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論文名稱(中文) 探討磷酸水解酶PP2A的B55δ調節次單元在大腸癌腫瘤形成及轉移中扮演的角色
論文名稱(英文) Investigate the Role of the B55δ Regulatory Subunit of Protein Phosphatase 2A in the Tumorigenesis and Metastasis of Colorectal Cancer
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 107
學期 2
出版年 108
研究生(中文) 朱沛容
研究生(英文) Pei-Jung Chu
學號 T16064035
學位類別 碩士
語文別 英文
論文頁數 91頁
口試委員 指導教授-蔣輯武
口試委員-洪良宜
口試委員-林博文
中文關鍵字 蛋白質磷酸酶2A型(PP2A)  調節性次單元B55δ  大腸直腸癌  腫瘤形成  轉移 
英文關鍵字 PP2A  B55δ regulatory subunit  Colorectal cancer  Tumorigenesis  Metastasis 
學科別分類
中文摘要 大腸直腸癌為世界第三常見及最容易造成死亡的癌症排行第三,大多數的大腸直腸癌病人發生轉移的現象與其不良的預後相關,因此找尋大腸直腸癌過程中的生物標記物對於大腸直腸癌病人的預後診斷以及標靶治療相當重要。蛋白質磷酸酶2A型(PP2A)為一種絲氨酸/蘇胺酸磷水解酶,已知具有抑癌的功能。其完全酶組成主要由結構蛋白A次單元,催化蛋白C次單元以及種類多樣的調節性B次單元所組成,其中B次單元可決定PP2A完全酶的受質選擇性以及其在細胞中的座落位置。調節次單元可以分為四個家族B (B55或PR55),B’ (B56或PR61),B’’ (PR72)和B’’’ (PR93或PR110)。而B55δ次單元屬於B55家族成員並由PPP2R2D基因所編碼出來的蛋白,在許多文獻中已經指出其在細胞週期的有絲分裂中扮演重要的調控者。也有文獻指出在肝癌中,PP2A-B55δ可以透過對於小分子核糖核酸-133b (microRNA-133b)的調控來促進肝癌病人化學治療的效果;在胃癌中,PP2A-B55δ可能透過抑制哺乳動物雷帕黴素靶蛋白通路(mTOR)來促進胃癌腫瘤的生長及轉移。然而,其在大腸及其他種癌症中扮演什麼角色目前仍不清楚。在數據庫資料搜尋,我們發現B55δ在大腸直腸癌的腫瘤組織中相較於正常組織都是降低表現的,然而高表現的B55δ卻造成大腸直腸癌病人的存活率下降。綜合上述,我們假設B55δ可能在大腸直腸癌的進程中扮演不同的角色。首先,我們分析了B55δ在七個不同的大腸癌細胞株中的表現。接著我們建立過度表現B55δ或以核糖核酸干擾法將B55δ表現減低之細胞株去探討B55δ是否會調控腫瘤細胞的增生。從結果我們發現,B55δ的過度表現會在沒有影響到細胞存活率的情況下抑制HCT116及SW620細胞株的生長。出乎意料的是,在細胞群落形成實驗(Colony formation assay)的結果顯示,B55δ降低表現時也會去抑制SW620的細胞複製形成群落的能力。此外,B55δ在HCT116和SW620的細胞中降低表現時,細胞形態呈現拉長的、紡錘狀的數目增加;反之,過度表達B55δ時則會減少這類型態的細胞數。從細胞遷移(Transwell migration assay)及侵襲實驗(Transwell invasion assay)的結果顯示,B55δ在HCT116和SW620的細胞中大量表達時會增加細胞爬行及侵襲的能力,相反的,降低B55δ的表達則會顯著的降低細胞爬行和侵襲的能力。為了更清楚了解B55δ影響細胞爬行及侵襲能力是否透過上皮-間質細胞轉換(epithelial-mesenchymal transition, EMT)的調控。在我們探究的EMT分子標記中,我們發現在HCT116以及SW620細胞中B55δ的大量表現會造成E-cadherin表現降低及Snail表現增加,而B55δ降低表現時會導致E-cadherin的增加,有趣的是,在SW620細胞中也造成Snail的表現增加。綜合以上的結果,我們發現B55δ能夠抑制HCT116及SW620細胞的生長,但會促進HCT116和SW620細胞的遷移和侵襲能力以及E-cadherin的喪失,但可能並不是只有透過Snail來造成。綜合我們的結果,B55δ可能在大腸直腸癌進展的早期階段抑制腫瘤發生,但是在晚期可能透過上皮-間質細胞轉換的調控來促進轉移。
英文摘要 Colorectal cancer (CRC) is the third most common type of cancer and the third most common cause of cancer deaths in the world. CRC patients with distant metastases at the time of diagnosis are associated with worse prognosis. Therefore, it is urgent to find more biomarkers and therapeutic targets for improving detection, diagnosis, and prognosis and survival for patients with CRC. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase in eukaryotic cells and mostly acts as a tumor suppressor in human cancer. The PP2A holoenzyme is composed of a structural A subunit, a catalytic C subunit, and a variable regulatory B subunit. The regulatory B subunits determine the substrate specificity and subcellular localization of PP2A. The regulatory B subunits have been categorized into four families, B (B55 or PR55), B' (B56 or PR61), B” (PR72) and B'” (PR93 or PR110). The B55δ subunit, a member of B55 family and encoded by the PPP2R2D gene, plays a crucial role in regulating mitosis in the cell cycle. Data mining of expression profiles of B55δ showed differential expression levels of B55δ in different types of cancer, and reduced expression levels of B55δ were found in tumor parts as compared to that of the normal counterparts in datasets of CRC specimens. However, higher expression levels of B55δ in tumor tissues were associated with reduced survival rate in a subset of CRC patients. Additionally, differential expression levels of B55δ were found in different CRC cell lines. We hypothesized that B55δ may play a dual role in colorectal tumor progression. In agreement with the known role of B55δ in cell cycle, growth curve analysis showed that stable B55δ overexpression reduced proliferation of both HCT116 and SW620 cells compared to cells with vector only. B55δ overexpression or knockdown did not affect steady-state viability of HCT116 and SW620 cells. Similarly, using colony formation assay, both HCT116 and SW620 cells with B55δ overexpression showed reduced colony number compared to that of cells with vector only. Unexpectedly, the colony number of SW620 cells with stable knockdown of B55δ expression was also reduced compared to that of cells with vector only. Furthermore, B55δ overexpression increased the number of both SW620 and HCT116 cells with epithelial-like morphology, and B55δ knockdown increased the number of SW620 and HCT116 cells with mesenchymal morphology as compared to that of cells stably expressing vector. However, transwell migration assay showed that B55δ overexpression increased the migration ability, whereas B55δ knockdown reduced the migration ability of both HCT116 and SW620 cells. In addition, transwell invasion assay showed that B55δ overexpression increased the invasion ability, whereas B55δ knockdown reduced the invasion ability of SW620 cells. We further analyzed several EMT markers to elucidate whether B55δ regulates molecular changes of EMT of SW620 cells. The data showed that E-cadherin is negatively regulated by B55δ in both HCT116 and SW620 cells, but Snail is both negatively and positively regulated by B55δ in SW620 cells. In summary, our results showed that B55δ inhibits proliferation of CRC HCT116 and SW620 cells, but down-regulates the level of E-cadherin and promotes migration and invasion of CRC cells. Our finding suggests that it may suppress tumorigenesis in early stages of CRC progression, but promote metastasis in later stages of CRC progression.
論文目次 中文摘要 III
Abstract V
致謝 VII
List of Contents IX
List of Figures XI
List of Tables XII
List of Abbreviations XIII
Introduction 14
Colorectal cancer (CRC) 15
Protein phosphatase 2A (PP2A) 16
The structure of PP2A 16
The B subunit of PP2A 17
The B55δ regulatory subunit of protein phosphatase 2A 17
Cell cycle 18
PP2A-B55δ regulates mitosis of cell cycle 19
Epithelia-Mesenchymal Transition (EMT) in cancer metastasis 20
Table 1. Molecular markers of epithelial and mesenchymal cell types 21
Hypothesis 22
Materials and Methods 24
Antibodies and Reagents 25
Table 2. Primary and secondary antibodies applied in Western blotting 26
DNA constructs 26
Table 3. List of lentiviral shRNA constructs 27
Reagents of DNA cloning 27
Cell culture and cell lines 27
Table 4. Cell lines used in this thesis and the characteristics of each cell line below 29
Retrovirus and Lentivirus preparation 31
Retrovirus and Lentivirus transduction 32
Western blotting 33
Cell proliferation assay 33
Transwell® migration assay 33
Transwell® invasion assay 34
Colony formation assay 34
Results 35
The B55δ regulatory subunit may have dual roles in tumor progression of CRC 36
The protein levels of B55δ vary among several colorectal cancer cell lines 36
Stable overexpression or knockdown of expression of B55δ did not affect the levels of PP2A-Aα/β and PP2Ac in both SW620 and HCT116 cells 37
B55δ downregulates cell proliferation in both SW620 and HCT116 cells 37
Stable overexpression or knockdown of B55δ affects morphology of SW620 and HCT116 cells 38
B55δ promotes motility of colorectal cancer cells 38
B55δ enhances the invasion ability of colorectal cancer cells 38
B55δ negatively regulates the level of E-cadherin in SW620 and HCT116 cells by up-regulating Snail 39
Conclusion 40
Discussion 42
The morphology of SW620 and HCT116 cells regulated by B55δ overexpression or knockdown is not consistent with changes of their motility regulated by B55δ 43
B55δ negatively regulates expression of E-cadherin but has a dual role in regulating expression of Snail 43
The role of B55δ in colorectal cancer progression 45
B55δ as a biomarker and therapeutic target of CRC 45
References 47
Figures 56
Appendix 87
作者簡歷 91
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