過去研究發現利用生產蜆精剩餘的蜆肉經由熱水輔助蛋白酶水解所生產的蜆肉水解物 (Corbicula fluminea hydrolysate, CFH)，可促進三陰性乳癌 (triple-negative breast cancer, TNBC) 細胞凋亡、加成化療藥物療效、抑制細胞遷徙及癌症幹細胞等癌惡化現象。由於高溫水解可能減少活性胜肽的產量及降低生物活性，而非熱加工之高壓加工 (high pressure processing, HPP) 可提高蛋白質水解度並減少蛋白質熱變性。因此本研究目的為利用 HPP 輔助蛋白酶水解蜆肉，以生產抗癌胜肽。首先以反應曲面法 (response surface methodology, RSM) 得知 HPP 蜆肉蛋白水解物 (Corbicula fluminea protein hydrolysate, pCFH) 之最佳生產條件為，40 g 蜆肉粉添加 2% Umamizyme G 水解 3 小時，再加入 1% pepsin 水解 1 小時，再經 450 MPa 處理 15 分鐘。所得之 pCFH 其可溶性蛋白質、胜肽含量及酵素水解度分別為 1.98 mg/mL、450.98 mg/mL 及 6.60%。其次，膠體層析結果顯示，相較於常壓輔助蛋白酶水解 CFH，HPP 可提高 157-2856 Da 之間低分子量胜肽之產率。pCFH 對人類乳癌 MDA-MB-231 細胞的半抑制濃度 (half maximal inhibitory concentration, IC50) 為 0.89 mg/mL，而 pCFH 對於正常細胞之 IC50 大於 2.50 mg/mL。繼續探討 pCFH 對於人類 TNBC 細胞模式 MDA-MB-231 細胞之抗癌作用機轉，分別以 MTT assay、trypan blue exclusion assay、群落形成及細胞週期分析細胞增生能力及化療敏感性。利用流式細胞儀測量細胞凋亡和癌症幹細胞特徵。以 wound healing assay 及 transwell migration assay 觀察細胞遷移能力。並以 ELISA 定量 MMPs、FADD、caspases 活性及 cytochrome c 釋放。MDA-MB-231 細胞處理 pCFH (0.45、0.90和1.80 mg/mL) 可抑制細胞增生、提升化療藥物 Doxorubicin 及 Paclitaxel 之敏感性，細胞存活率分別為控制組之 86.2%、73.1% 和 62.8% 及 85.8%、70.8% 和 58.3%。且經由粒線體途徑，造成粒線體膜電位下降、釋放 cytochrome c、活化 caspase 9；以及外源性途徑，增加 FADD 表現、提高 caspase 8 活性並活化 caspase 3/7，促進細胞凋亡。並可通過抑制細胞外 MMP-2、MMP-9 表現及降低細胞膜上 PDGFA 蛋白表現，延緩細胞傷口癒合及垂直遷移能力。此外，pCFH 可減少 MDA-MB-231 細胞之幹細胞特性，包括球體生成、CD44+/CD24- 比例及 ALDH+ 表現。綜合上述，高壓輔助酵素萃取可提升 pCFH 之低分子量胜肽含量，且具有抑制 TNBC 細胞惡化之潛力。

Previous study proved that hot water-assisted hydrolysate of Corbicula fluminea protein (CFH) promoted cell apoptosis, increased chemo-sensitivity, inhibited cell migration, and suppressed cancer stem cell properties in triple-negative breast cancer (TNBC) cells. Thought high-temperature hydrolysis might reduce the yield of bioactive peptides and their bioactivity, while high pressure processing (HPP) could increase the degree of protein hydrolysis, and reduce thermal denaturation of protein. Therefore, this study aimed to use HPP-assisted protease hydrolyzed CFH (pCFH) to produce anticancer peptides. Firstly, the response surface methodology found the optimal conditions for pCFH production was 40 g of freshwater clam muscle powder, add 2% Umamizyme G to hydrolysis for 3 hours, then add 1% pepsin to hydrolysis for 1 hours, and process under 450 MPa for 15 minutes. The soluble protein concentration, peptide concentration and degree of hydrolysis of pCFH were 1.98 mg/mL, 450.98 mg/mL and 6.60%, respectively. Secondly, the results of gel permeation chromatography showed that HPP improved the yield of low molecular weight peptides between 157-2856 Da as compared with the atmospheric-assisted protease hydrolysed CFH. Furthermore, this study investigated the anticancer effects and mechanisms of pCFH on human TNBC MDA-MB-231 cells. The half maximal inhibitory concentration (IC50) of pCFH on MDA-MB-231 cells was 0.89 mg/mL, while the IC50 of normal cells was more than 2.50 mg/mL. The cell proliferation and chemosensitivity were analyzed by MTT assay, trypan blue exclusion assay, colony formation, and cell cycle analysis, respectively. pCFH-regulated apoptosis and cancer stem cells (CSC) properties were measured by flow cytometry. In addition, cell migration was observed by wound healing assay and transwell migration assay. Furthermore, the activities of MMPs, FADD, and caspases, as well as cytochrome c release were analyzed by ELISA. Treatment with pCFH (0.45, 0.90 and 1.80 mg/mL) could inhibit cell proliferation and enhance the chemosensitivity in MDA-MB-231 cells. Doxorubicin and Paclitaxel were inhibited the cell viability to 86.2%, 73.1%, and 62.8%, as well as 85.8%, 70.8%, and 58.3% of control, respectively. Moreover, pCFH-induced apoptosis via mitochondrial-mediated pathway, decreased the mitochondrial membrane potential, released cytochrome c, and activated caspase 9, simultaneously, via extrinsic pathway, increased the expression of FADD, and improved the activity of caspase 8, and caspase 3/7. Besides, pCFH attenuated cell migration through decreasing of extracellular MMP-2, and MMP-9 activation, and the suppressed PDGFA expression on cell membrane. Additionally, pCFH decreased CSC properties, including spheroid formation, CD44+/CD24- ratio, and ALDH+ expression on MDA-MB-231 cells. In conclusion, HPP-assisted protease hydrolysation increased the content of low molecular weight peptides of pCFH, and it reveal inhibory effects on cancer progression of TNBC cells.

摘要 I
Abstract II
縮寫表 IV
目次 VI
第一章 前言 1
第二章 文獻回顧 2
第一節、乳癌 2
一、 定義及現況 2
二、 三陰性乳癌 (triple-negative breast cancer, TNBC) 2
三、 癌細胞入侵及轉移機制 3
四、 細胞遷移能力相關因子 3
五、 乳癌幹細胞 (breast cancer stem cells, BCSC) 4
六、 乳癌化學治療藥物 4
七、 乳癌化療藥物抗性 6
第二節、蜆肉水解物 7
一、 臺灣蜆 (Corbicula fluminea) 7
二、 蜆之應用 8
三、 蜆肉水解物之生理活性 8
第三節、高壓加工 (high pressure processing, HPP) 10
一、 HPP 介紹 10
二、 HPP 輔助酵素萃取蛋白質 10
三、 HPP 之應用 10
第四節、反應曲面法 (response surface methodology, RSM) 11
第三章 研究目的 12
第四章 研究設計 13
第五章 研究方法 14
第一節、蜆肉水解物萃取與分析 14
一、 製備蜆肉水解物 14
二、 可溶性蛋白質定量 15
三、 胜肽含量分析 15
四、 總固形物含量 16
五、 酵素水解度分析 16
六、 膠體層析過濾 (gel permeation chromatography, GPC) 17
第二節、細胞培養 17
一、 MDA-MB-231 細胞培養液配製 17
二、 MDA-MB-231 細胞培養 17
三、 細胞繼代 18
四、 人類正常細胞 (normal cells) 18
第三節、抗腫瘤活性測定 18
一、 MTT Assay 18
二、 錐蟲藍排除法 (trypan blue exclusion assay) 19
三、 細胞群落形成 (colony formation) 19
四、 化療藥物敏感性試驗 20
第四節、細胞週期分析 20
第五節、細胞凋亡分析 21
一、 細胞凋亡現象 21
二、 粒線體膜電位變化 21
三、 Cytochrome c 釋放 21
四、 FADD 分析 22
五、 Caspases 活性分析 23
第六節、細胞遷移能力及機制 23
一、 傷痕癒合試驗 (wound healing assay) 23
二、 轉移盤移行試驗 (transwell migration assay) 23
三、 MMPs (matrix metalloproteases) 表現分析 24
四、 PDGFA (Platelet-derived growth factor Alpha) 表現分析 24
第七節、癌症幹細胞特徵分析 25
一、 球體生成能力分析 25
二、 幹細胞表面標誌物 CD44+/CD24- 表現 25
三、 ALDH (aldehyde dehydrogenase) 表現 25
第八節、統計分析 26
第六章 結果與討論 27
第一節、探討高壓輔助酵素萃取蜆肉水解物之最佳生產條件 27
第二節、pCFH 對人類正常細胞及 MDA-MB-231 細胞存活率之影響 29
第三節、pCFH 提升 MDA-MB-231 細胞化療敏感性 30
第四節、pCFH 誘導 MDA-MB-231 細胞凋亡及機轉 31
第五節、pCFH 抑制 MDA-MB-231 細胞遷移作用及機轉 33
第六節、pCFH 減少 MDA-MB-231 細胞之幹細胞比例 34
第七節、pCFH 抑制 MDA-MB-231 細胞惡化之可能機制 35
第八節、pCFH 之蛋白質分子量區間 36
第七章 結論 37
參考文獻 38
圖表 47
附錄 87

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