臺灣博碩士論文加值系統

MBNL3屬於Muscleblind-like (MBNL) 基因家族，與強直型肌肉萎縮症第一型(DM1)之病理機制有密切關係。已知哺乳動物Mbnl3主要表現在高度增生的組織並在肌肉分化過程表現量大幅度下降。我們實驗室先前發現表現shMbnl3 RNA 的C2C12老鼠肌纖維母細胞(shMbnl3 C2C12) cyclin D1表現量會降低，細胞週期受到干擾且提早老化。在此論文第一部分研究中，我證實(1)Mbnl3和cyclin D1表現量恢復後，可明顯增加shMbnl3 C2C12細胞的增生速率;(2)Mbnl3調控cyclin D1的表現係透過Sp1影響其轉錄效率;(3)shMbnl3 C2C12細胞溶小體含量大幅增加，這解釋了其老化標誌SA--gal活性上升的原因。這些結果顯示Mbnl3會透過Sp1/Cyclin D1途徑調節C2C12細胞的生長及老化。在第二部分的研究我首先利用即時定量PCR(qRT-PCR)發現多種腫瘤細胞株，包括卵巢癌(6/6)、膀胱癌(5/7)、口腔癌(1/4)和肝癌(2/2)，的MBNL3 RNA表現量明顯高於相對應的非腫瘤細胞株。進一步以卵巢癌HeyC2及CP70細胞株shMBNL3模型發現抑制MBNL3表現後會嚴重影響癌細胞的存活，表示MBNL3對腫瘤細胞的生長是必須的。由於DM1病人罹癌率比一般人高，這些發現顯示MBNL3可能參與腫瘤生成過程。

Muscleblind-like 3 (MBNL3) belongs to MBNL family that has been implicated in the pathogenesis of myotonic dystrophy type 1 (DM1). Mbnl3 expression is abundant in proliferative tissues and greatly decreases during differentiation. Our laboratory previously found that Mbnl3 knockdown interferes with cell cycle progression and induces senescence through cyclin D1-mediated pathway in C2C12 myoblasts. The first part of my study aimed to confirm the effect of Mbnl3 knockdown on C2C12 cells. My results indicated that (1) both restoration of Mbnl3 and cyclin D1 expression could increase the proliferation rate of Mbnl3 knockdown C2C12 cells, (2) Mbnl3 regulated cyclin D1 transcription possibly through altering Sp1 expression, and (3) the lysosomal content was increased in Mbnl3 knockdown myoblasts, which explains the upregulation of SA--gal activity. These results demonstrated that Mbnl3 may regulate the proliferation and senescence of C2C12 cells through Sp1/cyclin D1 pathway. Recent reports indicate that DM1 patients are at increased risk in developing cancers. The second part of my study aimed to unravel the role of MBNL3 in tumorigenesis. By comparing the RNA level in cancer cells to that in non-tumorigenic counterpart using qRT-PCR, our results revealed that MBNL3 expression was greatly up-regulated in most cancer cell lines examined, including those derived from ovary (6/6), bladder (5/7), oral (1/4), and liver (2/2) cancers. Moreover, knocking down MBNL3 expression severely affected the survival of cancer cells. These results suggest that MBNL3 may play a role in tumorigenesis.

中文摘要................................1
Abstract.................................2
序論........................................4
強直型肌肉萎縮症................4
DM致病分子機制..................5
Muscleblind-like (MBNL)基因家族.........9
MBNL3與肌肉再生....................12
細胞週期與腫瘤生成.................14
細胞老化和DM...........................16
材料與方法.................................19
一、 細胞培養............................19
二、 慢病毒製備........................20
三、 慢病毒感染........................21
四、 Cyclin D1 promoter選殖.21
五、 定點突變............................23
六、 cyclin D1 promoter活性測試.........24
七、 細菌轉型............................25
八、 及時定量之反轉錄聚合酵素連鎖反應........26
九、 蛋白質萃取與西方點墨法.27
十、 MTT細胞存活檢測.............30
十一、 老化指標beta-Galactosidase染色....30
十二、 酸性胞器指標Acirdine orange染色...31
十三、 統計分析(Statistical analysis)....31
結果.....33
一、 Mbnl3透過轉錄機制調控cyclin D1的基因表現........33
二、 抑制Mbnl3表現對Sp1/Cyclin D1路徑的影響...........35
三、 抑制Mbnl3造成溶小體內容物增多..........................37
四、 MBNL3在不同癌細胞株的表現量調查....................38
五、 建立MBNL3弱化的癌細胞............................40
六、 抑制MBNL3表現對卵巢癌細胞增生及cyclin D1表現的影響...42
七、 抑制MBNL3表現誘導HeyC2細胞老化....................45
討論......46
未來展望...53
圖表......54
附錄......73
參考文獻...84
圖表目錄
圖 一 Mbnl3或cyclin D1的救援對Mbnl3 knockdown C2C12細胞生長速率的影響..54
圖 二 Mbnl3表現量改變對cyclin D1 mRNA表現量的影響......................55
圖 三 Mbnl3調控cyclin D1 promoter的活性.............................56
圖 四 Sp1對調控cyclin D1 promoter的活性扮演重要角色....................58
圖 五 抑制Mbnl3表現對Sp1/cyclin D1路徑的影響..........................59
圖 六 MBNL3 shRNA處理造成C2C12細胞老化...............................60
圖 七 MBNL3和cyclin D1 mRNA在正常卵巢細胞和卵巢癌細胞株中的表現情形......61
圖 八 MBNL3和cyclin D1 mRNA在正常膀胱細胞和膀胱癌細胞株中的表現情形.......62
圖 九 MBNL3和cyclin D1 mRNA在正常肝細胞和肝癌細胞株中的表現情形..........63
圖 十 MBNL3和cyclin D1 mRNA在正常口腔細胞和口腔癌細胞株中的表現情形.......64
圖 十一 Homo sapiens MBNL3 mRNA 和MBNL3 shRNA目標位置...............65
圖 十二 MBNL3 shRNA處理對HeyC2細胞cyclin D1表現量的影響...............66
圖 十三 MBNL3 shRNA處理對HeyC2細胞型態及增生的影響.....................67
圖 十四 MBNL3 shRNA處理對CP70細胞cyclin D1表現量的影響................68
圖 十五 MBNL3 shRNA處理對CP70細胞型態及增生的影響......................69
圖 十六 MBNL3 shRNA處理對HeLa細胞cyclin D1 mRNA表現量的影響...........70
圖 十七 MBNL3 shRNA處理對HeLa細胞型態及增生的影響......................71
圖 十八 MBNL3 shRNA處理對HeyC2細胞老化的影響..........................72

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