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研究生:陳宣冘
研究生(外文):Chen, Shiuan-Yin
論文名稱:藉慢病毒載體調控之RNAi抑制EGFR與MRP2以提升口腔癌的化療成效
論文名稱(外文):Enhancing chemosensitivity of oral cancer by downregulation of EGFR and MRP2 genes via lentivirus vector-mediated RNAi.
指導教授:戴建國戴建國引用關係
指導教授(外文):Tai,Chien-Kuo
口試委員:蕭光明李文乾
口試委員(外文):Hsiao,Kuang-MingLee,Wen-Chien
口試日期:2011-07-26
學位類別:碩士
校院名稱:國立中正大學
系所名稱:分子生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:82
中文關鍵詞:化學敏感性RNA干擾口腔癌
外文關鍵詞:chemosensitivityRNAioral squamous cell carcinoma
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口腔癌的死亡率為全台灣癌症排名第五,廣泛用於治療口腔癌的化療藥物為順鉑(Cisplatin)和 5-氟尿嘧啶(5-FU)。然而,由一些臨床報告顯示口腔癌病患有續發性抗藥性的發生。在本研究我們期望透過抑制抗藥基因的表現以提升癌細胞對於 Cisplatin 和 5-FU 的敏感性。實驗室過去的研究發現在口腔鱗狀上皮細胞癌(OSCC)中,抑制 EGFR 的表現會造成細胞對於 Cisplatin 和 5-FU 的 IC50 值分別下降 20% 和 52%。但是在裸鼠皮下之腫瘤模式中,以 Cisplatin 治療腫瘤細胞 OC2/shEGFR 與對照組 OC2/shRFP 細胞相比,腫瘤的生長並無明顯差異。另外,多重抗藥性相關蛋白2(MRP2)也曾被證實與腫瘤的抗藥性相關。本研究降低 OSCC 中MRP2 的表現量,可以使細胞對 5-FU 的 IC50 值下降。因此,我們以 OC2 細胞合併抑制 EGFR 以及 MRP2 的表現量(OC2/shEGFR/shMRP2),觀察是否可以更進一步地降低細胞對於 5-FU 的 IC50 值。我們已証實 OC2/shEGFR/shMRP2 中 EGFR 和 MRP2 的 mRNA 表達量有顯著的降低,EGFR 蛋白質的表現量亦下降約一半,但在細胞增生率實驗中與對照組相比,並不會因為 EGFR 和 MRP2 基因受到抑制而影響到細胞的增長。以細胞毒殺性實驗與對照組相比,OC2/shEGFR/shMRP2 細胞對於 5-FU 的敏感性約增加 5 倍;並將細胞暴露在不同濃度的 5-FU 於 24 小時後,細胞位於 sub-G1 的分布有增加的趨勢。以裸鼠皮下之 OC2/shEGFR、OC2/shEGFR/shMRP2 細胞腫瘤,發現以 5-FU 藥物治療均可以抑制腫瘤的增長。
另外,為了進一步模擬在臨床上病人使用化療藥物治療後產生抗藥性的現象,我們亦建立三株具有抗藥性之細胞株。由 Cisplatin 所建立起的抗藥細胞株 OC2CisR 與親本細胞 OC2 相比對於 Cisplatin 的 IC50 值有提升約 3 倍,抗藥細胞株的 MRP2 和 MRP3 基因的表現量也有提升,在裸鼠皮下之 OC2CisR 腫瘤增長速度亦快於 OC2 腫瘤。但若將 OC2CisR 細胞合併抑制 MRP2 和 EGFR 可以減少細胞對於 Cisplatin 的 IC50 值,証實利用慢病毒載體調控 RNAi 的機制,可以恢復抗藥細胞株對於 Cisplatin 的敏感性。
Oral squamous cell carcinoma (OSCC) is the fifth most common cancer in Taiwan, and the tumor incidence has a high mortality rate. Cisplatin and 5-FU are widely used chemotherapeutic drugs in the treatment of OSCC. However, some clinical studies have found that patients suffering from OSCC exhibited secondary drug resistance. In this study, we desire to reduce the drug resistance of OSCC through knockdown drug resistant genes for elevating chemosensitivity to cisplatin and 5-FU. In previous study, we have found that knockdown of EGFR, resulted in 52% and 20% decrease towards 5-FU and cisplatin IC50, respectively. However, in vivo tumor model proved that after treatment of cisplatin, the tumor growth of the EGFR-knockdown OC2 cells showed no significant difference compared to that of control OC2 cells. Currently, ATP-binding cassette multidrug resistance transporter 2, MRP2, was reported to be involved in drug resistance of human tumors. In our OSCC cell line, knockdown of MRP2 resulted in decrease of 5-FU IC50, but no change in cisplatin IC50. We therefore test whether simultaneous knockdown of MRP2 and EGFR genes in OC2 (OC2/shEGFR/shMRP2) could result in further decrease of drug IC50. OC2/shEGFR/shMRP2 cell clones with reduced expression of targeted MRP2 and EGFR mRNA, result in a modest decrease in EGFR protein level, but we observed no differences in proliferation rates between OC2/shEGFR/shMRP2 and control OC2 cells. In vitro, sensitivity of OC2/shEGFR/shMRP2 against 5-FU increased by 80%, compared to control cells in terms of IC50, and they also exhibited an increase in sub-G1 population after 24 hours exposure to 5-FU. In vivo, the growth of OC2 solid tumors expressing shEGFR or simultaneously expressing shEGFR and shMRP2 was significantly inhibited by 5-FU in transplanted nude mice model. In addition, we have established a stable drug resistant cell line by exposing 3 OSCC lines to low drugs concentration until their resistance indexes increase. During this process we were mimicking the emergence of drug resistant OSCC tumor in patients. Interestingly, the IC50 for cisplatin in OC2CisR, the established cisplatin-resistant OC2 cell line was 3-fold higher than that in parental OC2. Of the three ABC transporters (MRP1, MRP2, MRP3), MRP2 and MRP3 was found to be elevated in resistant cell line. Our in vivo data showed that cisplatin resistant cell line OC2CisR reduced the inhibitory effects of cisplatin on growth of tumors in nude mice. Dramatically, simultaneous knockdown of MRP2 and EGFR genes in OC2CisR can result in further decrease of cisplatin IC50. Our investigation demonstrated that lentivirus-mediated RNAi silencing targeting MRP2 and EGFR might reverse the cisplatin-related drug resistance of OC2CisR against cisplatin.
中文摘要 I
Abstract II
1. 緒論 1
1.1 口腔癌 1
1.2 化療藥物 2
1.3 NF-κB基因與口腔癌抗藥性之關係 3
1.4 Survivin基因與口腔癌抗藥性之關係 4
1.5 MRP2基因與口腔癌抗藥性之關係 5
1.6 EGFR基因與口腔癌抗藥性之關係 6
1.7 RNA干擾 7
1.8 RNA干擾之慢病毒(lentivirus)載體 8
1.9 動機 9
2. 材料與方法 11
2.1 細胞株及其培養 11
2.2 建立抗藥性細胞株 11
2.3 慢病毒質體系統 12
2.4 pLKO_TRC008-shMRP2質體的構築 12
2.5 病毒製備 13
2.6 病毒感染與細胞篩選 14
2.7 細胞生長與細胞毒殺性測試 14
2.8 mRNA 表現量 15
2.9 西方墨點法 16
2.10 細胞週期分析 17
2.11 細胞凋亡分析 18
2.12 動物治療效果測試 18
2.13 統計分析 19
3. 結果 20
3.1 慢病毒載體所攜帶的 shRNA 可以有效地抑制特定基因的表達。 ………………………………………………………………………..20
3.2 shNF-κB 可以降低 OCSL 細胞中 55% 的 NF-κB 表現量,並且提升 Cisplatin 的治療成效。 21
3.3 降低細胞中 Survivin 的表現量是無法增進口腔癌細胞株對於 Cisplatin 以及 5-FU的化學敏感性。 21
3.4 shMRP2 可以降低 OCSL 細胞中 70% 的 MRP2 表現量,並且提升 5-FU 的治療成效。 22
3.5 shEGFR 以及 shEGFR/shMRP2 可以降低 OC2 細胞中 EGFR 和 MRP2 的表現量,並且提升 5-FU 的治療成效。 23
3.6 OC2/shEGFR 以及 OC2/shEGFR/shMRP2 之老鼠皮下腫瘤,可以提升 5-FU 的治療成效。 26
3.7 抗藥株細胞有高度表現 MRP2 和 MRP3。 28
3.8 抗藥株細胞之功能性分析 29
3.9 以裸鼠皮下之腫瘤模式確抗藥性細胞 OC2CisR 對於 Cisplatin的敏感性較低。 31
3.10 shEGFR/shMRP2 可以提升抗藥性口腔癌細胞株 OC2CisR 對於 Cisplatin 和 5-FU 的敏感性。 31
4. 討論 33
5. 參考文獻 39

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