臺灣博碩士論文加值系統

大腸直腸癌是目前全世界主要造成男性與女性因惡性腫瘤而死亡的癌症，根據行政院衛生署最新統計，大腸直腸癌之罹患率在台灣目前已攀升至第一位。然而，絕大多數癌症患者 (90%) 並非死於腫瘤本身，而是死於癌症轉移 (metastasis)。目前癌症治療方式以手術和化療為主，但仍有副作用和癒後復發等問題；隨著化學藥物療法受到限制，醫學轉而求助替代補充療法或傳統醫學治療，因此中草藥研發備受關注。
本研究即以一具有高度轉移特性之大腸直腸癌細胞株 SW620 作為體外篩選藥物之平台，並且回顧文獻選出 13 種具有抑制癌細胞轉移潛力之中草藥天然化合物，包含穿心蓮內酯 (Andrographolide)、吳茱萸鹼 (Evodiamine)、薑黃 (Curcumin)、泛黃芩素 (Wogonin)、黃芩素 (Baicalein)、黃芩苷 (Baicalin)、白楊素 (Chrysin)、雷公藤內酯 (Triptolide) 、雷公藤紅素 (Celastrol)、厚朴酚 (Magnolol)、異厚朴酚 (Honokiol)、薑辣素 (6-gingerol) 和薑烯酚 (6-shogaol)，藉此比較這些天然化合物抑制腫瘤轉移能力，並探討可能作用機制。
本實驗共可分作三階段。階段一，以 MTT assay 篩選出具有抑制癌細胞增生能力之天然化合物。在 13 種天然化合物中，有 7 種在 500 μM 以下可有效抑制 SW620 生長，其中以 curcumin (Cur) 和 honokiol (Hon) 效果最佳 (IC50 皆為 30 μM)，因此以 Cur 和 Hon 進入第二階段試驗。
階段二，分別以傷口癒合試驗 (Wound healing assay) 以及細胞侵入性試驗 (Boyden chamber assay) 評估天然化合物抑制腫瘤細胞爬行 (migration) 和入侵 (invasion) 能力。Cur 和 Hon 皆可有效抑制 SW620 爬行，並且呈現劑量效應；在入侵能力試驗部分，Cur 之抑制率由濃度低至高 (5, 10, 30 μM) 分別為 65%, 69% 和 93%，Hon 則為 40%, 70% 和 69%，以上結果顯示，Cur 和 Hon 皆具有效抑制癌細胞轉移之特性。
階段三，以西方點墨法 (Western blotting) 探討天然化合物抑制轉移之作用機制。實驗結果顯示，Cur 和 Hon 無法影響 MMP9 以及 MMP2 之蛋白質表現；但皆可以顯著降低活化態 (active form) 以及未活化 (pro-form) 之 MMP7 蛋白表現量，並且呈現劑量效應。另外，Cur 和 Hon 可以維持細胞膜上 E-cadherin，穩定細胞間黏著力，並抑制與 E-cadherin 形成 adheren junction 的 β-catenin 鬆脫，避免 β-catenin 轉入細胞核帶動下游癌化與轉移相關基因之表現，進而達到抑制細胞轉移之作用。

Colorectal cancer (CRC) is the major cancer which causes people dead worldwide. In Taiwan, according to the Bureau of Health Promotion, Department of Health, CRC has reached the first place in cancer incidence. Tumor cell metastasis is the most malignant feature during cancer progression and accounts for the major factor (90%) of mortality.
Current cancer treatment includes surgery and chemotherapy, but there are still side effects and recurrence problems. Therefore, nowadays medicine profession pays more attention to the research and development of traditional Chinese herbal medicines (TCM). As a Consequence, our aim was to find the potential TCM to decrease the metastastic rates of colorectal cancer.
In our study, we used the colorectal cancer cell line, SW620, which has high metastasis ability for in vitro assays. We also chose 13 pure compounds, which have the potential for anti-metastasis, from TCM based on the literatures to investigate the anti-metastastic ability of those pure compounds and the possible mechanism. The pure compounds include Andrographolide, Evodiamine, Curcumin, Wogonin, Baicalein, Baicalin, Chrysin, Triptolide, Celastrol, Magnolol, Honokiol, 6-gingerol and 6-shogaol.
There are three phases of our experiments. In phase one, we tested the ability of anti-proliferation of those pure compounds by MTT assay. Then we selected curcumin (Cur) and honokiol (Hon), which are more effective than the others, to conduct bioactivity test.
In the second phase, we used would-healing assay and Boyden chamber assay to analyze the potential of anti-migration and anti-invasion of Cur and Hon. Results showed that both of Cur and Hon had the inhibitory ability of anti-migration on SW620 in a dose-dependent manner. Besides, they also effectively reduced cell invasion. The inhibition rates of the treatments of different concentration of Cur (5, 10, 30μM) were 65%, 69% and 93%. For Hon, they were 40%, 70% and 69%. The data demonstrated that both of Cur and Hon could suppress the metastasis of SW620.
Finally in phase three, we investigated the possible mechanism of the anti-migration effect of Cur and Hon. Using western blotting assay, we found that although Cur and Hon could not decrease MMP2 and MMP9 expression, they could significantly inhibit active and pro-form MMP7 protein expression with dose-dependency. Moreover, both of Cur and Hon could augment the expression and stability of E-cadherin proteins on the cell membrane to prevent the disruption of cell contacts. They could also avoid β-catenin to translocate into nuclear binding downstream targets such as MMPs (especially MMP7) thus downregulated cell metastasis.
In conclusion, our findings suggest that Cur and Hon could maintain the expression of E-cadherin on cell membrane, avoid β-catenin translocation and then suppress the translation of MMP-7 protein, thus inhibit the metastasis of human colorectal cancer cell line SW620.

謝誌 II
摘要 i
Abstract iii

第一章、文獻回顧 1
第一節、大腸直腸癌 (colorectal cancer, CRC) 1
(一) 罹患率及現況 1
(二) 分類與成因 1
1-2-1. 遺傳性息肉症 (familial polyposis coli, FAP) 2
1-2-1-1. 腺瘤 (adenoma) 2
1-2-1-2. 布茲傑格症候群 (Peutz-Jeghers syndrome, PJS) 2
1-2-2. 遺傳性非息肉症大腸直腸癌 (HNPCC) 2
1-2-3. 非遺傳性大腸直腸癌 (sporadic colorectal cancer) 3
1-2-3-1. 增生性息肉 (Hyperplastic polyp or Metaplastic polyp) 3
1-2-3-2. 腺瘤 (adenoma) 3
1-2-3-3. 非遺傳性缺陷瘤 (hematoma) 4
1-2-3-4. 發炎性息肉或偽息肉 (Inflammatory bowel disease, IBD or pseudo polyp) 4
(三) 分級與發展 5
1-3-1. Dukes’ system 5
1-3-2. TNM staging system 5
(四) 治療 7
1-4-1. 血管新生抑制劑 7
1-4-1-1. Avastin (Bevacizumab) 8
1-4-2. 表皮生長因子抑制劑 10
1-4-2-1. Cetuximab 10
第二節、癌細胞轉移 (metastasis) 11
(一) 重要性 11
(二) 機制 13
2-2-1. 步驟 13
2-2-2. 類型 13
2-2-2-1. 單一細胞侵犯型 (single cell invasion) 13
2-2-2-2. 集體細胞侵犯型 (collective cell invasion) 14
(三) 細胞連結機制 15
2-3-1. 細胞與細胞之連結 (cell–cell junctions) 15
2-3-1-1. 穿膜醣蛋白 (E-cadherin，uvomorulin or L-CAM) 16
2-3-1-2. 穿膜醣蛋白之胞外區域 (extracellular domain of E-cadherin (ED)) 16
2-3-1-3. 穿膜醣蛋白之穿膜區域（transmembrane domain of E-cadherin (TD)） 17
2-3-1-4. 穿膜醣蛋白在細胞質之區域（cytoplasmic domain of E-cadherin (CD)） 17
2-3-1-5. E-cadherin/β-catenin complex (E-cad/β-cat) 17
2-3-2. 細胞與基質之連結 (Cell-matrix junctions) 23
(四) 金屬基質蛋白酶 (Matrix metalloproteinases) 24
2-4-1. 簡介 24
2-4-2. 結構與分類 24
2-4-3. MMPs 與轉移關係 30
2-4-3-1. MMP2 的表現 32
2-4-3-2. MMP9 的表現 32
2-4-3-3. MMP7 的表現 32
2-4-4. MMPs之抑制藥物 34
第三節、具抑制大腸直腸癌轉移潛力之中草藥 35
(一) 穿心蓮 (Andrographis paniculata) 35
3-1-1. 穿心蓮內酯 (Andrographolide, Andro) 35
(二)吳茱萸 (Evodia Rutaecarpa) 35
3-2-1. 吳茱萸鹼 (Evodiamine) 36
(三) 薑黃 (Curcuma longa ) 36
3-3-1. 薑黃素 (Curcumin) 36
(四) 厚朴 (Magnolia officinalis Rehd.et Wils.) 37
3-4-1. 厚朴酚 (Magonolol) 與異厚朴酚 (Honokiol) 38
(五) 黃芩 (Scutellariae radix) 38
3-5-1. 泛黃芩素 (Wogonin) 38
3-5-2. 黃芩素 (Baicalein) 39
3-5-3. 黃芩苷 (Baicalin) 39
3-5-4. 白楊素 (Crysin) 39
(六) 雷公藤 (Tripterygium wilfordii) 40
3-6-1. 雷公藤紅素 (Celastrol) 40
3-6-2. 雷公藤內酯 (Triptolide) 40
(七) 薑 (Zingiber officinale) 40
3-7-1. 薑辣素 (6-gingerol) 與薑烯酚 (6-shogaol) 41

第二章、實驗目的與設計 46
第一節、實驗目的 46
第二節、實驗設計 47
(一) 實驗流程 48
(二) 實驗架構 49
2-2-2. Part 2: Bioactivity test 50

第三章、實驗材料與儀器 52
第一節、實驗材料 52
(一) 細胞來源與型態 52
(二) 藥品試劑 52
第二節、實驗儀器 55
第四章、實驗方法 56
第一節、樣品配置 56
第二節、細胞培養 56
第三節、細胞存活率 (MTT assy) 58
第四節、腫瘤細胞爬行能力試驗 (Wound-healing assay) 60
第五節、腫瘤細胞入侵能力試驗 (Invasion assay) 61
第六節、蛋白質萃取與定量 (Protein extraction) 64
第七節、SDS-PAGE 電泳分析 66
第八節、西方點墨法 (western blotting) 69

第五章、結果與討論 71
第一節、MTT test 71
第二節、Bioactivity study 76
(一) Curcumin 抑制 SW620 細胞之轉移能力 77
2-1-1. 腫瘤細胞爬行能力試驗結果 (migration assay) 77
2-1-2. 腫瘤細胞入侵能力試驗結果 (Invasion assay) 80
(二) Honokiol 抑制 SW620 細胞之轉移能力 82
2-2-1. 腫瘤細胞爬行能力試驗結果 (migration assay) 82
2-2-2. 腫瘤細胞入侵能力試驗結果 (Invasion assay) 85
(三) Bioactivity study 小結 87
第三節、Molecular mechanism 88
(一) Curcumin 對於 SW620 細胞之目標蛋白質表現之影響 88
3-1-1. Cell-matrix：MMP2, MMP9 以及 MMP7 88
3-1-2. Cell-cell：E-cadherin 以及 β-catnin 蛋白表現量 92
3-1-3. Curcumin 抑制轉移作用機制之小結 97
3-2-1. Cell-matrix：MMP2, MMP9 以及 MMP7 蛋白表現量 99
3-2-2. Cell-cell：E-cadherin 以及β-catnin 蛋白表現量 105
3-2-3. Honokiol 抑制轉移作用機制之小結 109
(三) Molecular mechanism 小結 110
3-3-1. 細胞與基質之連結 (Cell-matrix junctions) 110
3-3-2. 細胞與細胞之連結 (Cell-cell junctions) 111

第六章、結論 115
第七章、參考文獻 117
第八章、附錄 129

行政院衛生署, 2012
行政院衛生署, 2013
以薑黃素做為口腔癌化學預防與治療藥物之潛力及其作用機轉之研究
郭彥彬，2004

MEROPS http://merops.sanger.ac.uk/index.shtml
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