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研究生:陳宥任
研究生(外文):Yu-Jen Chen
論文名稱:TGF-β在細菌影響胰臟癌惡化所扮演的角色
論文名稱(外文):Role of TGF-beta signaling pathway in bacteria-affected pancreatic cancer progression
指導教授:詹明修詹明修引用關係
指導教授(外文):Ming-Shiu Jan
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:生化微生物免疫研究所
學門:生命科學學門
學類:其他生命科學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:72
中文關鍵詞:牙周致病菌胰臟癌轉化生長因子-β
外文關鍵詞:Porphyromonas gingivalisPancreatic cancerTransforming growth factor β
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   胰臟癌是惡性腫瘤之一,五年內存活率只有5-6%,目前缺乏有效的治療。乙型轉化生長因子 (Transforming growth factor-β; TGF-β)為多功能性細胞激素。當TGF-β功能喪失或訊息傳遞異常突變,將導致細胞異常增生、誘導上皮間質轉化 (epithelial-mesenchymal transition; EMT) 及轉移。由流行病學、微生物相及本實驗室動物實驗的研究,牙周致病菌牙齦卟啉菌 (Porphyromonas gingivalis; P.gingivalis) 為胰臟癌的致病因子之一。在動物模式中,我們發現益生菌可抑制小鼠之胰臟癌惡化。本研究主要探討TGF-β訊息路徑是否參與益生菌減少胰臟癌惡化的機制。人類胰臟癌細胞株BxPC-3與P. gingivalis培養液共同作用,我們發現TGF-β訊息路徑相關分子包括TGF-β1, Smad2, Smad3, and Smad4顯著增加,其磷酸化的Smad2和Smad3也增加。而Smad7蛋白顯著降低。為了瞭解TGF-β訊息路徑在P. gingivalis促進胰臟癌進展所扮演的角色,利用LSL-KrasG12D; Pdx-1-Cre (KC) 基因轉殖胰臟癌小鼠口腔塗抹P. gingivalis。一個月後,我們發現TGF-β及其下游訊息分子Smad2,Smad3,Smad4在胰腺細胞的細胞質中明顯增加。另外也發現TGF-β訊息路徑活化之phospho-Smad2和phospho-Smad3則有入細胞核的情況,則Smad7的表現量降低。給予益生菌治療抑制P. gingivalis處理之胰腺細胞TGF-β訊息路徑的活化。已知Smad3會調控PD-1的表現,結果顯示口腔塗抹P. gingivalis使PD-1和PD-L1表現增加,而給予益生菌則抑制PD-1和PD-L1的表現。在BxPC-3與P. gingivalis培養液共同作用,也發現PD-1與PD-L1 (及SHP-2) 蛋白表現增加。綜合以上結果,我們在活體外及活體內的實驗均證實給予P. gingivalis活化TGF-β 與PD-1/PD-L1訊息路徑與胰臟癌的惡化程度呈正相關性。重要的是,益生菌會抑制胰臟癌進展之TGF-β訊息路徑的活化。未來我們將更進一步來了解P. gingivalis和益生菌透過何種機制來調控TGF-β/Smad與PD-1/PD-L1訊息路徑。
Pancreatic cancer is one of the malignant tumors which survival rate is only 5-6% in 5 years, and has no effective therapeutic strategy. Transforming growth factor-β(TGF-β) is a multifunctional cytokine that can inhibit cell growth. Loss of function or mutation of TGF-βwill cause the abnormal proliferation of cells. According the findings through epidemiological studies, microbiota analysis and our animal studies, the periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) may act as a risk factor of pancreatic cancer. We also found that oral administration of probiotics could inhibit pancreatic cancer progression in vivo. In this study, we analyzed whether downregulation of TGF-βsignal pathway play a role of probiotics in the pancreatic cancer suppression. We found that TGF-βsignaling pathway-associated molecules including TGF-β1, Smad2, Smad3, and Smad4 proteins were significantly increased, and phosphorylation levels of Smad2 and Smad3 were increased too. In addition, protein level of Smad7 protein decreased in P. gingivalis culture broth-treated human pancreatic cancer BxPC-3 cells than non-treated cells in vitro. To understand whether the TGF-βsignaling pathway play role in the pathogenesis of P. gingivalis–promoted pancreatic cancer progression, LSL-KrasG12D;Pdx-1-Cre (KC) transgenic pancreatic cancer mice were oral smear periodontal pathogens P. gingivalis. After one month, we found that TGF-βand its downstream signaling molecules Smad2, Smad3, Smad4 were significantly increased in the cytoplasm of pancreatic cells. In addition, nucleus translocation of phospho-Smad2 and phospho-Smad3 through TGF-βsignaling pathway activation were found too. Smad7 protein expression were decreased in pancreatic tissues from P. gingivalis-treated KC mice. On the other hand, probiotic treatment cold reverse the activation of TGF-βpathway by P. gingivalis-treatment. It has been known that Smad3 control immune check point PD-1 expression. Our results indicated that P. gingivalis treatment increased, but probiotics treatment suppressed, PD-1 and PD-L1 protein expressions. The enhancement of protein levels of PD-1 and PD-L1 (also SHP-2) by P. gingivalis treatment were found in P. gingivalis culture broth-treated BxPC-3 cells too. In conclusion, TGF-βand PD-1/PD-L1 pathway activation were observed after P. gingivalis-treatment in vivo and in vitro and it was correlated with the pancreatic cancer progression. More importantly, probiotics administration may reverse the activation of TGF-βpathway in the development process of pancreatic cancer. What are the mechanisms of P. gingivalis and probiotics for regulating TGF-βand PD-1/PD-L1 signal pathway should be clarified in more detail in the future.
中文摘要 I
Abstract II
表目錄 V
圖目錄 VI
縮寫表 VIII
第一章、緒論 1
一、 胰臟癌 (Pancreatic cancer) 1
二、 牙周病 (Periodontal disease) 3
三、 轉化生長因子-β (Transforming growth factor beta,TGF-β) 5
四、 益生菌 6
第二章、研究動機 7
第三章、材料與方法 8
一、 實驗動物 8
二、 DNA電泳 8
三、 牙齦卟啉單孢菌 (Porphyromonas gingivalis, P. gingivalis) 培養 13
四、 P. gingivalis口腔感染 14
五、 小鼠器官處理 17
六、 小鼠胰臟石蠟包埋切片及紫木蘇與伊紅染色法 (委託力沛有限公司處理) 18
七、 免疫組織化學染色 (委託力沛有限公司處理) 20
八、 細胞培養 22
九、 西方墨點法 25
第四章、 實驗結果 33
第五章、 討論 37
第六章、 參考文獻 41

表目錄

附表 一、 Primer sequence 11
附表 二、 PCR reaction mixture for Kras 12
附表 三、 PCR reaction mixture for Cre 12
附表 四、 作用時間及溫度 12
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