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系統識別號 U0026-1607202001280500
論文名稱(中文) 飲食中之天然化合物抑制結腸直腸癌形成過程及惡性結腸直腸癌細胞生長之機制探討
論文名稱(英文) Investigating the molecular mechanisms of natural dietary compounds in inhibiting colorectal carcinogenesis and malignant colorectal tumor growth
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 108
學期 2
出版年 109
研究生(中文) 吳家慶
研究生(英文) Jia-Ching Wu
電子信箱 wujiaching@gmail.com
學號 S78001026
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-王應然
共同指導教授-潘敏雄
召集委員-羅至佑
口試委員-何元順
口試委員-黃步敏
口試委員-郭靜娟
口試委員-吳炳慶
中文關鍵字 結腸直腸癌  食品汙染  植化素  化學預防  細胞凋亡  細胞自噬  多環芳香烴  多甲氧基類黃酮  腸道菌相  原鈣黏附蛋白  表觀遺傳學 
英文關鍵字 Colorectal cancer  food contamination  phytochemical  chemoprevention  apoptosis  autophagy  PAH  PMFs  gut microbiota  protocadherin  epigenetics 
學科別分類
中文摘要   結腸直腸癌(colorectal cancer,CRC)已知為現今全球癌症主要死因之一。流行病學研究證實,CRC的形成與環境因素和生活習慣具有密切關聯性。而環境及工業汙染物因其具廣泛分佈的特性,於日常生活中難以避免與其接觸。近十年來,因發現食品汙染(特別是來自於環境中之汙染物)提高了化學汙染物誘發CRC的風險,因而食品汙染議題逐漸受到重視。天然化合物,又稱植化素(phytochemicals)因具多種有益於預防疾病及抑制化學致癌之功效,亦被當作化學預防試劑。而化學預防試劑常以誘發細胞凋亡(apoptosis)及細胞自噬(autophagy)之計畫性細胞死亡(programmed cell death,PCD),抑制癌細胞生長。
  多環芳香烴(polycyclic aromatic hydrocarbons,PAHs)為普遍存在環境中之致癌物,亦為常見的食品汙染源,並若經由日常飲食中攝入PAHs,將大幅提高CRC的好發風險。本研究第一部分將評估小鼠飲食中補充多甲氧基類黃酮(polymethoxyflavones,PMFs)對於抑制苯並[a]芘合併硫酸葡聚醣(benzo[a]pyrene/ dextran sulfate sodium,BaP/DSS)誘發CRC形成之功效及機轉。我們發現PMFs顯著預防BaP/DSS誘發結腸直腸腫瘤形成。並且PMF餵食組透過調節BaP之代謝產物,有效減少腸道組織中之BaP致癌性代謝物及DNA鍵結物(DNA adduct)的含量。於分子機轉層面,mRNA定序結果顯示PMFs改善了BaP/DSS所造成之分子機轉異常現象,其包含了抑制發炎反應、增加抗氧化相關標的和壓制癌細胞轉移相關基因等,並且改善了细胞自噬缺陷(autophagic defect)现象。此外,攝食PMFs亦有助於調整腸道菌相組成,使其與控制組之腸道菌相組成相似,並增加產丁酸酸益生菌之比例與減少CRC相關之有害菌之含量。此結果顯示日常飲食攝取PMFs將有助於預防BaP/DSS所誘發之結腸直腸癌致癌現象。
  於本研究第二部分,我們加以探討烯丙基硒半胱胺酸(Se-allylselenocysteine, ASC)之天然物誘導人類結腸直腸腺癌細胞株HT-29產生PCD,及表現原鈣黏附蛋白17(protocadherin 17,PCDH17)之相關分子機制。首先我們利用細胞自噬抑制劑,證實ASC具有透過誘導autophagy產生細胞毒性,進而抑制腺癌細胞株HT-29生長的能力。亦發現ASC誘導autophagy的同時,能藉由減少PCDH17啟動子之甲基化程度,進而提高PCDH17表現量。隨後我們利用轉染PCDH17 shRNA及其過度表現質體,發現PCDH17於ASC所誘導之autophagy中扮演重要的角色。我們亦以西方墨點法確認ASC主要經由AMPK/mTOR路徑誘導autophagy形成,並同時調控PCDH17的蛋白質表現。此外,我們亦利用HT-29異種移殖植模式(xenograft),證實於體內實驗中ASC亦具有透過autophagy抑腫瘤生長之活性。
英文摘要 Colorectal cancer (CRC) is one of the major causes of cancer-related mortality in both men and women worldwide. Epidemiological studies demonstrated that environmental and lifestyle factors have been strongly associated with CRC development. Environmental and industrial pollutant are difficult to avoid given their ubiquity in our global society. During the recent decade, food contamination (partially derived from environmental contaminants) has become increasingly serious matters as these factors elevate the risk of chemical contaminant-induced CRC. Natural dietary compounds, also called phytochemicals, chemopreventive agents exhibited several beneficial effects for the prevention of disease and the inhibition of chemically-induced carcinogenesis. Of note, the majority of cancer chemopreventive agents inhibit cancer growth by activating programmed cell death (PCD) mechanisms such as apoptosis and autophagy.
Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are pervasive in the environment and are a potential source of food contamination, with their ingestion via dietary sources greatly increasing CRC risk. The aim of the first part of this study is to evaluate the mechanism and efficacy of polymethoxyflavones (PMFs) supplementation on the colorectal development in benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMF-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including inhibited inflammation, activated anti-oxidation targets, suppressed metastasis genes and ameliorate autophagic defect. Additionally, consumption of PMFs also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.
In the second part, we investigated the underlying molecular mechanisms of Se-allylselenocysteine (ASC)-induced PCD and protocadherin 17 (PCDH17) expression in human colorectal adenocarcinoma HT-29 cell lines. The autophagic cell death is the cause in ASC-induced cytotoxicity that was inhibited by pretreatment with autophagy inhibitor. At the molecular level, ASC induced PCDH17 expression through decreased PCDH17 promoter hypermethylation. PCDH17 is also an important role in ASC-induced autophagy by HT-29 transfected with PCDH17 shRNA or expression plasmid. Our western blot analysis showed that ASC significantly induced autophagy via the AMPK/mTOR pathway that was also regulated PCDH17 expression. Additionally, we used the HT-29 tumor xenograft models to confirm the ability of ASC inhibited tumor growth. These results reveal that ASC is an effective inducer of autophagy through regulating the AMPK/mTOR and PCDH17 expression via epigenetic modification.
論文目次 Contents
博士論文口試合格證明 I
中文摘要 II
Abstract V
致謝 VII
Publication list XVII
Introduction 1
1. Relationship between environmental pollution and colorectal cancer 1
2. Bioactivation/detoxification of xenobiotics 2
3. Development of colorectal carcinogenesis 4
4. Cancer chemoprevention by phytochemicals 5
4.1 Polymethoxyflavones (PMFs) 6
4.2 Selenium (Se)-conjugated compounds 7
Objective 9
Materials and Methods 10
1. Reagents 10
2. Cell culture 10
3. Animals & experimental procedure 10
3.1. BaP/DSS-induced colorectal tumorigenesis 10
3.2. HT-29 tumor xenograft models 11
4. Cell viability assay 12
5. Detection of cell cycle distribution and apoptotic ratio 12
6. Detection and quantification of AVOs during autophagy formation 12
7. Monodansylcadaverine (MDC) staining 13
8. Measurement of global DNA methylation 13
9. Semi-quantitative reverse transcription–polymerase chain reaction (RT-PCR) 13
10. Bisulfite treatment and methylation-specific PCR (MSP) 14
11. Transfection of short-hairpin RNA (shRNA) or expressing plasmid 14
12. Western blot analysis 15
13. Immunohistochemical analysis (IHC) 15
14. BPDE–DNA adduct determination by ELISA kit 16
15. Detection of BaP metabolites from faeces by UPLC/MSMS 16
16. Quantification of mRNA expression by real-time PCR and targeted RNA sequencing 17
17. Taxonomic classification of gut microbiota by next generation sequencing 18
18. Statistical analysis 18
Experimental design 19
Part 1. Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate-induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice 19
Part 2. Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal denocarcinoma cells 20
Results 21
Part 1. Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate-induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice 21
1.1 Orally administrated PMFs prevent BaP/DSS-induced colorectal tumorigenesis 21
1.2 PMFs decreased BPDE-DNA adduct formation in colon tissue through modulated BaP metabolism 22
1.3 Comprehensive overview of how gene expression change from PMFs prevents BaP/DSS-induced colorectal carcinogenesis 23
1.4 Inducing defective autophagy may be an important role in BaP/DSS-induced colorectal carcinogenesis independent of the Wnt/β-catenin pathway 24
1.5 PMFs altered the composition of gut microbiota similar to control group and increased butylate-producing probiotics 26
Part 2. Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells 27
2.1 Inhibition of cancer cell growth in ASC- and MSC-treated colorectal cancer cell lines 27
2.2 Autophagy plays a mechanism in ASC-induced cytotoxic cell death 27
2.3 ASC induce tumor suppressor gene PCDH17 expression through decrease the PCDH17 promoter hypermethylation 29
2.4 ASC induces the expression of autophagy biomarkers through modulation of the AMPK signaling pathway 30
2.5 ASC inhibits tumor growth in HT-29 xenograft models 30
Discussion 32
Part 1. Study discussion 32
Part 2. Study discussion 34
Conclusion 38
Reference 40
Tables and Figures 53
Appendix 109 
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