在人類乳癌和其它的癌症病患中約有 30~40% 肇因於神經膠原致癌基因大放大或過度表現。3,3'-二吲哚甲烷 (DIM) 為吲哚三甲醇 (I3C) 在酸性條件下所形成的雙聚體， 和 I3C 比起來，DIM 具有較穩定且較好的抗癌效果。
從最近的文獻得之 3,3'-二吲哚甲烷對於不同的癌細胞有抗增生和促進細胞凋亡的功能。在本研究中，我們首先證實 3,3'-二吲哚甲烷可抑制神經膠原致癌基因的表現。再者，更發現 3,3'-二吲哚甲烷對於神經膠原致癌基因過度表現的癌細胞，不僅能有效抑制癌細胞的存活率及降低內生性p185HER2/neu的表現，也可抑制因神經膠原致癌基因所引發的細胞癌變和轉移能力。
這些結果證實3,3'-二吲哚甲烷可做為對抗神經膠原致癌基因的標靶抗癌藥物。
關鍵字：神經膠原致癌基因、3,3'-二吲哚甲烷、轉移

HER2/neu oncogene is known to be amplified and/or over-expressed in approximately 30-40% of human breast cancers and many other cancers. And, 3,3’-Diindolylmethane (DIM) is a dimer of indole-3-carbinol (I3C) that is formed under acidic conditions and unlike I3C is more stable with higher anti-cancer effects. Previous studies have shown the antiproliferative and proapoptotic effects of DIM in several cancer cells. In the present study, we demonstrated for the first time that DIM suppresses the HER2/neu oncogene expression. Furthermore, we also found DIM could inhibit the survival rate and downregulate the endogenous production of p185HER2/neu of HER2/neu-overexpressing cancer cells, as well as suppress the HER2/neu-mediated transformation and metastatic potential. These data suggest that DIM may act as a HER2/neu-targeting anticancer drug.

正文目錄
第一章  緒論	1
第一節 研究動機和目的	1
第二節 神經膠原致癌基因概論	3
一、簡介	3
二、神經膠原致癌基因和癌症	6
三、神經膠原致癌基因的訊息傳導	7
四、抑制神經膠原致癌基因表現之癌症治療研究	9
第三節 3,3'-二吲哚甲烷概論	12
一、簡介	12
二、3,3'-二吲哚甲烷(DIM)和藥理的關聯性	12
三、3,3'-二吲哚甲烷(DIM)對細胞的影響	14
第二章  材料與方法	16
第一節  實驗材料和方法	16
一、3,3'-二吲哚甲烷的配製	16
二、冷凍細胞之解凍	17
三、細胞繼代與保存	19
四、冷凍細胞	21
五、細胞計數及存活測試	24
六、3,3'-二吲哚甲烷(DIM)對癌細胞株之細胞型態的影響	26
七、細胞生長速率分析 ( MTT Assay)	26
八、西方墨點法 (Western blotting)	29
九、Scratch-Wound Assay	33
十、細胞移動性分析 (Cell Motility Assay)	34
十一、酵素圖譜活性分析 (Zymography)	36
十二、軟膠測試(Soft agar assay)	37
十三、啟動子活性測定（Luciferase assay and β-galactosidase assay）	39
十四、統計分析	41
第二節 主要儀器設備	42
第三章  結果	44
第一節  3,3'-二吲哚甲烷對p185HER2/neu 過表現細胞在增生有較佳的抑制效果	44
第二節  3,3'-二吲哚甲烷(DIM)抑制神經膠原致癌基因蛋白的表現	45
第三節 3,3'-二吲哚甲烷影響訊息傳遞途徑	47
第四節 3,3'-二吲哚甲烷抑制高表現 p185HER2/neu 癌細胞之轉移能力	47
第四章  討論	50
第五章  結論	53
第六章 參考文獻	54

 
圖目錄
圖1、3,3'-二吲哚甲烷對於人類卵巢癌SKOV3細胞株外觀型態上之影響	69
圖2(A)、3,3'-二吲哚甲烷對於1% FBS下抑制p185HER2/neu 過表現細胞株生長之影響	71
圖2(B)、3,3'-二吲哚甲烷主要於1% FBS下抑制p185HER2/neu 過表現細胞株生長	72
圖3、3,3'-二吲哚甲烷抑制細胞株的錨定能力(Anchorage-independent)	73
圖4、3,3'-二吲哚甲烷對於p185HER2/neu蛋白表現量之影響	74
圖5(A)、3,3'-二吲哚甲烷對p185HER2/neu蛋白分解途徑和啟動子活性之影響	75
圖5(B)、3,3'-二吲哚甲烷對p185HER2/neu蛋白分解途徑和啟動子活性之影響	76
圖6、3,3'-二吲哚甲烷對於p185HER2/neu下游之p-ERK1/2和p-p38訊息傳遞途徑之影響	77
圖7(A)、3,3'-二吲哚甲烷透過抑制p185HER2/neu而抑制轉移能力(一)	78
圖7(B)、3,3'-二吲哚甲烷透過抑制p185HER2/neu而抑制轉移能力(二)	79
圖7(C)、3,3'-二吲哚甲烷透過抑制p185HER2/neu而抑制轉移能力(三)	80

 
附表目錄
附表1、飲食預防試劑調控的蛋白質。(Manson et al., 2007)	81
附表2、細胞株基本資料	82
附表3、西方墨點法常用之抗體資料	83
附表 4、化學藥品及試劑（chemicals and reagents）	84

 
附錄目錄
附錄1、細胞培養使用之緩衝液	86
附錄2、西方墨點法使用之試劑溶液	87
附錄3、貝他半乳糖苷酶分析使用之緩衝液	89

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