靈芝在中國及東亞各國醫療保健和文化生活中的應用已有源遠流長的歷史。近年來，靈芝因其抗癌及免疫調節方面的功效而逐漸受到全球醫學界的重視。許多研究指出靈芝多醣具有促進免疫功能之活性，而靈芝三&;#33820;類化合物則能抑制腫瘤細胞生長，成為有潛力的抗癌藥物。本實驗室所使用的松杉靈芝子實體乾燥粉末經由薄層層析及高效液相層析技術鑑定其種源，且更進一步利用中草藥全球化聯盟主席鄭永齊院士所推廣的生物反應指紋分析平台，來監控靈芝萃取物之品質。結果顯示投予松杉靈芝甲醇萃取物的三組間之生物反應指紋圖譜極相似(PSI值＞0.95)，而投予松杉靈芝甲、乙醇萃取物的兩大組間之生物反應指紋圖譜相似但不同。因此，生物反應指紋可作為中草藥品質管制的分析平台。本實驗室之前的實驗結果顯示，松杉靈芝之甲醇萃取物能抑制人類卵巢癌細胞株SKOV-3的生長。並且，根據創傷癒合實驗的結果，推測松杉靈芝甲醇萃取物亦能減緩SKOV-3細胞的移動能力。為闡明靈芝甲醇萃取物對於SKOV-3細胞造成諸多影響所牽涉的分子機轉，本論文利用蛋白質二維凝膠電泳分離，及介質輔助雷射脫附游離飛行時間式質譜儀等蛋白質體學技術，探討投予靈芝甲醇萃取物後SKOV-3細胞整體蛋白質表現的改變。結果得到51個Mascot評分值大於65，即p值小於0.05的蛋白質，其中，在投予靈芝甲醇萃取物後表現量明顯增加的蛋白質有22個，而明顯減少的蛋白質有23個。之後將其中40個蛋白質匯入GeneGo Meta CoreTM，進行訊號傳遞網絡圖的建立，並以西方墨點法輔證。最後，根據實驗結果以及相關文獻的探討，提出三個松杉靈芝甲醇萃取物抑制SKOV-3生長的可能訊號傳遞機轉：(1) 抑制c-Src、c-Myc及其下游基因的表現，而抑制了SKOV-3細胞的增生。(2) 影響HSP90及HSP27的正常功能，因而抑制SKOV-3細胞的增生及存活。(3) 抑制SKOV-3細胞醣解作用，因而降低細胞生長。本研究結果將可提供以中草藥對抗卵巢癌的可能細胞機轉與治療方法之參考依據。

Ganoderma, also known as Reishi or Lingzhi, has been used for medicinal purposes for centuries. This herb has gained considerable attention for its anti-tumor and immunomodulatory activities. We have investigated the extracts from the Ganederma tsugae (Gt), one of the Lingzhi species locally cultivated in Taiwan, followed by TLC and HPLC profiles analysis and further monitored by genetic bioresponse fingerprinting (PhytoViewerBR, PhytoCeutica, Inc.). The bioresponse fingerprinting results reveal that the PSI (Phytomics Similarity Index) value for the 3 independent experiments is very similar (PSI > 0.95), showing that the Gt extracts are in good quality. Moreover, our previous studies have shown that Gt methanol extracts have growth inhibition effects on the human ovarian cancer SKOV-3 cells, and decrease the oncogene expression. The wound closure assay result demonstrates that Gt methanol extracts also reduce SKOV-3 cells motility. To further unravel the molecular mechanism involved, a proteomics approach, 2-D electrophoresis and MALDI-TOF mass spectrometry, was used to tell the differential changes of protein expression profile in SKOV-3 cells after treatment with Gt extracts. Of the 51 noticeable altered protein spots with MOWSE Score＞65 (i.e., p<0.05), 22 are up-regulated and 23 down-regulated. Forty characterized proteins were loaded on the GeneGo Meta CoreTM for building signaling network. Based on this signaling network followed by further Western blotting experiments, 3 possible molecular pathways leading to the growth inhibition of SKOV-3 cells by the Gt treatment have been proposed. Our results may provide possible cellular signaling networks of using the traditional Chinese medicine Ganoderma tsugae to treat ovarian cancer.

目 錄
頁次
中文摘要 i
英文摘要 ii
誌謝辭 iii
目錄 iv
表目錄 viii
圖目錄 ix
縮寫表 x
第一章 : 緒論 1
第一節、研究緣起與目的 1
第二節、靈芝 3
壹、靈芝概述 3
貳、靈芝醫療相關研究 4
参、實驗用松杉靈芝來源 6
肆、靈芝種源及成分品質鑑定 6
第三節、基因體生物反應指紋 8
壹、中草藥全球化聯盟 8
貳、基因體生物反應指紋圖譜 8
第四節、蛋白質體學 9
壹、概述 9
貳、蛋白質體學的發展及應用 10
参、蛋白質二維凝膠電泳分離 10
肆、質譜儀 11
第二章 : 材料與方法 12
第一節、實驗材料 12
壹、細胞株 12
貳、松杉靈芝 12
參、化學試劑藥品 12
肆、主要器材儀器 15
第二節、實驗方法 16
壹、細胞株培養 16
貳、細胞株生長曲線 16
參、松杉靈芝甲醇萃取 17
肆、創傷癒合試驗(Wound closure assay) 17
伍、靈芝萃取物對細胞株半數抑制濃度(IC50)的測量(CCK-8 assay) 18
陸、細胞RNA的抽取、Affymetrix人類微陣列分析以及基因體
生物反應指紋圖譜(Genomic Bioresponse Fingerprint) 18
柒、二維凝膠電泳(2-Dimension Gel Electrophoresis)及膠體影像分析 20
捌、膠體內蛋白質水解(In-gel digestion) 23
玖、介質輔助雷射脫附游離飛行時間式質譜儀及資料庫應用 24
拾、西方墨點法(Western blotting) 25
第三章 : 結果 27
第一節、細胞株培養 27
第二節、松杉靈芝萃取物對SKOV-3細胞株的影響 27
壹、松杉靈芝萃取物對SKOV-3細胞株形態的影響 27
貳、松杉靈芝萃取物對SKOV-3細胞株移動能力的影響 27
參、松杉靈芝萃取物對SKOV-3細胞株的半數抑制濃度(IC50) 28

第三節、SKOV-3細胞株對松杉靈芝萃取物的基因體生物反應指紋圖譜 28
第四節、以二維電泳、質譜分析及資料庫比對推測松杉靈芝對細胞的影響 29
壹、利用二維凝膠電泳及介質輔助雷射脫附游離飛行時間式質譜
分析投予松杉靈芝甲醇萃取物後表現量有差異的蛋白質 29
貳、匯整比較所有經2D-MS/MASCOT分析所得之蛋白質 30
參、受松杉靈芝甲醇萃取物影響的蛋白質間的相互作用 31
第五節、推測並驗證靈芝萃取物抑制SKOV-3細胞生長之分子機轉 32
壹、以西方墨點法確認松杉靈芝甲醇萃取物能抑制細胞內重要
訊息傳導以及生長相關蛋白質(c-Myc，ERK2，c-Src，HER2)
之表現量 32
貳、松杉靈芝甲醇萃取物抑制SKOV-3細胞生長之可能分子機轉 32
第四章 : 討論 33
第一節、基因體生物反應指紋圖譜分析結果之意義 33
第二節、蛋白質體學研究方法討論 33
第三節、與本實驗結果相關的文獻評析與闡釋 34
第四節、實驗結果釋論 35
第五節、本研究提出的假說 39
第五章 : 結論 41
第六章 : 參考文獻 42
第七章 : 圖表 48
第一節、表 46
第二節、圖 56

附錄 75
附錄一、常見靈芝形態 75
附錄二、神農本草經及本草綱目對靈芝的記載 76
附錄三、靈芝主要成分 77
附錄四、台灣地區常見靈芝一覽表(許瑞祥教授發表) 78
附錄五、靈芝萃取物成分之TLC、HPLC分析鑑定 79
附錄六、細胞株培養方法 80
附錄七、CCK-8 assay實驗設計 82
附錄八、SKOV-3細胞株RNA抽取之品質鑑定(Quality control) 83
附錄九、Affymetrix Chips Service Report 84
附錄十、Genes number by PhytoViewerBR 2.2 processing 91
附錄十一、試劑及緩衝液配製 93
附錄十二、二維凝膠電泳條件 98
附錄十三、GeneGo Meta CoreTM signaling networks legend 99

論文電子檔案上網授權書


表目錄
頁次
表一、利用PhytoViewerBR 2.2分析SKOV-3細胞株投予松杉靈芝萃取物
之Affymetrix人類微陣列基因表現資料進行各組間PSI
(Phytomics Similarity Index) matrix之分析比較 48
表二、Altered protein spots review 50
表三、比對SKOV-3細胞投予靈芝甲醇萃取物後2D-MALDI/TOF
(蛋白質表現) 及 Affymetrix (基因表現) 分析結果 54
表四、2D-MS分析所得蛋白質之功能分類 55


圖目錄
頁次
圖一、實驗流程圖 56
圖二、SKOV-3細胞培養 57
圖2.1、SKOV-3細胞株形態 57
圖2.2、SKOV-3細胞株生長曲線 58
圖三、靈芝(粉末)甲醇萃取流程 59
圖四、靈芝萃取物對SKOV-3細胞株之影響 60
圖4.1、靈芝甲醇及乙醇萃取物對SKOV-3細胞株生長形態之影響 60
圖4.2、創傷癒合試驗(Wound closure assay) 61
圖五、松杉靈芝萃取物對SKOV-3細胞株之半數抑制濃度(IC50)測量 62
圖六、利用PhytoViewerBR 2.2分析SKOV-3細胞株投予松杉靈芝萃取物之
Affymetrix人類微陣列基因表現資料得到生物反應指紋圖譜 63
圖七、二維凝膠電泳及膠體影像分析 65
圖八、利用GeneGo Meta CoreTM繪出各蛋白質相互關係之圖譜 67
圖九、表現量受靈芝甲醇萃取物所改變之生長相關蛋白質相關性網路圖 69
圖十、用西方墨點證明松杉靈芝甲醇萃取物(MeGt)對SKOV-3細胞內
重要訊息傳導以及生長相關蛋白質表現量之影響 70
圖十一、靈芝甲醇萃取物抑制SKOV-3細胞生長之可能分子機轉 74

第六章 : 參考文獻

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