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系統識別號 U0007-2807201517004800
論文名稱(中文) 十字花科蔬菜吲哚衍生物對於B16-F10小鼠黑色素瘤細胞分化及自噬作用之影響
論文名稱(英文) Effects of indole derivatives of cruciferous vegetable on differentiation and autophagy in murine B16-F10 melanoma cells
校院名稱 臺北醫學大學
系所名稱(中) 保健營養學研究所
系所名稱(英) Graduate Institute of Nutrition and Health
學年度 103
學期 2
出版年 104
研究生(中文) 蔡宜庭
研究生(英文) Yi-Ting Tsai
學號 M507102006
學位類別 碩士
語文別 中文
口試日期 2015-07-09
論文頁數 108頁
口試委員 指導教授-陳玉華
委員-許瑞芬
委員-楊素卿
中文關鍵字 黑色素瘤  indole-3-carbinol  細胞分化  自噬作用 
英文關鍵字 melanoma  indole-3-carbinol  differentiation  autophagy 
學科別分類
中文摘要 黑色素瘤是一種極惡性的腫瘤,其分化不良,惡性程度高,具高侵襲及轉移性,因此備受重視。在臨床上,黑色素瘤治療方式以手術為主,但若已發生轉移,手術切除一般無法控制病情,此時往往需考慮化學治療、標靶等其他療法,但其毒性及副作用可能使治療成效受限。因此,本研究主要探討在癌症治療上相對較新穎且有潛力的治療方式:誘導癌細胞良性分化及自噬作用。研究發現分化不良的細胞與原發組織相似性低,且其惡性程度較高、侵略性較強,故目前癌症治療策略希望能誘導癌細胞良性分化,研究認為黑色素瘤分化的指標包含:增加黑色素生成、上調tyrosinase活性、增加樹突狀結構產生等。此外,細胞自噬作用過程異常或自噬作用表現低下可能使細胞內清除受損的胞器的能力下降、增加氧化壓力、DNA變異及染色體不穩定性,而與癌症有關。研究亦發現自噬作用可能具抑制癌症的作用,且其作用低下可能與腫瘤形成、進展有關。
十字花科蔬菜具有降低癌症發生的作用,主要和其內富含的indole衍生物indole-3-carbinol (I3C)及其代謝產物3,3'-diindolylmethane (DIM)有關。因此本實驗擬以B16F10黑色素瘤細胞為模式,探討I3C與DIM對黑色素瘤細胞生長、分化及自噬作用的影響。細胞生長實驗部分以MTS及細胞計數法分析I3C及DIM介入對細胞存活率及生長的影響;分化實驗部分觀察細胞典型分化形態,測定細胞內及細胞釋出的黑色素,分析tyrosinase活性,黑色素生合成相關蛋白質MITF、tyrosinase表現,黑色素生合成相關基因MITF、tyrosinase、TRP-1、TRP- 2的mRNA表現,並以穿透式電子顯微鏡觀察黑色素體的形成;自噬作用探討部分分析自噬作用相關蛋白質磷酸化-mTOR、mTOR、LC3-I、LC3-II 之表現,並以穿透式電子顯微鏡觀察自噬體的形成。
結果顯示I3C (50、100 μM)及DIM (10、25、50 μM)處理72小時後,顯著降低細胞數;且於較高劑量I3C (100 μM)及DIM (50 μM)處理後使細胞出現樹突狀結構,於穿透式電子顯微鏡下亦觀察到有較多黑色素體產生,亦顯著增加tyrosinase的活性及胞內及胞外黑色素含量。此外,DIM 50 μM的劑量有增加細胞tyrosinase蛋白質表現量的趨勢並顯著增加tyrosinase、TRP- 2的mRNA表現。另外,I3C及DIM對於自噬作用相關蛋白質磷酸化mTOR (mammalian target of rapamycin)及LC3 (microtubule-associated protein 1 light chain 3)蛋白質表現量無明顯影響,且無觀察到增加自噬體的形成。因此本研究發現I3C及DIM可降低黑色素瘤細胞增殖並誘導其良性分化,但對於黑色素瘤細胞自噬作用無明顯影響。
英文摘要 Melanoma is one of the most malignant tumors due to its poorly differentiated and highly metastasized to vital organs, such as lungs, livers, and brain, so it’s been paid lot of attention. Surgical removal is the main treatment for most melanomas, and also melanoma patients generally undergo chemotherapy, radiotherapy, or other treatments. Although current cancer therapies are significant, these therapies are often with side effects, so that limited their clinical efficacy. Therefore, this study focuses on the relatively novel and potential therapeutic target for cancer: induction of cancer cell differentiation and autophagy. Studies indicate that differentiated melanoma tend to be less aggressive than undifferentiated melanoma, and is associated with slower cell proliferation. The dendritic cell morphology, increased melanin production, increased tyrosinase activity, are markers of differentiated melanoma cells. Some studies indicated autophagy is a mechanism of tumor suppression. Autophagy defect is associated with DNA damage, mutation, and genomic instability, and that contributes to pathological conditions, such as cancer.
It has been indicated that increasing consumption of cruciferous vegetable lowers the risks of cancers, and the glucosinolate derivatives, indole-3-carbinol (I3C) and its metabolite DIM (3,3'-diindolylmethane), are thought to contribute to the anti-cancer activities of these vegetables. Studies have been indicated that I3C can inhibit the growth of various cancer cell lines. However, the effects of DIM on melanoma are not known. Previously, we have indicated that I3C could increase melanin production in melanoma cells, and the biological activities may be associated with DIM. In this study, we investigated the effect of I3C and DIM on cell growth, differentiation and autophagy by using murine B16F10 melanoma cells. The suppressed effect in cell numbers was observed in B16F10 melanoma cells treated with 50-100 μM I3C and 10-50 μM DIM for 48 and 72 hours. To understand the effects of I3C and DIM on cell differentiation, cell morphology will be observed under a microscope, we found that DIM and I3C can induce dendrite morphological changes of B16F10 cells. Furthermore, the content of melanin (intra-cellular and extra-cellular melanin) in B16F10 cells were increased, when treated with 100 μM I3C and 50 μM DIM to the cells. On the other hand, DIM markedly stimulates melanin biosynthesis which was associated with increased tyrosinase activity, gene expression of tyrosinase as well as protein expression of tyrosinase and microphthalmia melanocyte-associated factor (MITF). Finally, we also found 100 μM I3C and 50 μM DIM treated B16F10 cells significantly increased the mature melanosomes compared with the control cells (observations from TEM). However, I3C and DIM treatment didn’t induce the increasing of autophagy related protein expression and autophagosomes after treatment.
In summary, I3C and DIM inhibited cell growth, stimulated expression of markers of melanoma cell differentiation, but showed no effected on autophagy.

論文目次 目次
摘要 I
Abstract III
致謝 VI
目錄 VII
表目錄 1
圖目錄 2
第一章、 前言 3
第二章、 文獻回顧 5
第一節、 黑色素瘤 5
第二節、 細胞分化與癌症 12
第三節、 細胞自噬作用 17
第四節、 十字花科蔬菜及其衍生物與癌症 25
第三章、 研究動機 30
第四章、 材料與方法 31
第一節、 實驗材料 31
第二節、 實驗方法 38
(一) 細胞培養 (Cell culture) 38
(二) 細胞毒性分析 (MTS assays) 38
(三) 細胞生長及存活率分析 (Cell growth and cell vialibity) 39
(四) 細胞形態學分析 (Morphology assay) 40
(五) 黑色素含量測定 (Measurement of melanin content)40
(六) Tyrosinase活性分析 (Tyrosinase activity assay)41
(七) 西方墨點法 (Western blot analysis) 42
(八) 細胞total RNA萃取及RT-PCR (Total RNA extraction and
real-time quantitative polymerase chain reaction) 45
(九) 穿透式電子顯微鏡觀察黑色素體及自噬體的形成
(Electron microscopy) 47
(十) 統計分析 (Statistical analysis) 47
第五章、 結果 49
第一節、 I3C及DIM對於細胞生長之影響 49
(一) 細胞毒性分析 49
(二) 細胞生長及存活率分析 52
第二節、 I3C及DIM對於細胞分化之影響 55
(一) 細胞形態學分析 55
(二) 穿透式電子顯微鏡觀察細胞內黑色素體 57
(三) 黑色素含量測定 59
(四) Tyrosinase活性分析 62
(五) 黑色素瘤黑色素生成相關蛋白質表現 64
(六) 黑色素瘤黑色素生成相關mRNA表現 67
第三節、 I3C及DIM對於細胞自噬作用之影響 69
(一) 穿透式電子顯微鏡觀察細胞內自噬體形成 69
(二) 自噬作用相關蛋白質表現 74
第六章、 討論 77
第一節、 實驗設計考量 77
第二節、 I3C及DIM對於細胞生長之影響 77
第三節、 I3C及DIM對於細胞分化之影響 78
第四節、 I3C與DIM比較 81
第五節、 I3C及DIM對於細胞自噬作用之影響 82
陸、 結論 84
柒、 參考文獻 85

表目次
表2.1、 I3C的抗癌活性 28
表4.1、 引子序列 48

圖目錄
圖2.1、皮膚結構 6
圖2.2、皮膚表皮層結構 7
圖2.3、黑色素瘤癌化過程與分生機制 10
圖2.4、黑色素瘤自我檢測五特徵 11
圖2.5、顯微鏡下觀察B16F10細胞分化 16
圖2.6、自噬作用 20
圖2.7、自噬作用的多個階段與分子調控 21
圖2.8、I3C及其衍生物DIM的生成 29
圖4.1、細胞實驗流程圖 37
圖5.1、 I3C及DIM處理24小時對於B16F10細胞之細胞毒性影響 50
圖5.2、 I3C及DIM處理48及72小時對於B16F10細胞之細胞毒性影響 51
圖5.3、 I3C及DIM對於B16F10細胞生長之影響 53
圖5.4、 I3C及DIM對於B16F10細胞存活率之影響 54
圖5.5、 I3C及DIM對於B16F10細胞之細胞型態之影響 56
圖5.6、I3C及DIM對於B16F10細胞黑色素體之影響 58
圖5.7、 I3C及DIM對於B16F10細胞內黑色素含量之影響 60
圖5.8、 I3C及DIM對於B16F10細胞釋放出的黑色素之影響 61
圖5.9、 I3C及DIM對於B16F10細胞tyrosinase酵素活性之影響 63
圖5.10、 I3C及DIM對於B16F10細胞tyrosinase蛋白質表現之影響 65
圖5.11、 I3C及DIM對於B16F10細胞MITF蛋白質表現之影響 66
圖5.12、 I3C及DIM對於B16F10細胞黑色素瘤分化相關mRNA表現之影響 68
圖5.13、電子顯微鏡下觀察到的自噬體 70
圖5.14、I3C及DIM對於B16F10細胞內粒線體型態之影響 71
圖5.15、I3C及DIM對於B16F10細胞磷酸化mTOR及mTOR蛋白質表現之影響 75
圖5.16、 I3C及DIM對於B16F10細胞LC3I及LC3II蛋白質表現之影響 76

參考文獻 衛生福利部—民國100年癌症登記報告

張雅琴 (2009). 十字花科蔬菜衍生物對腫瘤轉移暨相關黏附及分化之影響 台北醫學大學保健營養學系碩士論文

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