Research for esophageal carcinogenesis and differentiation induction therapy based on normal esophageal epithelial cells and esophageal stem cells

食管干细胞s1）人食管角质形成细胞干细胞的特征在于表达低亲和力神经营养因子受体p75 NTR和差异表达的细胞粘附分子β1和β4整联蛋白。候选干细胞可以通过基于这些细胞表面分子的不同表达水平的免疫细胞化学细胞分选从角质形成细胞中分级分离为次要细胞亚群。2）我们在体内研究了食管上皮细胞的分化，发现在食管癌发生的早期阶段，p75/NTR阳性的干细胞区室中存在初始的遗传改变和异常的细胞增殖，提示它们作为食管癌发生的初始靶细胞群发挥作用。3)食管癌细胞系中含有不同水平的p75/NTR阳性细胞，这些细胞比p75/阴性细胞能产生更大的集落。p75/NTR阳性细胞的生长被SiRNA显著抑制。这些结果表明 ...更多信息 艾德认为p75/NTR有可能成为食管癌治疗的靶点，并有可能成为食管癌干细胞的候选细胞。胃十二指肠反流和吸烟对正常食管细胞的影响：1）胆汁酸、胰蛋白酶和酸联合作用可显著上调正常人食管细胞考克斯-2的表达和E2的产生。结果提示，胃食管反流可诱导食管上皮细胞环氧合酶-2表达和E2的产生。环氧合酶-2特异性抑制剂可能对食管癌有化学预防作用。2）尼古丁诱导人食管鳞状上皮细胞中FHIT基因甲基化，其机制可能是通过上调Dnmt 3a的表达，进而导致Fhit蛋白表达的缺失。停止尼古丁暴露后不能检测到FHIT甲基化。有趣的是，我们没有发现任何p16 INK 4a甲基化的证据。因此，FHIT可能对烟碱治疗敏感，而不是p16/INK 4a。我们的研究结果表明，持续吸烟可能会导致食管癌的风险。少

Esophageal stem cell s1)Human esophageal keratinocyte stem cells are characterized by the expression of the low affinity neurotrophin receptor p75NTR and differentially expressed cell adhesion molecules, the β1 and β4 integrins. The candidate stem cells can be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. 2)We demonstrated esophageal epithelial differentiation in vivo and detected an initial genetic alteration and abnormal cell proliferation in the p75/NTR positive putative stem cell compartment during the early stages of carcinogenesis, suggesting their role as an initial target cell population for carcinogenesis. 3)Esophageal cancer cells lines contained several levels of p75/NTR positive cells and these cells could reproduce larger colonies than p75/negative cells. p75/NTR positive cells dramatically suppressed their growth by SiRNA. These results suggest … More ed that p75/NTR may become a good therapeutic target and might be a candidate of cancer stem cell of esophageal cancer.Effect of gastroduodenal reflux and smoking on normal esophageal cell.1)COX-2 expression and prostaglandinE2 production were significantly up-regulated in normal human esophageal cells by bile acid in combination with trypsin and acid. The results suggest that duodenogastroesophageal reflux may induce cyclooxygenase-2 expression and prostaglandinE2 production in esophageal epithelial cells. Cyclooxygenase-2 specific inhibitors may have a chemopreventive effect on esophageal carcinoma. 2)We found that nicotine induced FHIT methylation via up-regulation of de novo methyltransferase Dnmt3a followed by loss of Fhit protein expression in human esophageal squamous epithelial cells. FHIT methylation was not able to be detected after cessation of nicotine exposure. Interestingly, we could not find any evidence of p16INK4a methylation. Thus, FHIT might be sensitive to nicotinic treatment rather than p16/INK4a. Our results suggest that continuous smoking may induce the risk of esophageal cancer. Less