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系統識別號 U0002-1707200818475900
中文論文名稱 小蘖鹼可能藉由 p185HER2/neu 蛋白質降解進而抑制神經膠原致癌基因過表現引起的細胞增生與轉移
英文論文名稱 Berberine may inhibit cell proliferation and metastasis via degradation of p185HER2/neu in HER2/neu-overexpressing cancer cells
校院名稱 淡江大學
系所名稱(中) 化學學系碩士班
系所名稱(英) Department of Chemistry
學年度 96
學期 2
出版年 97
研究生中文姓名 林映妤
研究生英文姓名 Ying-Yu Lin
學號 695160613
學位類別 碩士
語文別 中文
口試日期 2008-06-21
論文頁數 61頁
口試委員 指導教授-莊子超
委員-高銘欽
委員-李守倫
中文關鍵字 小蘖鹼  神經膠原致癌基因  轉移 
英文關鍵字 Berberine  HER2/neu  Metastasis 
學科別分類 學科別自然科學化學
中文摘要 小蘖鹼為一種異喹啉生物鹼,存在於小蘖科植物的根、莖或樹皮中,具有抗心律不整及抗腫瘤的功效。為了找出小蘖鹼在 HER2/neu 過表現細胞中的化學預防分子作用機制,我們分析數個不同 p185HER2/neu 蛋白質表現量的細胞株,結果發現相較於正常 HER2/neu 表現量的細胞株,小蘖鹼會針對 HER2/neu 過表現的細胞株有較高抑制細胞存活率的效果。此外小蘖鹼在 HER2/neu 過表現的細胞株會有依劑量及依時間抑制 p185HER2/neu 蛋白質表現量的情形。進一步觀察發現小蘖鹼會抑制 p185HER2/neu 的活性及其下游 Akt 與 ERK 的活性。此外我們發現小蘖鹼會抑制 p185HER2/neu 過表現的卵巢癌細胞 (SKOV3) 的轉移能力。另外也證明了 EGF 會回覆藉由小蘖鹼所抑制的 MMP2 的活性,而 PI3K 的抑制劑會抑制由 EGF 所回覆的 MMP2 活性。綜合所有的實驗結果可說明,小蘖鹼會促進 p185HER2/neu 蛋白質降解而造成 HER2/neu 過表現細胞的損壞,並藉由抑制PI3K/Akt 訊號路徑進而減弱了由 p185HER2/neu 所調控的轉移情形。
英文摘要 Berberine, an isoquinoline alkaloid, present in the roots, rhizome and stem bark of Berberis species, has been shown to possess potent anti-arrhythmic and anti-turmor properties. To explore the molecular mechanism of the chemopreventive effects of berberine in the HER2/neu-overexpressing cancer cells, we examined several human cancer cell lines having different levels p185HER2/neu expression and found that berberine exhibited much more growth-inhibitory activity in the HER2/neu-overexpressing cancer cells than those cells expressing basal levels of p185HER2/neu. Depletion of p185HER2/neu was also observed in HER2/neu-overexpressing cancer cells in a dose- and time-dependant manner. We also demonstrate that berberine can downregulate the activated form of p185HER2/neu as well as Akt and ERK, downstream substrates of p185HER2/neu. Furthermore, we found that berberine is potent in suppressing transformation phenotype of SKOV3 cells (HER2/neu-overexpressing ovarian cancer cell) including metastasis-associated properties. We also elucidate that EGF specifically restores the activation of MMP2 after its activity was reduced by berberine; the restoration of MMP2 activity was also inhibited by PI3K inhibitor. These finding suggest that berberine can cause HER2/neu-overexoressing cancer cell damage by inducing degradation of p185HER2/neu, and then inhibiting the PI3K/Akt-signaling pathway to attenuate the p185HER2/neu mediated metastasis.
論文目次 目錄
謝誌---------------------------------------------------------------------------------I
中文摘要-------------------------------------------------------------------------III
英文摘要--------------------------------------------------------------------------V
目錄------------------------------------------------------------------------------VII
圖目錄-----------------------------------------------------------------------------X
表目錄----------------------------------------------------------------------------XI
附錄目錄------------------------------------------------------------------------XII
縮寫表--------------------------------------------------------------------------XIII
第一章、前言-----------------------------------------------------------------------1
第一節、實驗緣起與目的---------------------------------------------------1
第二章、序論-----------------------------------------------------------------------2
第ㄧ節、小蘖鹼---------------------------------------------------------------2
壹、小蘖鹼簡介 --------------------------------------------------------2
貳、小蘖鹼的生理功能------------------------------------------------2
第二節、癌細胞的生長------------------------------------------------------3
壹、簡介------------------------------------------------------------------3
貳、細胞增生------------------------------------------------------------3
参、癌細胞的轉移------------------------------------------------------4
肆、血管新生------------------------------------------------------------4
第三節、神經膠原致癌基因 (HER2/neu)--------------------------------5
壹、簡介------------------------------------------------------------------5
第四節、p185HER2/neu 與癌細胞生長、轉移及血管新生之關係-------7
壹、p185HER2/neu 與癌細胞生長之關係-----------------------------7
貳、p185HER2/neu 與癌細胞轉移之關係-----------------------------8
参、p185HER2/neu 與癌細胞血管新生之關係----------------------11
第五節、研究目標-----------------------------------------------------------12
第三章、材料與方法------------------------------------------------------------13
第一節、實驗材料-----------------------------------------------------------13
壹、細胞株 (Cell lines)-----------------------------------------------13
貳、抗體 (Antibodies)------------------------------------------------14
参、化學藥品與試劑 (Chemicals and reagents)------------------14
肆、主要儀器與器材--------------------------------------------------16
第二節、實驗方法-----------------------------------------------------------17
壹、小蘖鹼配置方法--------------------------------------------------17
貳、錐藍排除分析 (Trypan blue dye exclusion assay)----------17
参、西方墨點法 (Western blotting)--------------------------------18
肆、細胞傷痕試驗 (Scratch-wound assay)------------------------19
伍、細胞穿膜實驗 (Transwell assay)------------------------------20
陸、酶譜法 (Zymography)-------------------------------------------20
第四章、實驗結果---------------------------------------------------------------22
壹、小蘖鹼有效抑制 p185HER2/neu 過表現細胞株的存活率--22
貳、小蘖鹼抑制 p185HER2/neu 蛋白質是經由蛋白質的降解路徑--------------------------------------------------------------------23
参、小蘖鹼對 p185HER2/neu 下游 PI3K/Akt 與 ERK 路徑的影響--------------------------------------------------------------------24
肆、小蘖鹼抑制 SKOV3細胞的轉移能力-----------------------25
伍、小蘖鹼藉由 HER2/PI3K/Akt 路徑抑制 MMP2 酵素的活性--------------------------------------------------------------------26
第五章、討論---------------------------------------------------------------------28
第六章、結論---------------------------------------------------------------------34
第七章、參考文獻---------------------------------------------------------------35
圖-----------------------------------------------------------------------------------46
表-----------------------------------------------------------------------------------53
附錄--------------------------------------------------------------------------------58



圖目錄
圖 1. 小蘖鹼 (Berberine) 的結構圖及分子量---------------------------46
圖 2. 小蘖鹼有效抑制 p185HER2/neu 過表現細胞株的存活率---------47
圖 3. 小蘖鹼抑制 p185HER2/neu 蛋白質是經由蛋白質的降解路徑---48
圖 4. 小蘖鹼對 p185HER2/neu 下游 PI3K/Akt 與 ERK 路徑的影響49
圖 5. 小蘖鹼抑制 SKOV3細胞的轉移能力------------------------------50
圖 6. 小蘖鹼藉由 HER2/PI3K/Akt 路徑抑制 MMP2 酵素的活性-51
圖 7. 小蘖鹼抑制 SKOV3 細胞的增生與轉移之路徑-----------------52















表目錄
表1. 細胞株基本資料---------------------------------------------------------53
表2. 西方墨點法之抗體資料------------------------------------------------54
表 3. 化學藥品及試劑 (Chemicals and reagents)------------------------55




















附錄目錄
附錄 1. 細胞培養使用之緩衝液--------------------------------------------58
附錄 2. 西方墨點法 (Western blotting) 使用之緩衝液----------------59
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