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研究生:賴羿如
研究生(外文):I-Lu Lai
論文名稱:肝細胞轉形之分子機制及分子療程之探討
論文名稱(外文):Study on the Molecular Mechanism and Molecular Therapy for Hepatocellular Transformation
指導教授:項千芸侯庭鏞
指導教授(外文):Chien-Yun HsiangTin-Yun Ho
學位類別:碩士
校院名稱:中國醫藥學院
系所名稱: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:91
中文關鍵詞:肝細胞轉形活化蛋白 1甘草素黃酮類
外文關鍵詞:hepatocellular transformationactivator protein 1glycyrrhizinflavonoid
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中文摘要
肝細胞在受到如病毒、酒精或氧化緊迫持續傷害後,會由正常的肝細胞轉形成肝腫瘤細胞。肝癌形成與一般腫瘤一樣,可區分為initiation、promotion及progression三個階段,而promotion為一可逆且時序很長的時期,因此成為瞭解及延緩癌化進程的重要時段。Tumor promotion與體外培養之細胞轉形很相近,而由實驗室及前人之研究認為activator protein 1(AP-1)的活性對於tumor promotion及oncogenesis的進程而言,都是相關的。AP-1已知可調控細胞生長、分化及細胞凋亡,且許多造成腫瘤形成及細胞轉形的基因,都受到AP-1的調控。12-O-tetradecanoylphorbol 13-acetate(TPA)是為人熟知的腫瘤促進劑,其可活化AP-1的活性,且可使老鼠上皮細胞JB6轉形,因此本章藉由TPA分析AP-1的活性是否為肝細胞轉形所必須。由anchorage-independent transformation assay結果得知,Chang/AP-1和HepG2/AP-1重組細胞在以TPA處理下,可觀察到細胞轉形的情形。藉由luciferase assay及electrophoretic mobility shift assay(EMSA)得知,TPA的確可以在肝細胞中活化AP-1,並且增加AP-1與DNA結合之能力。利用Western blotting及訊息傳導抑制劑分析TPA的訊息傳導路徑,結果顯示TPA主要是經由mitogen-activated protein kinases(MAPK)中ERKs訊息傳導路徑活化AP-1。MEK抑制劑─PD98059或AP-1抑制劑-retinoic acid,皆可抑制由TPA所誘發之肝細胞轉形。以上結果顯示AP-1活性是肝細胞轉形時所必須的,所以是否能藉由抑制AP-1的活性進而抑制細胞轉形便成為以下實驗所要求證的主要目標。我們選定兩大類藥物進行分析,一為類似於類固醇結構的皂素類(saponin),其可能結合至glucocorticoid receptor而影響AP-1 complex;另一為具有抗氧化能力和調控MAPK訊息傳導路徑的黃酮類(flavonoid)。我們將測試這兩類藥物是否會干擾AP-1的活性,進而抑制肝細胞轉形。
屬於皂素類的甘草素(glycyrrhizin),在臨床上已證實具有抗發炎、抗潰瘍、抗過敏及抗腫瘤等療效。為了瞭解glycyrrhizin抗腫瘤的分子機轉,我們觀察細胞在正常血清及TPA處理之下調控AP-1活性的情形。由Chloramphenicol acetyltransferase(CAT)assay及EMSA實驗結果得知,glycyrrhizin確實可以活化上游具有AP-1/TATA的promoter,並且呈現濃度效應,而且在HepG2及Vero細胞中,都可以發現相同的結果,顯示glycyrrhizin對於AP-1的影響與細胞種類無關。另外由不同promoter─AP-1/TATA、AP-1/None及None/TATA,分析glycyrrhizin對其影響。結果發現glycyrrhizin可活化含有AP-1的promoter,顯示glycyrrhizin是藉由活化AP-1而調節CAT的表現。進一步的研究發現,glycyrrhizin於細胞在血清或TPA處理之下,對AP-1有不一樣的調節。Glycyrrhizin在細胞處理血清的情況下,會活化AP-1的活性,而在細胞處理TPA的情況下,則會抑制AP-1的活性。因此glycyrrhizin對AP-1的活性呈現不同的調控現象,這是否代表glycyrrhizin在不同情況下會扮演細胞增生及抑制腫瘤轉形的雙重角色呢?仍值得進一步探討。
黃酮類(flavonoid)多存在於食物如水果、酒當中,目前已知有些黃酮類可能藉由MAPK調控基因的表現。因此我們搜尋五大類共24種黃酮類,依其結構分為flavonols(包括quercetin、rutin、hyperin、kaempferol、morin、galangin、silibinin、3-hydroxyflavone)、flavones(包括baicalein、baicalin、chrysin、luteolin、apigenin、flavone)、flavanones(包括hesperetin、hesperidin、eriocitrin、naringenin、naringin)、flavanols(包括(+)-catechin、(-)-epicatechin)及isoflavones(包括gentisin、puerarin、formononetin)。首先針對五大結構分析在TPA存在下調控AP-1的情形,由luciferase assay顯示,flavonols及flavanols的結構,能抑制AP-1的活性,flavones及isoflavones能活化AP-1,而flavanones則沒有明顯的活化或抑制現象。再依其取代基的不同,分析能抑制AP-1活性的flavonols,發現其在C3位置如以OSugar基進行取代時,會比由OH基取代有更明顯的抑制情形。因此黃酮類調控AP-1的效應與其特定結構相關。進一步針對兩種黃酮類進行更深入的研究,第一種為屬於flavonols的morin,其可藉由減少p38 kinases蛋白質磷酸化的量,抑制AP-1的活性及肝細胞的轉形。第二種為屬於isoflavones的formononetin,其可藉由增加p38 kinases蛋白質磷酸化的量,活化AP-1的活性,但經p38 kinases所活化的AP-1活性並不會加成肝細胞的轉形。
因此在本論文中呈現肝細胞轉形的分子機轉及療程設定的可能,也證實不同藥物可在肝細胞轉形階段產生效應。未來希望併合這些用藥,在不同型式的動物模式中,測試其對肝癌生成的抑制作用,也希望在不久的將來能將其應用至人體試驗上,以期能降低肝癌的發生率及死亡率。
Abstract
Hepatocellular transformation is a long-term process that requires chronic exposure to the harm of virus, alcohol or oxidative stress. Activator protein 1 (AP-1), a nuclear transcription factor, consists of Jun/Fos heterodimer or Jun/Jun homodimer, and its transactivation is required for tumor promotion. AP-1 is an immediate early protein which plays important roles in the neoplastic transformation, cell proliferation, differentiation, and inflammation.
Carcinogenesis is divided into three stages of initiation, promotion, and progression. Promotion is a reversible and rate-limiting stage in the process of carcinogenesis. Previous studies indicated that the tumor promoter-12-O-tetradecanoylphorbol 13-acetate (TPA)-induced AP-1 activity is required for neoplastic transformation in JB6 cells. To analyze whether the AP-1 activity is essential for TPA-induced hepatocellular transformation, the anchorage-independent transformation assay was carried out. TPA promoted the formation of anchorage-independent colonies in hepatocytes, indicated that TPA could induce hepatocellular transformation. Additionally, TPA induced the AP-1 activity and enhanced the DNA-binding ability of AP-1 by luciferase assay and electrophoretic mobility shift assay (EMSA). To further analyze the signal transduction pathway involved in TPA-induced AP-1 activity, the mitogen-activated protein kinases (MAPK) inhibitor assay and Western blotting for MAPKs were performed. TPA stimulated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) and the TPA-induced AP-1 activity was inhibited by MEK inhibitor (PD98059), indicated that TPA-induced AP-1 activation was via ERKs pathway. Additionally, the retinoic acid, a well-known AP-1 inhibitor, and PD98059 inhibited the hepatocellular transformation. In conclusion, these data suggested that AP-1 activity is essential for hepatocellular transformation.
Glycyrrhizin, a major component of Glycyrrhiza uralensis (licorice) root, is a saponin and exhibits a number of pharmacological effects, including anti-inflammation, anti-ulcer, anti-allergy, and anti-carcinogenesis. In order to elucidate the molecular mechanism of glycyrrhizin-induced anti-carcinogenesis, the effect of glycyrrhizin on the activity of AP-1 in normal and TPA-treated conditions was analyzed. Glycyrrhizin induced the AP-1/TATA reporter activity in a dose-dependent fashion, which was judged by chloramphenicol acetyltransferase assay and EMSA. Similar result was observed in HepG2 and Vero cells, suggested that glycyrrhizin effect was cell type-independent. In addition, the cis element responsible for glycyrrhizin activity was AP-1 responsive element. Further analysis indicated that glycyrrhizin exhibited a different regulation on the AP-1 activity in serum- and TPA-treated cells. Glycyrrhizin induced the AP-1 activity in serum-treated cells; however, it inhibited the TPA-induced AP-1 activation in TPA-treated cells.
Flavonoids are a very large and important group of polyphenolic natural products, which can widely be found in the fruits, vegetables, and wine. Based on the structure, flavonoids are classified into flavonols, flavones, flavanones, flavanols, and isoflavones. Previous studies indicated that quercetin, a member of flavonols, exhibits the anti-tumor ability, we therefore analyzed the effect of 24 flavonoids on TPA-induced AP-1 activity in recombinant hepatocytes. Results demonstrated that flavonols and flavanols repressed the AP-1 activity; however, flavones and isoflavones enhanced AP-1 activity. Additionally, the functional group on C3 position of flavonols was substituted by sugar and hydroxyl group, respectively, exhibited a significant inhibition on AP-1 activity. Thus, the effect of flavonoids on AP-1 activity was related to their structures. We further analyzed the mechanisms of morin and formononetin on the regulation of AP-1 activity. Morin, a member of flavonols, inhibited the AP-1 activity and the DNA-binding ability of AP-1 by repressing the phosphorylation of p38 kinases. It also inhibited the hepatocellular transformation in a dose-dependent manner. Formononetin, a member of isoflavones, activated the AP-1 activity by enhancing the phosphorylation of p38 kinases. However, it didn''t induce the hepatocellular transformation. In conclusion, these results provide insight into the biological actions of saponin and flavonoids, and the molecular basis for the development of new chemoprotective agents for cancer.
目錄
頁數
誌謝
目錄
中文摘要------------------------------------------------------------------------------------------1
英文摘要------------------------------------------------------------------------------------------3
第一章 文獻探討------------------------------------------------------------------------------5
第二章 AP-1在肝細胞轉形過程中角色之分析----------------------------------------14
第三章 甘草素調節AP-1活性之分析---------------------------------------------------31
第四章 黃酮類對TPA誘導肝細胞轉形及AP-1活性之效應------------------------47
參考文獻----------------------------------------------------------------------------------------76
作者簡歷----------------------------------------------------------------------------------------90
著作權聲明-------------------------------------------------------------------------------------91
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