中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/50293
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    題名: 探討BP180調控攝護腺癌細胞伸展與移行之機制
    Molecular analyses of BP180 in regulation of prostate cancer cell spreading and migration activities
    作者: 張家誠;Chia-Cheng Chang
    貢獻者: 癌症生物學研究所碩士班
    關鍵詞: 攝護腺癌;膠原蛋白第17型;BP180;ADAM9;prostate cancer;migration
    日期: 2013-08-08
    上傳時間: 2013-10-02 11:18:54 (UTC+8)
    出版者: 中國醫藥大學
    摘要: 背景：
    膠原蛋白17型 (BP180)，是組成維持細胞貼附的半橋粒的其中一種元件。臨床上的證據顯示BP180的變異或缺損會導致皮膚組織間的分離。此外，BP180也被報導出對於細胞移動或遠端轉移扮演重要腳色。然而，這其中的詳細機制還未明朗。因此我們本篇研究致力於探討BP180在調控細胞移動或侵潤過程中的詳細機制。
    方法與材料：
    我們首先利用RNA干擾技術在PC3細胞中降低BP180表現。並且進行細胞貼附、伸展與移動之分析。。放線菌酮添加後觀察Integrin β4降解的現象。免疫沉澱技術以探知ADAM9與BP180、Integrin β4和plectin蛋白之間的相互作用
    。
    結果：
    我們注意到在不同的癌細胞中BP180有表現量上的差異，但攝護腺癌表現量最高。對攝護腺癌細胞以RNAi技術處理後降低BP180表現則能抑制細胞移動的能力，此外我們也能觀察到影響了細胞的延伸表現，但卻不影響細胞的貼附能力。更進一步的我們觀察到半橋粒之元件Integrin β4在ADAM9正常表現的細胞中隨著時間的降解，剔除ADAM9表現的細胞則無。

    結論：
    我們的結果指出ADAM9會與半橋粒的組成元件如BP180、Integrin β4與plectin相互作用，並已觀察到調控Integrin β4的內吞與降解。攝護腺癌細胞在抑制BP180的表現量後亦影響半橋粒構成進而影響整體細胞移行能力。
    因此，我們將來可藉由阻斷ADAM9和BP180的相互作用或直接抑制BP180之表現以達到抑制攝護腺癌細胞的轉移趨勢。
    Backgrounds:
    　　Collagen XVII (BP180), a major component of the hemidesmosome is critical in the maintenance of cell adhesion. Clinical evidences indicated mutation or loss of BP180 leaded to subepidermal tissue separation. In addition, BP180 has been shown to play an important role of cancer migration and metastasis. However, the detail mechanism is still not clear. Hence, we aimed to investigate the mechanisms of BP1 80 in regulation of cancer migration and invasion.
    Materials and Methods:
    　　We first knockdown the expression levels of BP180 in PC3 cell lines. Lentiviral knockdown of BP180 was constructed. Real-time PCR was used to confirm knockdown efficiency. Cell adhesion, spreading and migration assay was performed. ADAM9 followed by analysis of BP180, expression was performed. Protein Integrin β4 degradation of hemidesmosome components after knockdown of ADAM9 was determined by cycloheximide treated prostate cancer cells.
    Results:
    　　We noticed the differential expression pattern of BP180 across different cell lines, with strong expression in prostate cancer cells and lowest in lung cancer carcinoma, especially in PC3 cell. Inhibition of cell migration activities can be detected in prostate cancer cell line, PC3 after knockdown of BP180 expression. In addition, we also observed decreased cell spreading, as well as haptotactic migration activities on matrices. Furthermore, we confirmed the interaction of ADAM9 and Integrin β4 and observed the endocytosis and degradation. Furthermore, shedding of BP180 by ADAM9 reversed had been observed. But MMP inhibitor treated resulted in BP180 expression decreased.
    Conclusion:
    　　Our results indicated ADAM9 regulated hemidesmosome endocytosis and degradation by direct interaction with BP180. And knockdown of BP180 inhibited cell migration and spreading activities by upholding constitutive expression levels of hemidesmosome complex in prostate cancer cells.
    Therefore, it is plausible to hypothesize the therapeutic strategy by blocking ADAM9-BP180 interaction could inhibit cancer cell metastasis activities.
    顯示於類別:[癌症生物學研究所] 博碩士論文

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