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研究生:張以潔
研究生(外文):Yi-Chieh Chang
論文名稱:奧美拉唑誘導內質網壓力及自噬作用在大腸癌機轉之探討
論文名稱(外文):Exploiting Omeprazole Exhibits Anti-tumor Activity via Targeting Endoplasmic Reticulum Stress and Autophagy in Colorectal Cancer
指導教授:許美鈴許美鈴引用關係
口試委員:劉興華陳百昇
口試日期:2016-07-19
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:57
中文關鍵詞:大腸癌奧美拉唑STAT3TCPTP腹膜轉移
外文關鍵詞:Colorectal cancerOmeprazoleSTAT3TCPTPPeritoneal dissemination
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  • 下載下載:17
  • 收藏至我的研究室書目清單書目收藏:0
目前在所有癌症中大腸癌的死亡率高居第二,今年的統計數據更顯示台灣人的大腸癌發生率是世界第一,可見大腸癌治療的重要性與迫切性。近期在藥物研究的發展讓我們發現質子幫浦抑制劑(Proton pump inhibitor, PPI)有多樣的生物活性與藥理特性,有別於過往在臨床上治療胃潰瘍的功能。在本研究中指出,一種典型的PPI──奧美拉唑(Omeprazole, OMP)具抗腹膜轉移和抗腫瘤發生的特性,有潛力開發成新的抗癌藥物。動物實驗結果顯示,在免疫缺陷鼠中植入大腸癌細胞並透過PET/CT影像與組織切片染色觀察腫瘤生長情形,以口服方式給予OMP進行治療的動物組別可看到腫瘤生長被抑制、腹膜轉移與器官轉移情形改善。在細胞實驗中,OMP能抑制人類大腸癌細胞的增殖,並增強細胞凋亡。此外,OMP會活化去磷酸酶T細胞酪胺酸磷酸酶(T cell protein tyrosine phosphatase, TCPTP),造成信號轉導和轉錄激活因子3 (Signal transducer and activator of transcription, STAT3)的去磷酸化進而抑制STAT3的活性,由免疫沉澱與共軛焦顯微鏡影像觀察到TCPTP與p-STAT3之間的蛋白質交互作用。以西方墨點法觀察細胞蛋白質表現,可看到OMP激活內質網壓力,並誘導自噬作用發生,相關的生物標靶表現量增加。用shRNA基因靜默TCPTP的表現後,恢復STAT3/上皮細胞轉型成間質細胞(Epitheilia-to mesenchymal, EMT)所引發的腹膜轉移與器官癌轉移。令人驚喜的是,經由TCPTP的活化與STAT3的去磷酸化,OMP也可顯著抑制發炎相關的大腸腫瘤生成。這些一致的結果支持OMP作為一個潛在的候選藥物,能阻斷腫瘤進程,並在大腸癌的治療中具有臨床應用潛力。

Highly mortality of colorectal cancer is a second leading cause of cancer-related deaths in the world. Recent development in drug discovery has highlighted the diverse biological and pharmacological properties of proton pump inhibitors (PPIs). In this study, we characterized the anti-peritoneal dissemination and tumorigenesis activities of a novel omeprazole (OMP), which are typical PPIs effort to develop novel antitumor inhibitors. OMP inhibited peritoneal dissemination and organ metastasis in in vivo mouse xenograft models by PET/CT imaging and histology examination. OMP suppressed cell proliferation and enhanced apoptosis in vitro. In addition, OMP specifically inhibited the phosphorylations of STAT3 via T Cell Protein Tyrosine Phosphatase (TCPTP), a phospho tyrosine-specific protein phosphatase in colorectal cancer cells, but not PP2A, PTP1B or SHP-1/2. OMP induction magnified p-STAT3/ TCPTP interaction by immune-precipitation and confocal microscope image. OMP caused an increased in TCPTP phosphatase activity, along with Endoplasmic Reticulum (ER) stress activation and autophagy induction. Identify the specific ER stress or autophagy protein biomarker via western blotting abreast of the study. Gene silencing of TCPTP restored STAT3/ epithelial-mesenchymal transition (EMT)-induced peritoneal dissemination and organ metastasis axis. Surprisingly, OMP also significantly thwarted inflammation-associated colon tumorigenesis by endoscope image and histology analysis via de-phosphorylations of STAT3 and promoted TCPTP expression mechanism. These consistent results support the role of OMP as a potential drug candidate, blocked tumor progression and warrant the clinical development in the treatment of colorectal cancer.

中文摘要…………………………………………………………………..…i
英文摘要……………………………………………………………….……ii
目次……………………………………………………………………………iii
圖目次………………………………………………………………….……vi
第一章、 前言………………………………………………………….……...1
一、 奧美拉唑(Omeprazole, OMP) ………………………………………..1
二、 大腸直腸癌(Colorectal Cancer) ……………………………….……...1
(一) 流行病學……………………………….……………………………1
1. 飲食與生活習慣……………………………….…………………...1
2. 年齡與性別……………………………….…………………..……2
3. 遺傳因素…………………………………………………..……….2
4. 炎症性腸病(Inflammatory Bowel Disease, IBD) …………………2
(二) 篩檢方式…………………………………………………….……..2
1. 糞便潛血檢查…………………………..…….……………….……2
2. 大腸內視鏡……………………….……….……………….…….…2
3. 其他檢查………………………….…….…………….…………….2
(三) 治療方式……………………………….……………….…………2
三、 內質網壓力(Endoplasmic Reticulum Stress) …………………………3
四、 自噬作用(Autophagy) ……………..…………………………..……..3
(一) 自噬作用之分子機轉………..……………………………………..3
(二) 自噬作用與癌症…………..…………………….…………….…..4
五、 STAT3(Signal Transducer and Activator of Transcription 3) …………4
(一) STAT3的結構………………………………….………………..…..4
(二) STAT3的磷酸化……………………………….………….…….…..4
(三) STAT3與癌症……………………………….…………….…….…..5
六、 TCPTP(T Cell Protein Tyrosine Phosphatase) ………….………………5
(一) TCPTP與訊息傳導……………………………….……..…………..5
(二) TCPTP與癌症……………………………………………..….……..5
七、研究動機…………………………………………………..….……..5
第二章、 材料與方法……………………………….……………….……..7
一、實驗儀器……………………………………..…………….…….……..7
二、實驗材料…………………………………………………...…….……..7
(一) 常用緩衝溶液:附表一……………………………….……………50
(二) 實驗試劑:附表二……………………………….…………………52
(三) 實驗藥品:附表三……………………………….…………………53
(四) 實驗抗體:附表四……………………………….…………………56
(五) PCR primer:附表五……………………………….……………….57
三、 實驗方法……………………………………………………...……..7
(一) 細胞培養(Cell Culture) …………………………………...….……..7
(二) 細胞增生試驗(MTT Assay) ………………………………...……..8
(三) 蛋白質萃取(Protein Extraction) ………………………..…..……….8
(四) 西方墨點法(Western Blot) …………………………..….….……..8
(五) 免疫螢光染色(Immunofluorescence Stain) …………..……………8
(六) 免疫沉澱法(Immunoprecipitation) …………………..………..…9
(七) 去磷酸酶活性分析(Phosphatase Activity) ………..….…………9
(八) 流式細胞儀分析(Flow Cytometry) …………………..………….…9
(九) 細胞核質蛋白分離萃取(Nuclear/ Cytosol Protein Extraction)…...10
(十) 核酸干擾技術(RNA Interference) ……………………...…………10
(十一) 動物實驗(Animal Experiment)………………….………………10
   1. 異種移植動物模型(Xenograft Animal Model)…..………………10
    2. 結腸炎相關大腸癌動物模型
(Colitis-Associated Colon Cancer Animal Model, CAC)..………….10
(十二) 糞便潛血反應檢測(Feces Occult Blood Test, FOBT) ……………11
 (十三) 動物用細徑內視鏡…………………………………………...…11
(十四) 動物組織蛋白萃取……………………………………….…..…11
(十五) 蘇木素-伊紅染色(Hematoxylin and Eosin Stain, H&E stain).......11
(十六) 免疫組織染色(Immunohistochemistry Stain, IHC)……………..11
(十七) 免疫組織螢光染色
(Immunofluorescence Staining of Paraffin Section)………….….12
(十八) 核酸萃取(RNA extraction) ……………………………...……..12
(十九) 反轉錄聚合酶連鎖效應(Reverse Transcription-PCR)………...12
(二十) 聚合酶連鎖效應(Polymerase Chain Reaction)…………..……..12
(二十一) 電泳移動率試驗
(Electrophoretic Mobility Shift Assay, EMSA)…………..……...13
(二十二) 染色質免疫沉澱法
(Chromatin Immunoprecipitation, ChIP Assay)……………....13
第三章、 實驗結果………... ………... ………... ………... ………... ……….14
一、 奧美拉唑抑制小鼠體內腫瘤生長並改善腹膜轉移與器官轉移……14
二、 奧美拉唑抑制大腸癌細胞增生並引起細胞週期G2/M停滯 ……14
三、 奧美拉唑增加TCPTP活性並造成p-STAT3之去磷酸化……..14
四、 奧美拉唑誘導大腸癌細胞內質網壓力與自噬作用的形成………15
五、 抑制內質網壓力可回復奧美拉唑誘導的p-STAT3去磷酸化………15
六、 抑制自噬作用可減緩大腸癌細胞的抗藥性………………………16
七、 基因靜默TCPTP會恢復p-STAT3…………………………………16
八、 奧美拉唑影響EMT並透過STAT3調控MET表現………….16
九、 以組織學觀察奧美拉唑改善裸鼠體內腫瘤生長與轉移情形…..…17
十、 奧美拉唑可抑制炎症相關大腸癌(CAC)的腫瘤生長…………….…17
十一、 總結………………………………………………………………….18
第四章、 討論………………………………………………………………..19
第五章、 參考文獻…………………………………………………………...23
結果圖表…………………………………………………………………….. .29
附錄表………………………………………………………………………... 50


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