DC 欄位 | 值 | 語言 |
dc.contributor | 余幸司 | zh-TW |
dc.contributor | Yu, Hsin-Su | en |
dc.contributor | 臺灣大學:職業醫學與工業衛生研究所 | zh-TW |
dc.contributor.author | 曾禧凰 | zh-TW |
dc.contributor.author | Tseng, Hsi-Huang | en |
dc.creator | 曾禧凰 | zh-TW |
dc.creator | Tseng, Hsi-Huang | en |
dc.date | 2009 | en |
dc.date.accessioned | 2010-05-11T03:47:55Z | - |
dc.date.accessioned | 2018-06-29T17:26:16Z | - |
dc.date.available | 2010-05-11T03:47:55Z | - |
dc.date.available | 2018-06-29T17:26:16Z | - |
dc.date.issued | 2009 | - |
dc.identifier.other | U0001-1808200911343100 | en |
dc.identifier.uri | http://ntur.lib.ntu.edu.tw//handle/246246/182393 | - |
dc.description.abstract | 近年來鐵相關基因研究的快速進展,已經確立了肝臟在鐵代謝的重要地位,因為肝臟合成鐵荷爾蒙hepcidin。本研究目的在探討肝癌細胞內鐵空乏的原因,以及肝癌病人的鐵營養的失衡方向。驗在2005年10月開始,我們以普魯士藍作鐵染色及real-time polymerase chain reaction (PCR) 測量16 個鐵相關基因的mRNA,比較了從50位在2000年至2003年彰化基督教醫院的病人手術切除的肝癌及鄰近非癌組織之間鐵量及基因表現的差別。我們發現癌細胞呈現鐵的缺失及5個基因—hepcidin, ceruloplasmin, transferrin, transferrin receptor 1 及transferrin receptor 2—表現異常,其中以hepcidin的減少最為顯著,因此我們加做實驗,來探討hepcidin異常下降的原因。我們所做的包括以methylation-specific PCR來測試是否DNA甲基化,以免疫組織化學染色來觀察是否轉錄因子CEBPA減少,以real-time PCR檢驗是否轉錄因子HNF4A3增加。我們發現CEBPA有缺失現象,它的缺失又跟腫瘤期有關。CEBPA本身是很多肝特色基因的轉錄因子,也是腫瘤抑制蛋白。我們因此繼續做Kaplan–Meier活存分析及Cox比例風險模型分析,發現CEBPA缺失的病人的活存期較短。另外,以methylation-specific PCR偵測,沒有發現CEBPA有過度甲基化的情形。合分析看來,CEBPA與hepcidin的缺失可以解釋肝癌細胞內鐵空乏的現象;鐵調控基因的變化會造成組織的鐵過多,但紅血球系列卻鐵不足的矛盾的鐵平衡方向,因此再次傷害肝臟及加重可能原已存在的貧血程度。建議以CEBPA缺失做為肝癌治療標的以求抑制腫瘤生長,逆轉因CEBPA缺失造成的hepcidin減少及其它肝功能的崩壞,以延長病人生命改善生活品質。 另外,藉觀察比較數據提出一個假說:肝的非腫瘤部份可能有增加hepcidin的免疫反應以對抗肝本身的癌生長。 | zh-TW |
dc.description.abstract | Recent advance in the discovery of iron-regulatory genes (IRGs) has greatly renewed our view of iron metabolism, and established the importance of the liver for it secretes the iron hormone hepcidin. The study aimed to answer the long-term pathologic curiosity as to why hepatoma cells are iron-negative, and the almost never explored question about iron nutrition in patients with hepatocellular carcinoma (HCC). e began the experiments in October 2005, measuring iron stores with Perls’ Prussian blue stain and 16 IRGs’ expression with real-time polymerase chain reaction (PCR) in HCCs and adjacent nontumor specimens of 50 HCC patients, who received surgery in Changhua Christian Hospital between 2000 and 2003. We found iron was depleted and five IRGs—hepcidin, ceruloplasmin, transferrin, transferrin receptor 1 and 2—were dysregulated in HCC, with hepcidin particularly showing a dramatic reduction. o search for the cause of hepcidin reduction, we performed methylaiton-specific PCR but found hepcidin promoter not hypermethylated in HCC. However, immunohistochemistry shows a reduced expression of the transcription factor CEBPA, and real-time PCR shows another transcription factor HNF4A3 was upregulated.ecause CEBPA is also a tumor suppressor, and its reduction was found associated with advanced tumor stage in our study, we further performed Kaplan–Meier survival analysis and Cox proportional hazards analysis and found an association between reduced CEBPA expression and shortened patient survival. Further methylation-specific PCR did not reveal an increase of CEBPA methylation in HCC.everal implications may be drawn from the study. First, loss of CEBPA and hepcidin may play role in causing the iron-negative phenomenon in hepatoma cells. Second, the altered expression of IRGs in HCC may lead the body toward paradoxical directions of iron imbalance, with iron accumulated in tissues but deficient in erythroid cells, thus further damaging the liver and contributing to patient anemia. Third, targeting CEBPA downregulation for HCC treatment may inhibit tumor growth and restore much of hepcidin expression and liver functions, thus improving patient survival and quality of life. Finally, nontumor part of the liver may increase hepcidin to defend the body against HCC—the malignancy in the very same organ. | en |
dc.description.tableofcontents | Table of Contentsbstract 3要 5 Introduction 71.1 The prevalent hepatocellular carcinoma 81.2 Pathologic curiosity: iron-free foci in HCC 81.3 Clinical concern: iron imbalance in HCC patients 101.4 Hepcidin and other iron-regulatory genes 12 1.4.1 Hepcidin 13 1.4.2 Other iron-regulatory genes 14 1.4.3 Regulation of hepcidin expression 16 1.4.3.1 CEBPA 18 1.4.3.2 HNF4A 201.5 Drug targets: need to be more liver-specific 211.6 DNA methylation in HCC 23 Aims 25 Patients and methods 263.1 Patients 263.2 Specimens 273.3 Perls’ Prussian iron staining 273.4 Real-time polymerase chain reaction (PCR) for IRGs 283.5 Methylation analysis for hepcidin 293.6 Immunohistochemistry against CEBPA 303.7 Methylation analysis for CEBPA 313.8 Real-time PCR for HNF4A 313.9 Statistic analysis 32 Results 344.1 Comparison of iron stores between tumor and nontumor specimens 344.2 Comparison of gene expression between tumor and nontumor specimens 344.3 Relationships of gene expression with various parameters 354.4 Correlation of gene expression with iron stores and hemoglobin levels 364.5 Methylation status on hepcidin promoter 364.6 Comparison of CEBPA between tumor and nontumor specimens 374.7 Relationships of CEBPA expression with various parameters 374.8 CEBPA expression and patient survival 384.9 Methylaiton status on CEBPA promoter 404.10 Relationships of HNF4A3 expression with various parameters 40 Discussion 415.1 The altered iron stores and gene expression in HCC 415.2 Cause of hepcidin downregulation 435.3 Consequences of altered expression of iron-related genes 45 5.3.1 Pathologic implications 45 5.3.2 Clinical implications 48 5.3.3 Epidemiologic impacts 515.4 Limitations 53 Conclusions and perspective 55 References 58 Tables 77 Figures 950 Appendix 106 | en |
dc.format | application/pdf | en |
dc.format.extent | 869933 bytes | - |
dc.format.mimetype | application/pdf | - |
dc.language | en | en |
dc.language.iso | en_US | - |
dc.subject | 肝癌 | zh-TW |
dc.subject | 鐵調控基因 | zh-TW |
dc.subject | DNA甲基化 | zh-TW |
dc.subject | 鐵 | zh-TW |
dc.subject | Hepcidin | zh-TW |
dc.subject | CEBPA | zh-TW |
dc.subject | 貧血 | zh-TW |
dc.subject | 活存 | zh-TW |
dc.subject | Hepatocellular carcinoma | en |
dc.subject | iron-regulatory genes | en |
dc.subject | DNA methylation | en |
dc.subject | iron | en |
dc.subject | hepcidin | en |
dc.subject | anemia | en |
dc.subject | survival | en |
dc.title | 鐵調控基因在肝癌的表現及其病理、臨床與流行病學意義 | zh-TW |
dc.title | Expression of Iron-Regulatory Genes in Hepatocellular Carcinoma and Its Pathologic, Clinical, and Epidemiologic Significance | en |
dc.type | thesis | en |
dc.identifier.uri.fulltext | http://ntur.lib.ntu.edu.tw/bitstream/246246/182393/1/ntu-98-D92841002-1.pdf | - |
item.fulltext | with fulltext | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_46ec | - |
item.grantfulltext | open | - |
item.openairetype | thesis | - |
item.languageiso639-1 | en_US | - |
顯示於: | 環境與職業健康科學研究所
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