 pathway plays important roles in the regulation of cell proliferation, differentiation and cell survival. The caudal-related homeobox protein CDX2 is essential for the development of the intestine, and is related to gastric and gallbladder cancers with the intestinal phenotype. However, the roles of ERK1/2 phosphorylation (pERK1/2) and CDX2 in cholangiocarcinogenesis remain unknown.Methods We investigated the expression of pERK1/2, CDX2 and MUC2 in Thai cholangiocarcinoma (CCA) specimens by means of immunohistochemical staining, and compared the expression of these proteins with clinicopathological factors.Results The pERK1/2 protein was expressed in 29 of 59 (49.2%) CCA cases. Interestingly, in tubular-type CCA, the frequency of pERK1/2 expression was associated with a higher grade of differentiation (P = 0.001). CDX2 expression was observed in 22 of the 59 (37.3%) CCA cases, showed a relationship with MUC2 expression (P = 0.001), and was much higher in papillary-type than tubular-type CCA (P = 0.002).Conclusion These results imply that pERK1/2 may be important for the differentiation of tubular-type CCA, while CDX2 is related to the intestinal phenotype of papillary-type CCA.     

LI-cadherin: a marker of gastric metaplasia and neoplasia

BACKGROUND: Intestinal metaplasia is considered a risk factor for the development of gastric adenocarcinomas of the intestinal type and is found in approximately 20% of gastric biopsies. Conventional histology only detects advanced stages of intestinal metaplasia. AIMS: To study expression of the enterocyte specific adhesion molecule liver-intestinal (LI)-cadherin in intestinal metaplasia as well as in gastric cancer, and to evaluate its use as a diagnostic marker molecule. PATIENTS: Gastric biopsies (n=77) from 30 consecutive patients (n=30; aged 28-90 years) as well as surgically resected tissue samples (n=24) of all types of gastric carcinomas were analysed. METHODS: Single and double label immunofluorescence detection on cryosections of gastric biopsies; alkaline phosphatase antialkaline phosphatase method on paraffin embedded carcinoma tissue sections. RESULTS: Of 77 biopsies (from 30 patients), 12 (from 10 patients) stained positive for LI-cadherin. LI-cadherin staining correlated with the presence of intestinal metaplasia. Conventional histological diagnosis however failed to detect subtle gastric intestinal metaplasia (three of 10 patients). In contrast, only LI-cadherin and villin were positive in these cases whereas sucrase-isomaltase also failed to detect intestinal metaplasia in four of 10 patients. Well differentiated gastric carcinomas showed intense staining for LI-cadherin while undifferentiated carcinomas showed only weak diffuse cytoplasmic staining. CONCLUSIONS: To detect early metaplastic changes in the gastric mucosa, LI-cadherin has a sensitivity superior to sucrase-isomaltase and conventional histology and comparable with that of villin. Its specificity exceeds that of villin. Thus LI-cadherin represents a new, reliable, and powerful marker molecule for early detection of gastric intestinal metaplasia and well differentiated adenocarcinomas.     

CDX1/2在人Barrett's食管中的表达以及胆酸对CDX2表达的影响

目的: 观察Barrett's食管黏膜组织中CDX mRNA和蛋白表达,观察不同胆汁酸对人食管细胞株Eca-109 CDX2 mRNA表达水平的影响.方法: 收集内镜下正常食管组织( n = 5),反流性食管炎( n = 7),Barrett's食管( n = 8)标本. 采用RT-PCR测定CDX1和CDX2 mRNA表达;实时荧光定量PCR测定CDX2 mRNA表达. 用免疫组织化学染色法对CDX2蛋白进行定位. 人食管癌细胞株Eca-109分别在100、400、1000μmol/L胆酸(CA),脱氧胆酸(DCA),甘胆酸(GC)中培养,分别在0-24 h收取细胞,荧光定量PCR测定CDX2 mRNA表达.结果: CDX2 mRNA在正常食管组织中无表达,在Barrett's食管组、反流性食管炎组表达增高(9.6411±6.6823,3.9156±3.6700),与正常食管组之间比较均存在显著性差异( P = 0.006,0.025),但2组之间没有显著性差异( P = 0.133),CDX1在所有食管组织中均无表达. 免疫组织化学染色在Barrett's食管有CDX2蛋白胞核呈特异性染色阳性反应,反流性食管炎组织CDX2胞质显示细颗粒性染色(假阳性),正常的食管组织未发现特异性染色. CDX2 mRNA在未加药物处理的Ec a-109细胞株中没有表达,其表达量对DCA、GC、CA显示出时间和剂量依赖性.结论: CDX2基因异常表达在食管黏膜肠化生过程中可能具有较重要作用,CDX2基因的表达可能是Barrett's食管发生过程的早期事件.胆汁酸在体外实验上调CDX2基因表达,通过调节其表达在Barrett's食管发生中起重要作用.