p185HER2/neu 是一種致癌基因，p185HER2/neu 的過度表現與癌細胞的生長息息相關，在乳癌中 p185HER2/neu 的過度表現會增加癌細胞的轉移能力和減低預後情形。厚朴酚是從中藥厚朴 (Magnolia officinalis) 萃取出來的有效成分，至今已經發現有許多的藥理作用，例如：抗腫瘤、抗氧化及抗發炎。不過厚朴酚對 p185HER2/neu 過度表現癌細胞的效果還不清楚。在這裡，我們利用不同劑量和時間的方式，證明了厚朴酚可以誘導 p185HER2/neu 過度表現的癌細胞進行死亡。也發現厚朴酚可以抑制 HER2/neu 基因表現。我們也說明了厚朴酚可以降低 MMP2 的活性，再加入 EGF 之後又恢復了 MMP2 的活性。此外，LY294002 (PI3K 的抑制劑)，也經由 EGF 恢復了 MMP2 的活性。這些發現證明厚朴酚可以有效抑制 p185HER2/neu 的過度表現和部份經由 PI3K/Akt 途徑降低 p185HER2/neu 過度表現所媒介的癌細胞轉移。總論，相同的我們發現厚朴酚在 p185HER2/neu 過度表現的卵巢癌細胞中也具有抑制轉移性質的相關功能。

The oncoprotein HER2/neu is know to be overexpressed in several human cancers and it is associated with increased metastasis and poor prognosis. Magnolol, an active component extracted from Magnolia officinalis, has shown several pharmacological activities such as anti-tumor, anti-oxidant and anti-inflammatory effects. However, the effects of magnolol on the HER2/neu-overexpressing cancer cells are unknown. Here, we demonstrated that magnolol induced HER2/neu-overexpressing cancer cell death, in a dose- and time-dependent manner. We also reveled that magnolol could suppress the HER2/neu gene expression. We also elucidate that EGF specifically restores the activation of MMP2 after its activity was reduced by magnolol. Furthermore, LY294002, a PI3K inhibitor, attenuated the restoration of MMP2 activity by EGF. These finding suggest that magnolol can suppress HER2/neu expression, and then inhibiting the PI3K/Akt-signaling pathway to attenuate the p185HER2/neu mediated metastasis. Taken together, we found that magnolol is potent in suppressing metastasis-associated properties of HER2/neu-overexpressing ovarian cancer cells.

謝誌-------------------------------------------------------I
中文摘要--------------------------------------------------II
英文摘要-------------------------------------------------III
目錄------------------------------------------------------IV
附表、表目錄---------------------------------------------VII
附圖、圖目錄--------------------------------------------VIII
附錄目錄--------------------------------------------------IX
縮寫表-----------------------------------------------------X
第一章、	前言-實驗緣起與目的------------------------------1
第二章、	序論 -------------------------------------------2 
  第一節、神經膠原致癌基因 (HER2/neu) ---------------------2
    壹、神經膠原致癌基因的背景介紹-------------------------2
    貳、神經膠原致癌基因與癌症之關係-----------------------3
    叁、抑制神經膠原致癌基因的方法-------------------------3
  第二節、厚朴酚 (Magnolol) -------------------------------5
    壹、厚朴酚的背景介紹-----------------------------------5
    貳、厚朴酚與癌症之關係--------------------6             
  第三節、細胞凋亡 (Apoptosis) ----------------------------7
    壹、細胞凋亡的背景介紹---------------------------------7
    貳、細胞凋亡的三種機制---------------------------------8
  第四節、細胞轉移 (Metastasis) ---------------------------9
    壹、細胞轉移的背景介紹---------------------------------9
    貳、細胞轉移的過程------------------------------------10
第五節、細胞週期 (Cell Cycle) ----------------------------10
    壹、細胞週期的背景介紹--------------------------------10
    貳、細胞週期之調控------------------------------------11
  研究目標------------------------------------------------13
第三章、材料與方法----------------------------------------14
  第一節、實驗材料及相關儀器------------------------------14
壹、細胞株------------------------------------------------14
貳、抗體--------------------------------------------------14
叁、化學藥品與試劑----------------------------------------14
肆、主要儀器及器材----------------------------------------15
  第二節、實驗方法----------------------------------------16
     壹、解凍細胞-----------------------------------------16
     貳、繼代培養-----------------------------------------16
     叁、冷凍細胞-----------------------------------------17
     肆、收細胞-------------------------------------------18
     伍、西方墨點法 (Western blotting) -------------------18
     陸、細胞移動性分析 (Cell Motility Assay) ------------19
     柒、酵素圖譜活性分析 (Zymography) -------------------19
     捌、細胞生長速率分析 (MTT Assay) --------------------20
  第四章、實驗結果----------------------------------------21
     壹、厚朴酚影響人類卵巢癌 SKOV3 癌細胞之細胞型態------21
     貳、厚朴酚抑制人類 p185 過度表現癌細胞之生長---------21
 叁、厚朴酚抑制 p185HER2/neu 蛋白表現量 ------------------21
     肆、厚朴酚對 p185 過度表現 SKOV3 細胞的細胞週期相關蛋白之影響 ---------------------------------------------------22
 伍、厚朴酚抑制人類卵巢癌細胞 SKOV3 之侵入及轉移 ---------23
第五章、討論----------------------------------------------24
第六章、結論----------------------------------------------28
參考文獻--------------------------------------------------29
附表、表--------------------------------------------------43
附圖、圖--------------------------------------------------47
附錄------------------------------------------------------55

表目錄
附表1、細胞株基本資料------------------------------------------------------------ 43
附表2、西方墨點法使用之抗體--------------------------------------------------- 44
附表3、化學藥品及試劑------------------------------------------------------------ 46
表1、SKOV3 和 BT- 474 細胞加入厚朴酚經 48 小時後，細胞達半致死
     率所需濃度 (IC50) ---------------------------------------------------------- 47


















 附圖、圖目錄
附圖 1、厚朴酚之結構----------------------------------------------------------------6
附圖 2、細胞週期的調控機轉-----------------------------------------------------12
圖 1、厚朴酚對於人類卵巢癌細胞 SKOV3細胞株外觀型態上之影響
      ----------------------------------------------------------------------------------47
圖 2、厚朴酚抑制人類 p185HER2/neu 過度表現癌細胞之生長---------------48
圖 3、厚朴酚對於 p185HER2/neu 蛋白表現量之影響---------------------------49
圖 4、厚朴酚對於 HER2/neu 下游之 PARP 和 Caspase-3 訊息傳遞途徑
     之影響 -------------------------------------------------------------------------50
圖 5、厚朴酚對於人類 p185HER2/neu 過度表現的細胞週期相關蛋白之影響
      ----------------------------------------------------------------------------------51
圖 6、厚朴酚對於 HER2/neu 下游之 MAPK (Erk1/2) 訊息傳遞途徑之
      影響----------------------------------------------------------------------------52
圖 7、厚朴酚對於 SKOV3 細胞株轉移及酵素活性分析之影響----------53
圖 8、厚朴酚抑制 p185HER2/neu  蛋白質表現可能之途徑 ------------------54






附錄目錄
附錄1、細胞培養使用之緩衝液-------------------------------------------------55
附錄2、西方墨點法使用之試劑溶液-------------------------------------------56

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