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研究生:趙語馨
研究生(外文):Yu-Hsin Chao
論文名稱:探討ADAM17在肝癌中所調控之訊息傳導
論文名稱(外文):The ADAM17 signaling in hepatocellular carcinoma
指導教授:鄒安平
指導教授(外文):Ann-Ping Tsou
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術暨檢驗學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:61
中文關鍵詞:肝癌內皮生長因子受體
外文關鍵詞:HCCADAM17EGFR
相關次數:
  • 被引用被引用:0
  • 點閱點閱:158
  • 評分評分:
  • 下載下載:18
  • 收藏至我的研究室書目清單書目收藏:0
  在實驗室先前研究中,我們發現肝內特異性之腫瘤抑制性微核醣核酸(miRNAs),Hsa-miR-122可以影響腫瘤生成和肝內轉移能力,而此現象可能部份是經由其下游基因ADAM17執行作用導致。ADAM17為細胞膜上之金屬蛋白酶,在不同的腫瘤型態中已有報導指出會有表現量上升的情況,其中也包括肝癌。很多研究指出ADAM17所調節之蛋白質細胞外區域之切割現象對於EGFR訊息傳導路徑具有相當之重要性,而在68%之肝癌中已發現到EGFR會有過度表現之情形,因此我們推測ADAM17與EGFR訊息傳導對於肝癌生成可能有某些程度上之關連性。
而在本篇研究中,我們利用PLC細胞株,一株具有豐富EGFR自體分泌能力之肝癌細胞株,去探討ADAM17之生物意義。藉由shRNA沉寂ADAM17表現,可以經由干擾細胞週期而抑制細胞之增生,在體外亦會抑制細胞轉形能力,進一步也驗證在裸鼠試驗中可以有效減少腫瘤生成以及血管新生能力。
ADAM17沉寂之PLC細胞呈現出大而扁平之型態,偵測老化相關之β-半乳糖苷酶之細胞染色呈現大量陽性結果,另外也觀察到與老化相關之p21以及p16表現量上升。此外,在ADAM17沉寂後亦發現EGFR訊息傳導之活化下降,意指EGFR之訊息傳導減少可能是ADAM17沉寂後造成生物內影響之其一原因。
我的實驗結果顯示,ADAM17在肝臟腫瘤中扮演相當重要之角色,對於肝癌可能可做為新的治療標靶
In our previous study, we demonstrated that liver-specific miR122, a tumor suppressor microRNA which influences tumor formation and intrahepatic metastasis, exerts some of its action via its target, ADAM17 (a disintegrin and metalloproteinase domain 17). ADAM17, a membrane-bound metalloprotease, has been reported to be up-regulated in many cancer types including HCC. Numerous reports indicated that ADAM17-mediated ectodomain shedding is critical for activating EGFR signaling pathway. While elevated expression of EGFR was detected in 68% HCC, a plausible association between ADAM17 and EGFR signaling in hepatocarcinogenesis has not been addressed.
  In this study, we investigated the effect of ADAM17 in PLC cell line, which is a HCC cell line enriched with EGFR autocrine activity. Silencing of ADAM17 not only affected cell proliferation by disturbing cell cycle progression but also suppressed in vitro transforming activities as well as in vivo tumorigenecity and angiogenesis. ADAM17-knockdowned PLC cells display large flattened morphology and accumulate strong SA-β-gal cellular staining. Other features of cellular senescence included elevated protein levels of p21Cip1 and p16INK4a. Moreover, the activation of EGFR signaling was decreased after ADAM17-silencing, suggesting that reduced EGFR signaling may be partly responsible for ADAM17-mediated biological activities.
In conclusion, these experimental findings imply that ADAM17 plays an important role in the biology of liver tumor, and may become a new therapeutic target for HCC.
中英文名詞縮寫對照表 ………………………………………………1
中文摘要 ………………………………………………………………2
英文摘要 ………………………………………………………………3
緒論 ……………………………………………………………………4
論文研究動機 ………………………………………………………10
實驗材料 ……………………………………………………………11
實驗方法 ……………………………………………………………16
實驗結果 ……………………………………………………………25
討論 …………………………………………………………………32
結論與未來展望 ……………………………………………………36
參考文獻 ……………………………………………………………37
圖表 …………………………………………………………………45
附錄 …………………………………………………………………54
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