臺灣博碩士論文加值系統

大腸直腸癌盛行於已開發國家，近年來國內大腸直腸癌發生率逐年攀升，已成為國人發生人數最多的癌症。研究指出大腸直腸癌的發生與飲食型態有密切關係，目前主要的保健飲食建議為降低脂質及增加蔬果攝取量。蔬菜與水果富含多種膳食纖維、維生素、礦物質及植化素，大部分研究認為高蔬果飲食可降低罹患大腸直腸癌風險。考量國人近年飲食西化，脂質攝取量明顯增加，因此本研究以預防之觀點，透過微陣列分析於高脂飲食下個別探討攝食國人常食用之白色蔬果對小鼠大腸黏膜基因表現之影響，藉由基因表現差異評估對腸道保健之可能效益。實驗動物選用非近親交配品系雄性ICR小鼠，依照飼料組成分為六組：高脂組（HF）、高脂荔枝組（HFL）、高脂龍眼組（HFO）、高脂芭樂組（HFG）、高脂冬瓜組（HFW）及Chow diet組（Chow），高脂飼料提供脂質熱量百分比為30%，高脂蔬果組則於高脂飼料中添加10%蔬果乾粉。各組餵食四週後犧牲，採集大腸黏膜總RNA進行微陣列分析與執行Q-PCR加以驗證；採集血液與肝臟分析三酸甘油酯、膽固醇與維生素C濃度。高脂冬瓜組之體重增加與肝臟三酸甘油酯濃度低於高脂組與高脂水果組，然而高脂組與高脂蔬果組於攝食量無顯著差異。微陣列分析結果顯示，與低脂Chow組比較，高脂組小鼠大腸黏膜中於參與免疫反應、反應氧化壓力、細胞增生、細胞凋亡及脂質代謝相關等基因之表現量增加；與高脂組相比，高脂蔬果組小鼠大腸黏膜中於參與免疫反應、反應氧化壓力、細胞增生、細胞凋亡及脂質代謝相關等基因之表現量減少。Q-PCR驗證可見，高脂組大腸組織中發炎指標cyclooxygenase-2（COX-2）、細胞增生指標Ki-67基因表現量高於Chow組與高脂蔬果組。攝食高脂飲食會增加小鼠大腸環境中之免疫反應、細胞增生、細胞凋亡、脂質代謝與反應氧化壓力相關基因表現，顯示高脂飲食對大腸健康具較負面影響；於高脂飲食下攝取白色蔬果則與高脂飲食基因表現呈現相反結果，顯示攝取白色蔬果可改變高脂影響的趨勢，其中以冬瓜最具潛力。

Colorectal cancer (CRC) has become especially prevalent in developed countries. CRC has the highest incidence since 2006 in Taiwan and now is the 3rd leading cause of cancer death. Study evidence has suggested a close association between development of CRC and dietary patterns. To reduce the risk, dietary recommendations emphasize that low-fat and high-fruits and vegetables diet. In general, fruits and vegetables contain abundant mixture of disease-preventing substances including vitamins, minerals, dietary fiber and phytochemicals and the majority of epidemiological evidence supporting the high-fruits and vegetables diet is related to decreased risk of CRC. In recent years, human dietary pattern will incline to be more westernized, especially higher intake of fat. Therefore, we investigated the effect high-fat diets containing white fruits and vegetable on gene expression of colonic mucosa in ICR mice using DNA microarray technology. Male ICR mice of outbred strain were purchased from BioLASCO Taiwan Co., Ltd.
They were randomized by body weight into six experiment groups：a high-fat 93G (HF), a high-fat litchi group (HFL), a high-fat longan group (HFO), a high-fat guava group (HFG), a high-fat wax gourd group (HFW), and chow diet (Chow). A high fat basal diet (14.4% oil, 30 % Kcal from fat) was modified from AIN-93G. Fruits and vegetable experimental diets were prepared by adding lyophilized food powder to basal diet at 10% wt and adjusting the macronutrient contents to reach similar energy density.After feeding for four weeks, mice were killed by CO2 asphyxiation. Total RNA of colonic mucosa was extracted from each mice and pooled RNA sample corresponding to experiment group were subjected to Agilent Mouse Whole Genome Oligo Microarray assay using One-color Microarray hybridization protocol. Then, Q-PCR was used to validate the microarray results. The liver and serum was collected for analysis of triglyceride, cholesterol and vitamin C. The W group had lower weight gain and liver triglyceride level than HF93G and high-fat fruits groups. However, daily food intakes, estimated energy intake showed no significant difference among the HF93G and high-fat fruits and vegetable groups. Gene expression were increased in HF93G compared to Chow group, including related function to immune response, oxidative stress response, cell proliferation, cell apoptosis, and lipid metabolism. Gene expression were decreased in high-fat fruits and vegetable groups compared to HF93G group, including related function to immune response, oxidative stress response, cell proliferation, cell apoptosis, and lipid metabolism. Cyclooxygenase-2 (COX-2) and ki67 gene expression of individual mice was measured by Q-PCR and showed HF93G group had higher than Chow and high-fat fruits and vegetable groups. Collectively, these data suggest that consumption of a high-fat diet interferes with biological function involving colonic immune response, oxidative stress response, cell proliferation, cell apoptosis, and lipid metabolism, and may exert a proinflammatory stimulus in the colon.The white fruits and vegetables may be beneficial in decreasing adverse effect of high-fat diet.

口試委員審定書. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
謝誌. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ii
中文摘要. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii
英文摘要. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv
縮寫對照表. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
第一章 引言. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
第二章 文獻回顧. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
第一節 大腸直腸癌之流行病學. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
第二節 大腸直腸癌致癌機轉. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
一、遺傳性大腸直腸癌. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
二、大腸炎相關的大腸直腸癌. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
三、自發性大腸直腸癌. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
第三節 飲食型態與大腸直腸癌. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
一、脂質攝取對大腸直腸癌之影響. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
二、蔬果攝取對大腸直腸癌之影響. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
第四節 選定白色食材之成分與功效. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
第五節 評估大腸保健之動物研究模式. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
第六節 DNA微陣列技術. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
第三章 材料與方法. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
第一節 研究設計. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 18
第二節 實驗材料. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
一、食材與飼料成份. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
二、藥品與試劑. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
三、試劑配製. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
四、儀器. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24
第三節 實驗方法.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
一、實驗動物. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
二、飼養環境與動物分組. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
　 三、飼養流程. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
四、實驗飼料. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
（1）蔬菜與水果乾燥粉末製程. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..26
（2）飼料配製. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
五、動物犧牲與樣品收集. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
六、血清與肝臟之三酸甘油酯與膽固醇濃度測定. . . . . . . . . . . . . . . . . . . . . . 30
（1）血清三酸甘油酯濃度測定. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
（2）血清膽固醇濃度測定. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
（3）肝臟三酸甘油酯與膽固醇濃度測定. . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
七、血清總維生素C濃度測定. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
八、大腸組織固定與組織切片. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .33
九、Ki-67單株抗體之大腸免疫組織化學染色. . . . . . . . . . . . . . . . . . . . . . . . . 33
十、大腸組織免疫染色定量. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
十一、大腸黏膜RNA萃取. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
（1）RNA萃取流程. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
（2）RNA定量與品質確認. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
十二、DNA微陣列晶片實驗（DNA microarray）. . . . . . . . . . . . . . . . . . . . . . . 36
（1）實驗設計. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
（2）實驗流程. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37
（3）微陣列實驗結果分析– Gene Spring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
（4）微陣列實驗生物功能性結果分析– Gene Ontology（GO）. . . . . . . . . . 38
十三、定量即時聚合酶鏈鎖反應（Quantitative real time polymerase chain
reaction, Q-PCR）. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
（1）反轉錄反應. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38
（2）引子設計. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39
（3）Q-PCR實驗操作程序. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
（4）引子效率分析. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41
十四、統計分析. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

第四章 結果. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43
第一節 含白色蔬果之高脂飲食對小鼠生理狀況的影響. . . . . . . . . . . . . . . . . . .43
一、體重變化、攝食量與飼料利用率. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43
二、組織重量與組織相對重量. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44
三、血清與肝臟之三酸甘油酯與總膽固醇濃度. . . . . . . . . . . . . . . . . . . . . . . .44
四、血清總維生素C濃度. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
五、組織免疫染色. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
第二節 高脂飲食對小鼠個體生理狀況之影響. . . . . . . . . . . . . . . . . . . . . . . . . . .46
第三節 高脂與含白色蔬果之高脂飲食對小鼠大腸基因表現的影響. . . . . . . . .47
一、基因表現變化. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 47
二、基因之生物性功能分析. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
三、Myc、COX-2、Ki-67與Nrf2基因表現變化. . . . . . . . . . . . . . . . . . . . . .50
第五章 討論. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
第一節 高脂與含白色蔬果之高脂飲食對小鼠生理狀況的影響. . . . . . . . . . . . 120
一、攝食不同脂質含量之飼料對小鼠生理狀況之影響. . . . . . . . . . . . . . . . . 120
二、攝食高脂水果飼料對小鼠生理狀況之影響. . . . . . . . . . . . . . . . . . . . . . . 120
三、攝食高脂冬瓜飼料對小鼠生理狀況之影響. . . . . . . . . . . . . . . . . . . . . . . 121
四、體重差異對高脂組小鼠生理狀況之影響. . . . . . . . . . . . . . . . . . . . . . . . . 122
五、蔬果飲食對小鼠血清維生素C濃度之影響. . . . . . . . . . . . . . . . . . . . . . .122
第二節 高脂與含白色蔬果之高脂飲食對小鼠大腸基因表現的影響. . . . . . . . 123
一、免疫反應相關基因. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
二、反應氧化壓力相關基因. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
三、細胞增生與凋亡相關基因. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
四、脂質代謝相關基因. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
五、綜合討論. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
第三節 組內小鼠成長概況對本實驗結果之影響. . . . . . . . . . . . . . . . . . . . . . . . 127
第四節 實驗限制. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
第五節 結論. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
第六章 參考文獻. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
附錄一 動物實驗申請案審查同意書. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
附錄二 Lab diet 5001飼料組成. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147　附錄三 RNＡ品質確認. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
附錄四 每對引子之效率與熔解度曲線分析. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

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