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研究生:葉大森
研究生(外文):TS Yeh
論文名稱:人類肝癌去分化過程可調昇終端酵素活性並抑制細胞凋亡-體內及體外研究
論文名稱(外文):Dedifferentiation of Human Hepatocellular Carcinoma Up-regulates Telomerase But Inhibits Apoptosis ---- In vivo and in vitro study
指導教授:陳敏夫陳敏夫引用關係
指導教授(外文):MF Chen
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:102
中文關鍵詞:終端酵素肝癌去分化細胞凋亡
外文關鍵詞:TelomeraseHepatocellular carcinomaDedifferentiationApoptosis
相關次數:
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  • 收藏至我的研究室書目清單書目收藏:1
肝癌是台灣男性癌症死亡原因首位。雖然嘗試諸多治療方法,其預後仍是令人失望。人類肝癌組織學檢查發現大多數肝癌腫瘤有去分化現象,而後者也許可以解釋肝癌細胞猛烈的生物活性。細胞增殖及細胞凋亡的淨平衡決定腫瘤的命運。因之,我們擬研究肝癌細胞在去分化過程中增殖及凋亡的動力學演化。在體內模式方面,我們收集具組織學異質型態的肝癌,即腫瘤內腫瘤或融合性複合式腫瘤型態兩種。其特徵是同一腫瘤內有兩種以上不同分化期別的癌細胞,而各期別細胞可輕易分離、萃取、研究。比較同一腫瘤內不同組織期別癌細胞的各種變數差異在本實驗設計是可行而重要的,因為此類研究可提供分析肝癌細胞去分化過程中各類分子生物學方面的轉變之簡易模式。有關肝癌細胞增殖方面,我們利用TRAP來測量終端酵素活性,同時其三個次級單位 ( hTERT、TP1、及hTR ) 亦可利用RT-PCR來決定其mRNA表現。而另一個增殖變數,Ki-67,我們則利用免疫組織化學染色法來偵測。細胞凋亡的情況則利用TUNEL來偵測。至於體外研究方面,我們利用Hep G2細胞株給予SB ( sodium butyrate )處理,後者可使細胞株趨於分化良好。因之,此模式恰可模擬人類肝癌細胞的去分化過程之反相。在經過不同濃度的SB處理後,HepG2細胞外型,上清液內胎兒蛋白,白蛋白的濃度均分別觀察測定。HepG2細胞的生存活性以trypan blue exclusion test來測定。HepG2細胞的終端酵素活性以TRAP來測量。我們的實驗結果顯示,在體內模式方面,終端酵素活性及ki-67指數從同一腫瘤內分化良好的病灶至分化不良的病灶依次遞增;相反的,細胞凋亡指數則遞減。在體外模式方面,HepG2細胞在經過SB處理後型態漸趨成熟。上清液胎兒蛋白濃度依SB劑量增加而遞減。HepG2細胞生存活性依SB劑量增加而遞減,細胞凋亡指數則遞增。同樣的,HepG2細胞的終端酵素活性依SB劑量增加而遞減。我們的結論是人類肝癌去分化過程可調昇終端酵素活性而抑制細胞凋亡,二者可解釋肝癌細胞在臨床表現凶猛的生物活性。

Hepatocellular carcinoma remains to be the leading cause of death of men in Taiwan. Although multimodality trials have been extensively employed for management of this formidable disease, the result was disappointing and most of the patients died soon after the diagnosis. Morphologic examination shows dedifferentiation occurs in most of human HCC, which might be responsible for biological aggressiveness of the disease. The net equlibrium of proliferation and apoptosis of tumor cellls determine the fate of neogrowth. Therefore, we investigate the status of proliferation and apoptosis during the dedifferentiation of human HCC in vivo and iv vitro. For in vivo study, we recruit the patients of HCC with peculiar histologic heterogeneity, either nodule in nodule or confluent multinodular pattern, of which different histological grading cells exist within the same tumor and can be easily demarcated and isolated for study. It is feasible and significant to compare various parameters of different histologic foci within the same tumor in each subject, which represents the molecular changes during the dedifferentiation. To determine the dynamic change of proliferation capability, we titrate telomerase activity using the method of TRAP (telomeric repeat amplification protocol), as well the subunits of telomerase (mRNA hTERT, TP1, hTR) using the technique RT-PCR. Another proliferating parameter, Ki-67, was determined by immunohistochemical staining. Apoptosis status was determined by TUNEL. For in vitro study, we culture a cell line, Hep G2, which was treated with a differentiating agent, sodium butyrate, in various concentrations. By means of this model, we can simulate a reversal process of dedifferentiation of human HCC. The morphological change, Alpha-fetoprotein and albumin concentration of supernatant of Hep G2 cells treated with various concentrations of SB were measured, respectively. Viability of Hep G2 cells treated with SB was determined by trypan blue exclusion test. Again, telomerase activity of Hep G2 cells treated with SB was titrated by TRAP. Our results showed, in vivo, telomerase activity and Ki-67 labelling index increased from more differentiated foci to less differentiated foci of HCC cells; whereas apoptosis index decreased from more differentiated foci to less differentiated foci of HCC cells. For in vitro study, Hep G2 cells treated with SB became more differentiated. AFP concentration decreased in a SB dose-dependent manner. Viability of Hep G2 cells decreased in a SB dose-dependent manner. Again, telomerase activity of Hep G2 decreased in a SB dose-dependent manner. In conclusion, dedifferentiation of human HCC up-regulates telomerase activity but inhibits apoptosis, which well explain the biological aggressiveness of the disease.

中文摘要p 3
英文摘要p 5
第一章:肝癌組織去分化理論p 8
第二章:顆粒性球菌落刺激因子加強大白鼠肝切除後
之肝再生―終端酵素活性及細胞間質之動力學變化p 16
第三章:終端酵素可作為腫瘤標誌來區分惡性胰臟囊
腫及良性腫瘤及偽囊腫心p 28
第四章:終端酵素基因次級因子於人類肝癌的表現p 42
第五章:人類肝癌去分化過程可調昇終端酵素活性及
ki-67的表達p 53
第六章:人類肝癌去分化過程可調昇Bcl-2/Bax比率
進而抑制細胞凋亡¾ 與增殖指數相關性研究p 72
第七章:使用促分化劑治療肝癌細胞株可降低終端酵
素活性並促進細胞凋亡p 90

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1. 8.許添本、賴以軒,「工廠緊急疏散績效評估模擬模式之建立」,勞工安全衛生研究季刊,第五卷,第三期,第107-121頁,民國八十六年九月。
2. 7.許添本、田欣雷、賴以軒,「捷運車站行人流特性分析」,都市交通季刊,第十五卷,第一期,第1-11頁,民國八十九年三月。
3. 8.許添本、賴以軒,「工廠緊急疏散績效評估模擬模式之建立」,勞工安全衛生研究季刊,第五卷,第三期,第107-121頁,民國八十六年九月。
4. 8.許添本、賴以軒,「工廠緊急疏散績效評估模擬模式之建立」,勞工安全衛生研究季刊,第五卷,第三期,第107-121頁,民國八十六年九月。
5. 7.許添本、田欣雷、賴以軒,「捷運車站行人流特性分析」,都市交通季刊,第十五卷,第一期,第1-11頁,民國八十九年三月。
6. 7.許添本、田欣雷、賴以軒,「捷運車站行人流特性分析」,都市交通季刊,第十五卷,第一期,第1-11頁,民國八十九年三月。
7. 11.張俊彥,「木柵動物園遊客分佈與擁擠―以電腦模擬為例」,造園學報,第五卷,第二期,第97-113頁,民國八十八年。
8. 11.張俊彥,「木柵動物園遊客分佈與擁擠―以電腦模擬為例」,造園學報,第五卷,第二期,第97-113頁,民國八十八年。
9. 11.張俊彥,「木柵動物園遊客分佈與擁擠―以電腦模擬為例」,造園學報,第五卷,第二期,第97-113頁,民國八十八年。
10. 李美枝(民69)性別特質問卷的編製及男女大學生四種性別特質類型在成就動機、婚姻、事業及性態度上的比較。中華心理學刊,23(1),23-27。
11. 李美枝(民69)性別特質問卷的編製及男女大學生四種性別特質類型在成就動機、婚姻、事業及性態度上的比較。中華心理學刊,23(1),23-27。
12. 李美枝(民69)性別特質問卷的編製及男女大學生四種性別特質類型在成就動機、婚姻、事業及性態度上的比較。中華心理學刊,23(1),23-27。