2004 Fiscal Year Final Research Report Summary
Research for esophageal carcinogenesis and differentiation induction therapy based on normal esophageal epithelial cells and esophageal stem cells
| Project/Area Number |
14370385
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SHIMADA Yutaka Kyoto University, Graduate School of medicine, Department of Surgery & Surgical Basic Science, Lecturer, 医学研究科, 講師 (30216072)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Go Kyoto University, Graduate School of medicine, Department of Surgery & Surgical Basic Science, Assistant professor, 医学研究科, 助手 (50293866)
IMAMURA Masayuki Kyoto University, Graduate School of medicine, Department of Surgery & Surgical Basic Science, Professor, 医学研究科, 教授 (00108995)
YASUMOTO Shigeru Kanagawa Cancer Center Research Institute, Laboratory of molecular Cell Biology, Director, 臨床研究所, 研究所長
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| Project Period (FY) |
2002 – 2004
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| Keywords | Keratinocyte stem cell / p75 / NTR / Cyclooxygenase-2 / FHIT / Methylation / Esophageal cancer / Duodenogastroesophageal reflux / Cancer stem cell |
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| Research Abstract |
Esophageal stem cell s
1)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
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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
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