臺灣博碩士論文加值系統

目前治療基底細胞癌(basal cell carcinoma，BCC)的療法分為兩種，一種是侵入性的療法利用手術將病灶切除;而另一種是非侵入性的療法利用藥物塗抹或是口服藥物來達到毒殺癌細胞的效果。侵入性的療法雖然可以有效的移除癌細胞，但是對於年齡較高不適合動手術、術後不美觀的問題，使得非侵入性的療法逐漸受到重視。Imiquimod是類鐸受體7、8(Toll-like receptor 7、8，TLR7 and TLR8) 的配體(ligand)，在細胞及活體實驗中具有抗腫瘤及抗病毒的能力，臨床上是治療基底細胞癌的抗癌用藥。而現階段非侵入式療法所遇到的瓶頸是在處理藥物之後會有藥物抗性的產生，使得基底細胞癌在獲得藥物抗性的能力之後變成很難治療。目前對於BCC如何獲得藥物抗性的能力及相關的機制都是不清楚，所以我們實驗室透過BCC緩慢提高IMQ的濃度訓練出具有IMQ藥物抗性的細胞株BCC-R，透過BCC-R來模擬臨床具有IMQ藥物抗性的基底細胞癌進行研究。我的研究先證明BCC-R與BCC是具有不同的細胞特性，且BCC-R為IMQ藥物抗性的細胞株，接著去探討2株細胞的差異。我們發現BCC-R不論是否處理IMQ，Mcl-1表現是比較強的，使得BCC-R在處理IMQ之後比較不會細胞凋亡；而在IMQ誘導細胞自噬的部分，BCC-R在LC3-II的表現量確實是比BCC來的低，而BCC-R在細胞自噬相關的蛋白Beclin-1、ATG7和ATG16 表現量是比較高的。我們也從Microarray的數據發現BCC-R在溶小體相關的基因表現與BCC相比高達2倍的差異，我們也透過Lysotracker的結果證明BCC-R確實溶小體的量比較多，在處理IMQ之後溶小體的量又更多。BCC-R在溶小體的蛋白質LAMP1、LAMP2和CTSD表現量與BCC相比是較強的。而先前的文獻有提到癌細胞在處理IMQ之後，IMQ會進到溶小體內，而我們的實驗證明了BCC-R細胞株的溶小體在IMQ藥物抗性中扮演重要的角色。我們認為這些發現有助於臨床的研究，亦對於IMQ具有藥物抗性的機制提供了重要的方向。

Two approaches for treating basal cell carcinoma (BCC) are currently used; one is the surgical resection of lesions, and the other, a noninvasive approach, involves administering cytotoxic medication topically or orally to kill cancer cells. Although the surgical approach is effective in removing cancer cells, it is not recommended for elderly people who cannot undergo surgery or for people who are concerned about postoperative wounds and scars. Consequently, noninvasive BCC treatments have been increasingly emphasized. Imiquimod, a ligand of Toll-like receptors 7 and 8 (TLR7 and TLR8), has been demonstrated to be antitumor and antivirus in living cells and in vivo. Clinically, it is an anticancer drug for treating BCC. Drug resistance is currently the major bottleneck for the noninvasive approach because drug-resistant BCC is difficult to treat. Currently, neither how BCC develops its drug-resistant ability nor the mechanism for this development is known; to more profoundly understand these topics, our laboratory developed BCC-R, an imiquimod (IMQ)-resistant cell line, by gradually increasing the IMQ concentration on BCC. Subsequently, we used BCC-R to clinically stimulate the drug resistance of BCC to IMQ. Our study first demonstrated the different cell properties of BCC-R and BCC and that BCC-R is a cell line with drug resistance to IMQ. Subsequently, we examined the differences between the two cell lines and determined that regardless of whether they were treated using IMQ or not, the expression of Mcl-1 was always stronger in BCC-R than in BCC, which explains why BCC-R was less susceptible to apoptosis than BCC in IMQ treatment. As for IMQ-induced cell autophagy, the expression of LC3-II was indeed weaker in BCC-R than in BCC, but the expression of cell autophagy–related proteins, namely Beclin-1, ATG7, and ATG16, was determined to be stronger in BCC-R than in BCC.According to the microarray data, lysosome-related gene expression in BCC-R was two times greater than in BCC. The lysotracker results suggested that BCC-R had more lysosomes than BCC did, and the amount increased after IMQ treatment. Compared with BCC, BCC-R exhibited a stronger expression of lysosomal proteins LAMP1, LAMP2, and CTSD. Our experiment demonstrated that lysosomes may play a key role in the drug resistance of the BCC-R cell line to IMQ. Our findings are critical for clinical research, and they provide key insights into the mechanisms of drug resistance to IMQ.

中文摘要………………………………………………………………………………i
英文摘要………………………………………………………………………………ii
目錄……………………………………………………………………………………iii
第一章 緒論…………………………………………………………………………1

第一節…………………………………………………………………………………1

一、 細胞自噬……………………………………………………………………1
二、 細胞凋亡……………………………………………………………………4

第二節…………………………………………………………………………………7

一、 基底細胞癌…………………………………………………………………7
二、 Imiquimod…………......……………………………………………………8
三、 Imiquimod誘導細胞自噬與細胞凋亡……………..………………………8

第三節……………………………………………………………………………..…10

一、 藥物抗性…………………………………………………………………...10
二、 藥物抗性之理論…………………………………………………………...10
三、 基底細胞癌與藥物抗性...…………………………………………………11
四、 Imiquimod與基底細胞癌...………………………………………………12

第二章 研究目的………………………………………………………..…………13

第三章 研究材料與方法...…………………………………………...……………14

一、 細胞培養……………………………………………………………………14
二、 藥物配置……………………………………………………………………15
三、 細胞外觀……………………………………………………………………15
四、 細胞存活率分析……………………………………………………………15
五、 後天獲得藥物抗性的穩定度………………………………………………16
六、 細胞生長曲線………………………………………………………………16
七、 細胞群落形成分析…………………………………………………………17
八、 西方墨點法…………………………………………………………………17
九、 流式細胞儀之分析…………………………………………………………19
十、 Lysotracker…………………………………………………………………20
十一、 細胞移動分析………………………………………………………………21
十二、 結球實驗……………………………………………………………………21
十三、 Microarray分析……………….……………………………………………22
十四、 分析與統計方法……………………………………………………………22

第四章 結果...…………………………………………………...…………………23

一、證明Imiquimod抗性的基底細胞癌細胞株(BCC-R) ……………………….23
二、BCC-R在處理高劑量的Imiquimod之後，存活的細胞具有增值成群落的能力……………………………………………………………………………….…24
三、BCC-R對於由Imiquimod所誘導細胞凋亡是有抗性………………….……24
四、BCC-R會改變由Imiquimod所誘導細胞自噬…………………….…………25
五、BCC-R細胞株溶小體在Imiquimod抗性中扮演重要的角色…….…………25
六、BCC-R與BCC在皮膚分化上的差異…………...……………………………26
七、BCC-R具有較大的doubling time…………………………..…………………27
八、BCC-R與BCC相比較，較不像癌症幹細胞…...…………...……………….27
九、BCC-R細胞株移動能力是比較弱的………………………………………….28
十、BCC-R具有多重藥物抗性的能力…………………………………………….28

第五章 結論………………………………………………………………………..30

第六章 討論………………………………………………………………………..31

第七章 參考文獻…………………………………………………………………..37

第八章 實驗結果圖………………………………………………………………..45

圖一、證明Imiquimod抗性的基底細胞癌細胞株(BCC-R) ……………………..45
圖二、BCC-R對於Imiquimod所誘導的細胞凋亡和細胞自噬有抵抗力…………49
圖三、BCC-R細胞株溶小體在Imiquimod抗性中可能扮演重要的角色………...51
圖四、BCC與BCC-R在皮膚分化上的差異………………………….……………54
圖五、BCC-R與BCC相比較，比較不像癌症幹細胞………….…………………55
圖六、BCC-R細胞株移動能力是比較弱的……………………….……………….56
圖七、BCC-R具有多重藥物抗性的能力…………………….…………………….58
圖八、本研究的實驗結果總結………………………………………………………60

第九章 附圖與附表………………………………………………………………..61

附圖一、細胞自噬的進行機制示意圖………………………………………………61
附圖二、細胞凋亡的進行示意圖……………………………………………………62
附圖三、Imiquimod藉由刺激樹突細胞而活化細胞性免疫反應抑制腫瘤的存活63
附表一、抗體一覽表…………………………..……………………………………..64

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