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研究生:蔡儒億
研究生(外文):Ju-Yi Tsai
論文名稱:Cyr61在口腔癌細胞移動中所扮演的角色及其機轉
論文名稱(外文):The of Cyr61 in oral cancer migration
指導教授:郭彥彬郭彥彬引用關係
指導教授(外文):Yen-Ping Kuo
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:口腔生物科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:93
中文關鍵詞:口腔癌細胞移動血管新生細胞增生
外文關鍵詞:oral cancercell migrationangiogenesisproliferationCyr61FAKintegrinAktJNK
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中文摘要

Cyr61是一種分泌型蛋白,為 CCN family中第一個被發現的成員,當其由細胞分泌出去後即表現於細胞表面與細胞基質之間。Cyr61可作為細胞表面接受器 Integrin 的配體,其功用可調節細胞的附著、移動、增生、分化及參與血管新生,在許多癌症中被指出與 tumorgenesis 有關。 在臺灣, 衛生署 92 年癌症登記報告指出,口腔癌在臺灣男性十大癌症中標準化死亡率為第三位。 此外,口腔癌年增率達 14.42% 是臺灣地區年增率最高之癌症。因此我們有必要了解臺灣的口腔癌分子致癌機轉。較早之前的實驗室研究中指出,口腔癌病人癌化組織中 Cyr61 蛋白表現明顯較正常組織高,但是 Cyr61 在口腔癌的角色至今仍不明確。有鑑於此,本研究擬探討 Cyr61 在口腔癌進展過程所扮演的角色。我們將 Cyr61 轉殖到 Cyr61 表現量較低的 Ca9-22 細胞中,以 pcDNA3 當作 vector 控制組 (Ca9-22/Neo),獲得 Cyr61 蛋白表現量高於控制組的兩個細胞株 Ca9-22/Cyr61#1 和 Ca9-22/Cyr61#2。比較其生長速率、移動能力、及促血管新生能力的改變,結果發現大量表現 Cyr61 的兩個細胞株其生長速率較快、移動能力比對照組增加 10.7nm/hr。轉植(transplant) Cyr61 表現株細胞到嚴重複合免疫不全症( NOD-SCID mice )小鼠,結果 Cyr61 過量表現細胞株可增加腫瘤的整體體積約 2.5 倍且從外觀以及病理切片可發現較高密度的血管新生跡象。
根據前人研究指出 Cyr61 促進移動能力的機轉可藉由活化 Integrin /NF-kB/COX2 使胃癌細胞AGS移動能力增加。在乳癌( MCF7 )中 Cyr61 促進 stromal cell 分泌 Matrix metalloproteinase-1(MMP1)進而活化癌細胞上的 Protease-activated receptor-1(PAR1)使乳癌細胞增加移動力。然而在本研究發現口腔癌中 Cyr61 增加細胞移動的路徑不同於其他癌症,其影響路徑為:分泌到細胞外面的 Cyr61 藉由自體結合( autocrine ) 或異體結合 ( paracrine ) 和avb3 Integrin 結合,在前人研究的結果中藉由此訊息傳遞路徑產生自體迴路,分別使得 av 及 b3 在蛋白質層面也能增加;但在本實驗所得結果 Cyr61 則是增加 avb3 在細胞上的親和力而單獨的蛋白質在量上無明顯差異。Cyr61 和 Integrin 的結合使得 FAK 的 Y-397 被磷酸化再將訊息傳給 PI3K/Akt 以及 JNK 最終使細胞骨架改變協助細胞的移動。而此途徑可外加 LM609 ( avb3 functional blocking antibody ) 、 LY294002 ( PI3K inhibitor ) 以及 JNK inhibitor II 予以抑制。
本篇結果首次證實 Cyr61 在口腔癌中為促進癌化因子,對於細胞增生、移動能力、腫瘤形成以及血管新生皆有顯著的影響;其中影響細胞移動的機制為 Cyr61/avb3 – FAK - PI3K/Akt/ JNK 和目前在其他癌症所發現的路徑不同。因此,可藉由抑制訊息傳遞路徑的成員來阻斷 Cyr61 對口腔癌細胞的移動能力以冀望在未來可作為新興藥物開發之策略。
Abstract

Cyr61 is one of members of CCN family; these proteins are secreted proteins act as ligands between cell surface and extracellular matrix. When ligand-receptor complex formation, Cyr61 could regulate cell adhesion, migration, proliferation, differentiation and angiogenesis. The incidence of oral cancer in Taiwan has being more and more serious but we still cannot cure it. Our laboratory found Cyr61 had high expression levels in patients but we did not know the function of Cyr61 in oral carcinogenesis. So we established the Cyr61-overexpressed stable clones in Ca9-22, which had lower Cyr61 expression. Clones were named Cyr61#1 and Cyr61#2, the other hand used pcDNA3 as vector control was named Neo.
Cyr61-expressed clones could promote cell proliferation, in vivo tumor formation in NOD-SCID mice, angiogenesis and migration. It was the first time we identified Cyr61 is an oncogene in oral cancer. The mechanism of Cyr61-induced cell migration is different from others, in our study Cyr61 increase its receptor avb3 integrin expression on cell membrane, and then activate this heterodimer to recruitment of FAK. Recruited FAK is autophosphorylated at Tyr-397, active FAK phosphorylate PI3K-Akt Ser473 and JNK Thr183/Tyr185, respectively to increase the cell migration. This effect could recover by treatment of LM 609, avb3 integrin functional blocking antibody, PI3K inhibitor: LY294002, Wortmannin and JNK inhibitor: JNK inhibitor II.
These results suggest that interrupting the communication of Cyr61-induced signaling may provide an alternative therapeutic approach for the treatment of oral cancer.
中文摘要…………………………………………………………………………1
英文摘要(Abstract)…………………………………………………………3
導論(Introduction)…………………………………………………………..4
第一節 口腔癌的病理與流行病學………………………………………..4
第二節 Cyr61………………………………………………………………7
第三節 Integrin……………………………………………………………13
第四節 Focal adhesion kinase……………………………………………..16
第五節 研究動機………………………………………………………….19
材料方法(Material and Method)…………………………………………..20
結果(Result)
口腔癌病理切片含有高量 Cyr61 蛋白質的表現………………………..31

建立 Cyr61 持續表現細胞株……………………………………………..31

Cyr61 可促進口腔癌細胞 Ca9-22 的生長速率………………………….32

Cyr61 可促進口腔癌細胞在小鼠體內形成腫瘤………………………...32

Cyr61 可促進細胞的移動能力…………………………………………...33

Cyr61 可使細胞受器
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