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研究生:王政欽
研究生(外文):Cheng-chin Wang
論文名稱:探討肝型磷酸果糖激酶在肝癌細胞的角色
論文名稱(外文):Investigation of the role of L-type phosphofructokinase in hepatoma
指導教授:張文粲
指導教授(外文):Wen-Tsan Chang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物化學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:81
中文關鍵詞:瓦式效應磷酸果糖激酶肝癌細胞
外文關鍵詞:phosphofructokinasewarburg effecthepatoma
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葡萄糖是多數生物體的能量基本來源,當葡萄醣進入細胞後首先會進行糖解作用,在糖解作用的第三個酵素果糖磷酸激酶(PFK-1),是速率決定步驟的酵素,將6-磷酸果糖激酶的一號碳上面進行磷酸化作用而生成1,6-雙磷酸果醣,此步驟為一不可逆反應並確定葡萄糖進入醣解作用。從過去研究顯示癌細胞在缺氧情況下會提高糖解作用的效率來獲得更多能量,這也是俗稱瓦式效應()。PFK-1裡的PFKL(liver isoform)在肝臟具有專一性表現,因此我使用核醣核酸干擾技術*將肝癌細胞中的肝型磷酸果糖激酶沉默,選用的細胞是最惡性的SK-Hep1,研究其對細胞的生長影響情形。從實驗結果得到,當SK-Hep1的肝型磷酸果糖激酶被抑制
掉之後,在細胞的生長速度上並沒有沒顯的抑制作用,然而在細胞型態和細胞之間的作用卻有有明顯的差異,例如可以觀察到細胞攤開的能力較好,亦即spreading的能力增加,而且和野生型比較起來,當細胞生長密度變高後,細胞堆疊的情形較差,顯示出肝型磷酸果糖激酶的抑制雖然對細胞的存活並沒有致命性影響,但是細胞可能藉由形態的改變來適應;在另一方面,當肝型磷酸果糖激酶被抑制掉的時候,粒線體的膜電位會有小幅度的增加,可能是細胞透過提高TCA cycle來獲得能量,不過在反應性氧化系物(ROS)並無明顯變化,所以TCA cycle只有小程度的上升情形。還有在乳酸堆積的偵測並無明顯差異,所以無氧呼吸並沒有受到影響。最後使用不同的電子傳遞鏈複合蛋白的抑制物處理,發現在低濃度的Rotenone(複合蛋白一的抑制物)處時,PFKL被沉默的細胞出現抵抗性,在TTFA(複合蛋白二的抑制物)處理時則都會有嚴重死亡情形,兩種藥物處理之下,穩定沉默型的細胞的粒線體膜電位上升程度比野生型高。
目前已知的結果來看,也許在肝臟細胞癌化的過程,肌肉或血小板型的同源酵素的基因表現會被啟動,而造成PFKM或PFKP的代償作用,畢竟PFK-1是糖解作用的關鍵酵素。
Glucose is the universal energy source of most cells. When a glucose is transported into a cell, it will get into glycolysis in the cytoplasm. Phosphofructokinase(PFK-1) is the third enzyme that phosphorylates the first carbon of fructose-6-phosphate into fructose-1,6-bisphosphate and a unreversible rate-limiting enzyme also. It makes sure that a glucose is taken into glycolysis at this step. In the past researches, a tumor cell elevates the efficiency of glycolysis in an anaeorobic environment. It is known as “Warburg Effect”. One isozyme, PFKL, in PFK-1 is specifically expressed in the liver. I silenced the gene expression level of PFKL by RNAi technology in the most progressive hepatoma, SK-Hep1, to investigate the role in liver cancer. By results, there were not differences between wild type and stable-knockdown cells in growth but in mophorlogy and cell-cell interaction especially in high cell density. It seemed to get better spreading ability and less vertical stacking. Despite that it’s not lethal but it’s possible that the cells adapted the condition of silenced PFKL by changing mophorlogy. In another hand, it was increased in mitochondrial membrane potential in PFKL-stable-knockdown cells. It revealed that the cells obtain more energy by elevating the level of TCA cycle. But it was not changes in the experiments of ROS detection. Moreover, there were no distinctive differences in LDH assay. When treated with the inhibitors of the complexes in electron transport chain, PFKL-stable-knockdown cells were resistant to low dose of rotenone but not TTFA.
In my experimental results, it is possible that the gene expression of muscle or platelet isozymes are promoted as tumoriogenesis in hepocytes and results in compensation of PFKL by PFKM or PFKP. As we know, PFK-1 is a key enzyme in glycolysis after all.
目錄………………………………………………………………………………… I
圖表目錄………………………………………………………………………… IV
中文摘要…………………………………………………………………………VI
英文摘要……………………………………………………………………VII
第一章 緒論……………………………………………………………………… 1
1-1 細胞的生長與能量代謝………………………………………………………… 1
1-2 葡萄糖的能量代謝……………………………………………………………… 1
1-3 糖解作用………………………………………………………………………… 2
1-4 磷酸果糖激酶的調控…………………………………………………………… 3
1-5 能量代謝與腫瘤細胞的關係…………………………………………………… 4
1-6 無氧呼吸……………………………………………………………………… 5
1-7 p53和TIGAR的功能與能量代謝的關係..................................................................5
1-8 研究緣起…………………………………………………………………………6
第二章 實驗材料與方法……………………………………………………… 8
A. 實驗材料………………………………………………………………………8
A-1 勝任細胞……………………………………………………………………… 8
A-2 限制酵素……………………………………………………………………… 8
A-3 使用的細胞株………………………………………………………………… 8
A-4 化學藥品……………………………………………………………………… 8
A-5 試劑…………………………………………………………………………… 11
A-6 抗體…………………………………………………………………………… 11
A-7 培養液………………………………………………………………………… 12
A-8 細菌用培養基(LB medium)…………………………………………………… 13
A-9 緩衝液………………………………………………………………………… 13
A-10 各種試劑配製……………………………………………………………… 18
A-11 勝任細胞之製備…………………………………………………………… 19
A-12 儀器設備…………………………………………………………………… 19
B.方法 …………………………………………………………………………… 20
B-1細胞的培養程序………………………………………………………………20
B-2基本分子生物技術………………………………………………………………21
B-3細胞相關實驗……………………………………………………………………27
(1) 短暫性轉染
(2) 雙重冷光基因活性的測定
(3) 蛋白質定量
(4) 西方墨點法
(5) 建立穩定細胞株
(6) 免疫螢光染色分析
(7) Cell Growth細胞生長實驗
(8) Wound healing cell migration assay傷口癒合細胞爬行分析
(9) MTT cell proliferation assay細胞增殖分析
(10) Colony formation assay群落形成能力分析
(11) 粒線體膜電位偵測實驗 (tetramethylrhodamine methyl ester,
TMRM/Rhodamine123)
(12) 藥物抑制細胞生長實驗
(13)在培養液去除L-glutamine實驗
第三章 實驗結果……………………………………………………………… 35
3-1篩選有效沈默siPFKL和shRNA的表現載體………………………………… 35
3-2 利用增強型綠螢光短暫性轉染確認pSuper表現shRNA的效率…………… 35
3-3 篩選持續沉默PFKL在SK-Hep1細胞株的穩定表現株……………………… 35
3-4 觀察穩定沉默PFKL的SK-Hep1細胞生長情形……………………………… 36
3-5 細胞型態分析………………………………………………………………… 36
3-6 細胞爬行能力分析…………………………………………………………… 37
3-7 粒線體膜電位和細胞內ROS偵測………………………………………… 38
3-8 乳酸堆積情形偵測………………………………………………………… 38
3-9 代償作用的測定………………………………………………………………39
3-10 電子傳遞鏈複合蛋白一(complex I)抑制…………………………………… 39
3-11 電子傳遞鏈複合蛋白二(complex II)抑制………………………………… 41
3-12 能量代謝和腫瘤抑制基因的變化……………………………………………42
第四章 討論………………………………………………………… 43
4-1 PFKL沉默對於SK-Hep1生長和型態方面的影響…………………………… 43
4-2 其他isoform的影響…………………………………………………………… 43
4-3 有氧呼吸作用的變化………………………………………………………… 45
4-4 無氧呼吸的變化………………………………………………………………46
第五章 參考文獻……………………………………………………………… 48
第六章 實驗圖表……………………………………………………………… 57






圖表目錄
圖一、能量代謝和酵素催化調控…………………………………………………. 57
圖二、利用siRNA 評估系統來分析各個siRNA 序列………………………… 58
圖三、利用冷光篩選有效siRNA………………………………………………… 59
圖四、利用螢光蛋白篩選有效siRNA…………………………………………… 60
圖五、篩選有效shRNA…………………………………………………………… 61
圖六、短暫性轉染…………………………………………………………………. 62
圖七、持續沉默PFKL穩定株…………………………………………………… 63
圖八、有效的持續性沉默細胞株………………………………………………… 64
圖九、觀察有效持續沉默細胞株的生長情形…………………………………… 65
圖十、群落形成………………………………………………………………………66
圖十一、細胞週期變化觀察…………………………………………………………67
圖十二、傷口癒合實驗……………………………………………………………68
圖十三、細胞外觀之觀察………………………………………………………… 69
圖十四 細胞骨架之觀察…………………………………………………………70
圖十五、粒線體膜電位偵測情形………………………………………………… 71
圖十六、Reactive oxygen species, (ROS) 偵測情形…………………………… 72
圖十七、代償作用分析……………………………………………………………73
圖十八、使用電子傳遞複合物一(complex I)的抑制物Rotenone處理偵測生長情形…………………………………………………………………………………… 75
圖十九、使用電子傳遞複合物一(complex I)的抑制物Rotenone處理偵測粒線體膜電變化情形……………………………………………………………………… 76
圖二十、使用電子傳遞複合物二(complex II)的抑制物TTFA處理偵測生長情形
……………………………………………………………………………………78
圖二十一、使用電子傳遞複合物二(complex II)的抑制物TTFA處理偵測粒線體膜電變化情形………………………………………………………………………… 79
圖二十二 使用西方點墨法偵測醣解酵素和腫瘤抑制基因的變化情形…………80
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