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研究生:郭子雷
研究生(外文):Tzu-Lei Kuo
論文名稱:探討APC基因在胰臟癌形成與惡化中所扮演的角色
論文名稱(外文):Investigation of APC gene functional roles in pancreatic cancer initiation and progression
指導教授:鄭光宏鄭光宏引用關係
指導教授(外文):Kuang-hung Cheng
學位類別:博士
校院名稱:國立中山大學
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:英文
論文頁數:123
中文關鍵詞:胰臟癌APC黏液性囊泡腫瘤p53單股缺失立體腫瘤球轉移小鼠模式
外文關鍵詞:HaploinsufficiencyMucinous cystic neoplasmsp53APCPancreatic cancermetastasismice modeltumor organoid
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Chapter Ⅰ
抑癌基因APC為家族性大腸瘜肉症中的致病基因,其調控WNT訊息傳遞並且參與許多腸胃消化道中癌症的發生。在此我們首先在小鼠胚胎發現APC的表達會調控胰島細胞的發育與成熟,並開發出一種非kras突變所誘導的胰臟癌小鼠模式。在此小鼠模式中,專一性利用APC的單股缺失搭配p53基因剃除會發展出胰臟腺癌前病灶-黏液性囊泡腫瘤。透過組織切片染色分析在小鼠胰臟病灶中發現大量分泌黏液素以及圍繞著卵巢樣間質細胞,其像似於人類黏液性囊泡腫瘤的特徵並且在約30%小鼠中會進一步惡化轉移到肝臟與胃部。此研究主要臨床意義在於找出WNT訊息傳遞可用在人類黏液性囊泡腫瘤中新的治療策略。
Chapter Ⅱ
胰臟癌是現有人類罹患的惡性腫瘤當中最致命與最具侵襲性之癌症且難以診斷以及預後不佳的一種,因此發展胰臟癌的研究模式極為重要。在此研究中我們利用基因改造小鼠去探討kras 活化所誘發的胰臟早期病變並搭配抑癌基因APC 和p53 的突變所產生的胰臟癌。在這個模式中,在小鼠胰臟很早期就會產生PanIN的病變且快速惡化成胰臟腺癌進一步侵犯其他組織與轉移到其他器官。在小鼠全基因譜分析中我們發現APC 的突變會調高runx3 基因的表現以及下游SPP1 和COL6A1 的活化進而導致癌細胞的侵襲性增加與轉移。另外我們利用此小鼠產生的胰臟癌去建立類器官的立體腫瘤球模擬真實活體中的情形,在此模式中PKA53 立體腫瘤球發展出具侵襲性的指狀分肢以及病理特徵,其類似於在活體小鼠中所發生的情形,因此這個全面性立體腫瘤球的模式將有利於胰臟癌的治療篩選以及早期診斷和精確治療的發展。
Chapter Ⅰ
Adenomatous polyposis coli (APC), a tumor suppressor gene critically involved in familial adenomatous polyposis, is integral in Wnt/β-catenin signaling and is implicated in the development of sporadic tumors of the distal gastrointestinal tract including pancreatic cancer (PC). Here we report for the first time that functional APC is required for the growth and maintenance of pancreatic islets and maturation. Subsequently, a non-Kras mutation-induced pre-malignancy mouse model was developed; in this model, APC haploinsufficiency coupled with p53 deletion resulted in the development of a distinct type of pancreatic premalignant precursors, mucinous cystic neoplasms (MCNs), exhibiting pathomechanisms identical to those observed in human MCNs, including accumulation of cystic fluid secreted by neoplastic and ovarian-like stromal cells, with 100% penetrance and the presence of hepatic and gastric metastases in > 30% of the mice. The major clinical implications of this study suggest targeting the Wnt signaling pathway as a novel strategy for managing MCN.
Chapter Ⅱ
Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Here, we investigate the effects of concomitant p53 and APC mutation on neoplasms initiated by oncogenic Kras in pancreas mice. In this model, APC haploinsufficiency coupled with p53 deletion and kras activation resulted in an earlier appearance of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers. Through analysis of microarray data in mice revealed APC mutant upregulated runx3 expression and downstream target SPP1 and COL6A1 that stimulating cell migration and dissemination. We also established tumor organoid models from KPC and PKA53 mice, these organoid format multicellular invasive strands show PKA53 cell were highly invasive potential than KPC cell that identical to mice model. These comprehensive 3D cell culture model of murine PDAC progression would facilitate investigation of therapeutic targets, and diagnostics for PDAC.
Contents
論文審定書 i
Chinese Abstract ii
English Abstract iii
Abbreviations vi
Chapter Ⅰ
Introduction 2
Materials & methods 4
Results 15
Discussion 25
Figures 29
Tables 55
References 60

Chapter Ⅱ
Chinese Abstract 67
English Abstract 68
Introduction 69
Results 79
Discussion 86
Figures 91
Tables 107
References 111
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