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博碩士論文 etd-1222110-192336 詳細資訊
Title page for etd-1222110-192336
論文名稱
Title
透明質酸合成酶在大鼠神經膠質瘤細胞中之表現
Expression of hyaluronan synthase in C6 glioma cells
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
96
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2010-12-17
繳交日期
Date of Submission
2010-12-22
關鍵字
Keywords
神經膠質瘤、CD44、透明質酸合成酶、透明質酸
Glioma, hyaluronan synthase (HAS), hyaluronic acid (HA), CD44
統計
Statistics
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中文摘要
神經膠質瘤 (glioma) 源於神經膠細胞,為一種最常見且致死率極高的原發性腦瘤,其形成的病因至今尚未完全明朗。神經膠質瘤細胞具高度侵潤性,可在腦內進行大範圍擴散,以手術方式很難將其完全清除,病患的癒後極差,且神經膠質瘤細胞對於化學治療及放射線治療具有高度抵抗性,大部分惡性神經膠質瘤患者即使經過治療後,存活時間大約只有 12 至 15 個月。神經膠質瘤細胞的侵潤性是由細胞表面黏附蛋白與細胞外基質交互作用所調控,在相關研究中指出,中樞神經系統中含量豐富的細胞外基質成份-透明質酸與其主要受體蛋白 CD44 之間的結合可調控神經膠質瘤細胞的運動性、腫瘤形成能力以及抗藥性。另外,此結合也能促進透明質酸的生成,然而在此過程中透明質酸合成酶表現量所受到的影響,仍未有研究明確的報導。在本研究中,分別觀察大鼠神經膠質瘤細胞-C6 在 cd44 基因默化以及添加透明質酸的條件下,透明質酸合成酶表現量的變化。我們發現添加透明質酸會導致透明質酸合成酶表現量上升,而將 cd44 基因默化會降低其表現量,然而此時再添加透明質酸則會回復透明質酸合成酶的表現,此表現量的變化在基因及蛋白質層面皆相同。另外,添加透明質酸會減緩細胞增生速率,降低 CD44 以及星狀膠細胞分化指標蛋白-GFAP表現量,並增加 brain tumor stem cell 指標蛋白-nestin 的表現,使細胞表現神經幹細胞的特性;且僅將cd44 基因默化也會成相同的結果。然而將cd44 基因默化後再添加透明質酸,會造成 CD44 表現量上升,並促進細胞分化及增生。基於以上結果,得知在神經膠質瘤細胞中,透明質酸與 CD44 之間的結合可能存在正回饋機制,並藉此機制促進透明質酸的生成,且透明質酸可藉由與 CD44 結合來調控神經膠質瘤細胞的分化與增生。
Abstract
Giloma derive from glial cell, which is the most common malignant and deadly primary tumor that affects the brain and nervous system, and the possible causes are not fully understood. Glioma cells are highly invasive, and can spread to distant area of the brain, this invasive behavior makes complete tumor debulking virtually impossible. Glioma even resists to high dose of radiotherapy and chemotherapy, the prognosis of malignant glioma remains dismal and the estimated median survival time is 12-15 months. The previous studies showed that the interaction of hyaluronan (HA), the abundant component of the ECM in the adult central nervous system, with cell-surface receptors, CD44 is able to mediate motility, tumor formation and multidrug resistance of glioma. In addition, the interacted between HA and CD44, that could up-regulate glioma HA production. But the effect of hyaluronan synthases (HAS) expression in this regulation mechanism was not described clearly. In this study, the HAS expression was a target gene in the rat glioma cell line-C6 on the conditions of HA addition or cd44 gene silence, respectively. The results showed that HA addition increased the HAS expression, and cd44 gene silence caused the less expression of HAS, and which could restored by HA addition. Futher, the HA addition could prolong cell proliferation , decrease the expression of the CD44 and GFAP, the astrocyte differentiation marker, and increase brain tumor stem cell marker-nestin expression, and this result could reappear by the cd44 gene silence alone. However, instead the stemness of cell, the cell toward differentiation and proliferation by HA addition after the cd44 gene silence. From those results, the interaction between HA and CD44 could exist the positive feedback to trigger the HA production, and HA could regulate cells proliferation and differentiation by interaction with CD44 in the glioma cells.
目次 Table of Contents
目錄
致謝.............................................................. I
摘要.............................................................. II
Abstract ......................................................... III
目錄............................................................... V
表目錄............................................................ IX
圖目錄............................................................. X

第一章 緒論........................................................ 1
第二章 材料與方法.................................................. 8
一、細胞培養 ..................................................... 8
1.1 C6細胞生長培養液配製....................................... 8
1.2 1X PBS 配製................................................. 8
1.3 C6 細胞培養................................................ 8
1.4 C6 細胞解凍................................................ 9
1.5.C6 細胞繼代培養............................................ 9
1.6 C6 細胞保存 ............................................... 9
二、E.coli 轉型作用 (transformation) 及質體製備................. 10
2.1 LB agar plate 製備 ...................................... 10
2.2 LB 培養液配製 ........................................... 10
2.3 E.coli 勝任細胞 (competent cell) 製備 ................... 10
2.4 E.coli 轉型作用.......................................... 10
2.5 質體抽取 ................................................ 11
三、真核細胞轉染 (Transfection)................................. 12
四、透明質酸 ( Hyaluronic acid (HA) ) 培養皿製備................. 12
五、細胞密度及形態觀察........................................... 13
5.1 干擾顯微鏡 (DIC) 觀察.................................... 13
5.2 細胞面積分析............................................. 13
六、細胞生長曲線 (growth curve) 與 RNA 萃取..................... 13
6.1 細胞生長曲線 (growth curve) ............................. 13
6.2 RNA 萃取 ................................................ 13
七、Reverse Transcription PCR (RT-PCR)........................... 14
7.1 RT-PCR 反應步驟 ........................................ 14
7.2 RT-PCR 反應條件......................................... 14
7.3 RT-PCR 核酸產物電泳 .................................... 15
7.4 RT-PCR 結果之量化與分析................................. 15
八、西方墨點轉漬法分析 (Western blot Analysis).................... 15
8.1 蛋白質萃取 .............................................. 15
8.2 Bis-Tris Gel 電泳分析.................................... 16
8.3 蛋白轉漬與訊號偵測 ...................................... 16
8.3.1 轉漬緩衝液配置 ...................................... 16
8.3.2 TBST 配製 ........................................... 16
8.3.3 蛋白轉漬與抗體呈色 .................................. 17
九、流式細胞儀分析 (Flow Cytometer)............................. 17
9.1 免疫螢光染色 (Immunofluorescence stain) ................. 17
9.1.1 細胞膜上之蛋白染色 .................................. 17
9.1.2 細胞內之蛋白染色 .................................... 18
9.2 細胞週期分析 (PI stain) ................................ 18
十、統計分析 ................................................... 19
第三章 結果 ...................................................... 20
一、has (has1,has2,has3) 與 cd44, gfap 以及gadd45a 基因在大鼠神經膠質瘤細胞-C6 中的表現狀況 ...................................... 20
二、透明質酸對 C6 細胞內 HAS, CD44, GFAP 以及 GADD45A 表現量之影響.............................................................. 20
2.1 透明質酸對細胞生長速率及細胞形態之影響................... 20
2.2 透明質酸對 has, cd44, gfap 以及gadd45a 在基因表現上之影響.21
2.3 透明質酸對 HAS, CD44 以及 GFAP 在蛋白質表現上之影響 ..... 21
2.4 透明質酸對細胞週期之影響................................. 22
三、細胞表面黏著分子 - CD44 對 C6 細胞內 HAS, CD44, GFAP 以及 GADD45A 表現量之影響............................................ 22
3.1 cd44 基因默化效率........................................ 22
3.2 CD44 對細胞生長速率及細胞形態之影響...................... 23
3.3 CD44 對 has, gfap 以及gadd45a 在基因表現上之影響......... 24
3.4 CD44 對 HAS 以及 GFAP在蛋白質表現上之影響................ 24
3.5 CD44 對細胞週期之影響.................................... 25
四、透明質酸對 CD44 基因默化之細胞內 HAS, CD44, GFAP 以及 GADD45A 表現量之影響...................................................... 25
4.1 透明質酸對 sh4 生長速率及細胞形態之影響.................. 25
4.2 透明質酸對 sh4 細胞內 has, cd44, gfap 以及gadd45a 在基因表現上之影響...................................................... 26
4.3 透明質酸對 sh4 細胞內 HAS, CD44, GFAP 以及GADD45A 在蛋白質表現上之影響.................................................... 26
4.4 透明質酸對 sh4 細胞週期之影響............................ 27
五、Nestin 蛋白於大鼠神經膠質瘤細胞內的表現情形................. 27
第四章 討論....................................................... 29
第五章 總結與展望................................................. 34
參考文獻.......................................................... 35
附錄 儀器與材料................................................... 79
一、 儀器設備................................................ 79
二、 試劑.................................................... 80
附圖.............................................................. 82
附圖一、 C6 細胞進行轉染使用的載體之 restriction map............. 82
附圖二、透明質酸與 CD44 影響腫瘤幹細胞分化途徑模型圖............. 83
表目錄
表一、 引子序列表...................................................47
表二、 抗體列表.....................................................48
圖目錄
圖一、大鼠神經膠質瘤細胞-C6內has,cd44,gfap及gadd45a基因之表現....49
圖二、透明質酸對 C6細胞密度及細胞生長曲線之影響.................... 50
圖三、透明質酸對 C6 細胞形態及表面積之影響......................... 51
圖四、透明質酸對C6細胞之has,cd44,gfap及gadd45a基因表現量之影響.... 52
圖五、透明質酸對 C6 細胞膜上 CD44 及 GFAP 蛋白質表現量之影響....... 53
圖六、透明質酸對 C6 細胞內 CD44 及 GFAP 蛋白質表現量之影響......... 54
圖七、透明質酸對 C6 細胞內 HAS1 蛋白質表現量之影響................. 55
圖八、透明質酸對 C6 細胞之 HAS2 蛋白質表現量之影響................. 56
圖九、透明質酸對 C6 細胞週期之影響................................. 57
圖十、 cd44 基因默化後細胞內 cd44 基因之表現....................... 58
圖十一、 cd44 基因默化後細胞膜上 CD44 蛋白質之表現................. 59
圖十二、 cd44 基因默化後細胞內 CD44 蛋白質之表現................... 60
圖十三、 cd44 基因默化對細胞密度及細胞生長曲線之影響............... 61
圖十四、 cd44 基因默化對細胞形態及表面積之影響..................... 62
圖十五、 cd44 基因默化對has,cd44,gfap及gadd45a基因表現量之影響.... 63
圖十六、 cd44 基因默化對細胞膜上 CD44 及 GFAP 蛋白質表現量之影響....64圖十七、 cd44 基因默化對細胞內 CD44 及 GFAP 蛋白質表現量之影響..... 65
圖十八、cd44 基因默化對細胞內 HAS1 蛋白質表現量之影響.............. 66
圖十九、cd44 基因默化對 HAS2 蛋白質表現量之影響.................... 67
圖二十、 cd44 基因默化對細胞週期之影響............................. 68
圖二十一、透明質酸對 sh4 細胞密度及細胞生長曲線之影響.............. 69
圖二十二、透明質酸對 sh4 細胞形態及表面積之影響.................... 70
圖二十三、透明質酸對 sh4 細胞之 has, cd44, gfap 及 gadd45a 基因表現量之影響............................................................ 71
圖二十四、透明質酸對 sh4 細胞膜上CD44及GFAP蛋白質表現量之影響......72
圖二十五、透明質酸對 sh4 細胞內CD44及GFAP蛋白質表現量之影響........73
圖二十六、透明質酸對 sh4 細胞內 HAS1 蛋白質表現量之影響.............74
圖二十七、透明質酸對 sh4 細胞之 HAS2 蛋白質表現量之影響.............75
圖二十八、透明質酸對 sh4 細胞週期之影響.............................76
圖二十九、透明質酸之添加與 cd44 基因默化對 C6 細胞之 nestin 蛋白質表現量之影響...........................................................77
圖三十、透明質酸以及 CD44 對 C6 細胞之 has, cd44, gfap 及 gadd45a 基因表現量之影響統整圖.................................................78
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