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系統識別號 U0026-0812200911125189
論文名稱(中文) 真菌幾丁寡醣之抑癌潛能評估與機轉之探討
論文名稱(英文) Evaluate the anti-cancer potency and related pathways of chitosan oligosaccharides
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 92
學期 2
出版年 93
研究生(中文) 沈坤德
研究生(英文) kun-Te Shen
電子信箱 david.s@ms1.url.com.tw
學號 s7691112
學位類別 碩士
語文別 中文
論文頁數 81頁
口試委員 召集委員-何元順
指導教授-王應然
口試委員-潘敏雄
口試委員-余俊強
中文關鍵字 LLC-bearing mice腫瘤生長與肺轉移模式  SCID mice抗腫瘤生長動物模式  真菌幾丁寡醣  人類肝癌細胞 
英文關鍵字 LLC-bearing mice tumor growth and lung metastasi  SCID mice anti-tumor growth model  Chitosan oligomers  HepG2 cell 
學科別分類
中文摘要   幾丁寡醣(Chitosan oligosaccharides)廣泛存在於甲殼類動物的外骨骼、真菌類、昆蟲與酵母菌的細胞壁中,為幾丁質與幾丁聚醣進一步以化學或酵素法分解而成之無毒性小分子,並且具有低黏度、低分子量及水溶性等特性。由於過去的研究指出幾丁寡醣具有降低膽固醇、抗氧化、增強免疫活性、抗菌及抗腫瘤生長的功能,近年來幾丁聚醣及幾丁寡醣已經成為熱門的健康食品。但由於幾丁寡醣在抗腫瘤生長與抗惡性癌細胞轉移相關機轉的資料目前仍缺乏並有待於進一步的研究。本研究目的為評估由真菌中萃取之真菌幾丁寡醣之抗癌及抗轉移能力及其相關機制之探討。在體外(in vitro)實驗方面,利用MTT assay方法篩選真菌幾丁寡醣對不同癌細胞株抑制生長情形,結果顯示真菌幾丁寡醣抑制人類肝癌細胞(HepG2 cell)生長效果最顯著(抑制能力約達50 %),另外真菌幾丁寡醣於細胞週期中可以抑制S phase,進一步利用BrdU cell cycle analysis assay分析細胞DNA合成之情形,發現HepG2 細胞加入真菌幾丁寡醣後S phase有被抑制之現象,而於西方墨點法分析細胞週期相關蛋白中,cyclin D3、p21及p27表現有上升的趨勢而cyclin A、cyclin B及cdk-2有下降的趨勢;而跟癌症轉移相關的蛋白之ㄧ(MMP-9),其活性也有顯著之下降。在體內(in vivo)實驗方面,在SCID mice抗腫瘤生長動物模式中,高劑量真菌幾丁寡醣略有抑制人類肝癌腫瘤生長之情形。另外在真菌幾丁寡醣抗轉移模式中,利用LLC-bearing mice腫瘤生長與肺轉移(切除或不切除腫瘤)這兩種模式來評估真菌幾丁寡醣是否具有抗癌症轉移之能力,不論是切除或不切除腫瘤模式中,隨著劑量之上升,初期原發性腫瘤體積及肺轉移之程度有下降趨勢。結果顯示,真菌幾丁寡醣可能於癌症之化學預防具有其潛在抗癌之能力。
英文摘要   Chitosan oligosaccharides are widely present in the exoskeleton of crustaceans and in cell walls of fungi, insects and yeast. There are nontoxic oligomers derived from chitin and chitosan by either chemical or enzymatic hydrolysis. Previous studies indicated that chitosan oligosaccharides have ability to lower hyperlipidaemia, antioxidant, immuno-enhancing effects, antifungal and anti-tumor activity, making it becoming a popular healthful food in the past few years. So far, the mechanisms of anti-tumor growth and anti-metastasis of malignant cells by chitosan oligosaccharides are unclear and needed further investigation. In the present works, the in vitro and in vivo studies were designed to evaluate the anti-cancer potency and related pathways of chitosan oligosaccharides. In in vitro studies, we found that chitosan oligosaccharides significantly inhibited human hepatocellular carcinoma (HepG2 cells) proliferation by using MTT assay. Flow cytometry analysis of cell cycle distribution indicated that the percentage of S phase reduced in cells treated with chitosan oligosaccharides. In addition, BrdU incorporation assay revealed a decreased DNA synthesis rate in chitosan-treated HepG2 cells. Cell cycle-related gene expression were analyzed by western blot and the results indicated that cyclin D3, p21 and p27 were up-regulated, while the cyclin A, cyclin B and cdk-2 were down-regulated. Moreover, we also found that the activity of one of metastasis related proteins (MMP-9) could be inhibited in LLC cells . In in vivo studies, we also found that chitosan oligosaccharides inhibited the growth of HepG2 xenografts in SCID mice. In LLC-bearing mice tumor growth and lung metastasis model, tumor volume in early stage and lung colonies could be inhibited by chitosan oligosaccharides. Our results suggest a potential anti-cancer potency of chitosan oligosaccharides in caner chemoprevention.
論文目次 中文摘要..........................................................I
Abstract..........................................................II

第一章、緒論......................................................1
第一節、研究動
機..................................................1

第二章、文獻回顧..................................................2
第一節、幾丁質、幾丁聚醣與幾丁寡醣簡介............................2
第二節、癌症之化學預防............................................3
第三節、幾丁寡醣之生理活性........................................4
第四節、幾丁寡醣之安全性及副作用..................................5
第五節、細胞週期之調控............................................5
第六節、SCID mice腫瘤誘發模式(SCID mice xenograft model)........6
第七節、癌症之轉移及MMPs所扮演之角色..............................7
第八節、癌細胞誘發肺臟轉移模式
(Lewis lung carcinoma metastasis model).........................8

第三章、研究目的及重要性..........................................10

第四章、研究架構..................................................11
第一節、細胞實驗(In vitro)......................................12
第二節、動物實驗(In vivo).......................................15

第五章 研究材料與方法.............................................17
第一節、研究材料..................................................17
I、藥品試劑.......................................................17
II、常用儀器......................................................18
III、常用溶液.....................................................19
第二節、研究方法..................................................21
I、體外實驗(In Vitro)...........................................21
(一)細胞解凍步驟................................................21
(二)細胞繼代培養步驟............................................21
(三)細胞冷凍步驟................................................22
(四)細胞計數....................................................23
(五)細胞存活率偵測分析(MTT assay).............................23
(六)細胞週期DNA分析(Flow cytometry).............................24
(七)BrdU細胞週期分析............................................25
(八)蛋白質電泳分析..............................................26
(九)Gelatin Zymography assay....................................30
II、體內實驗(In Vivo)...........................................32
(一)SCID mice腫瘤誘發實驗.......................................32
(二)LLC-bearing mice之腫瘤誘發肺轉移實驗........................33
(1)移除腫瘤模式..................................35
(2)未移除腫瘤模式................................35
III、統計分析.....................................................36

第六章、實驗結果..................................................37
第一節、利用MTT assay方法篩選真菌幾丁寡醣對不同癌細胞株
抑制生長情形..............................................37
第二節、真菌幾丁寡醣對HepG2細胞細胞週期之影響.....................37
第三節、真菌幾丁寡醣對HepG2細胞DNA合成之影響......................38
第四節、真菌幾丁寡醣對HepG2細胞調控細胞週期相關蛋白表現之影響.....38
第五節、利用SCID小鼠抗腫瘤生長模式評估真菌幾丁寡醣抗
HepG2腫瘤生長之潛能.......................................39
第六節、真菌幾丁寡醣對LLC細胞存活率之影響.........................40
第七節、利用LLC-bearing mice腫瘤生長與肺轉移(移除腫瘤模式)
評估真菌幾丁寡醣之抗轉移能力..............................40
a.實驗過程小鼠體重變化及健康狀況..................................40
b.真菌幾丁寡醣抑制腫瘤生長之情形..................................40
c.真菌幾丁寡醣抑制肺轉移及影響存活時間之結果......................41
第八節、利用LLC-bearing mice腫瘤生長與肺轉移(未移除腫瘤模式)
評估真菌幾丁寡醣之抗轉移能力..............................41
a.實驗過程小鼠體重變化及健康狀況..................................41
b.真菌幾丁寡醣抑制腫瘤生長的情形..................................42
c.真菌幾丁寡醣抑制肺轉移及影響存活時間之結果......................42
第九節、真菌幾丁寡醣對LLC細胞MMP-2及MMP-9活性之影響...............43

第七章、討論......................................................44
第八章、結論及建議................................................49
第九章、參考文獻..................................................50
附錄..............................................................60
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