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研究生:吳俊賢
研究生(外文):Jyun-Sian Wu
論文名稱:新穎微脂體 Lipid calcium phosphate組合siRNA下調HIF-1α與EGFR癌化基因治療之口腔癌研究
論文名稱(外文):Novel liposomal Lipid calcium phosphate combined with siRNA for knockdown of HIF-1α and EGFR genes in oral cancer treatment
指導教授:陳信銘陳信銘引用關係
口試委員:江俊斌
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:口腔生物科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2019
畢業學年度:108
語文別:中文
論文頁數:99
中文關鍵詞:口腔癌脂質磷酸鈣DOPA缺氧誘導因子-1α上皮生長因子受體微小干擾RNA
外文關鍵詞:Oral cancerLipid calcium phosphateDOPAHypoxia-inducible factor-1αEpidermal growth factor receptorSmall interference RAN
DOI:10.6342/NTU202000476
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癌症是台灣人排行第一的死亡原因,占總死亡人數27.7%,平均每天約有130人死於癌症。其中台灣口腔癌的發生率是世界第一,主要原因與飲食文化中有嚼食檳榔的行為有關。本研究使用新型微脂體磷酸鈣技術Lipid calcium phosphate (LCP),組合Hypoxia-inducible factors-1α (HIF-1α) 與Epidermal growth factor receptor (EGFR) 的small interfering RNA (siRNA) 利用DOPA (1,2-dioleoyl-sn-glycero-3-phosphate, sodium salt)、DOTAP (1,2-dioleoyl-3-trimethylammonium-propane, chloride salt)、DSPE–PEG-2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000], ammonium salt) 等化合物包覆成為奈米大小之微脂體粒子。LCP HIF-1α & EGFR siRNA微脂體的平均粒徑約在38.6 ± 7.4 nm,膜電荷為50.2 ± 0.8 mV。以體外細胞實驗驗證siRNA序列可以有效抑制60% HIF-1α蛋白質表現和抑制81% EGFR蛋白質表現。

體內動物實驗使用異種移植SAS口腔癌細胞之裸鼠的動物模型,用BALB/cAnN.Cg-Foxn1nu/CrlNarl品系的裸鼠在其皮下移植SAS口腔癌細胞,並等待其腫瘤成長是180-201 mm3的口腔癌腫瘤隨機分配5組實驗,分別為正向控制組 (PBS)、負向控制組 (LCP Control siRNA)、HIF-1α siRNA對照組 (LCP HIF-1α siRNA)、EGFR siRNA對照組 (LCP EGFR siRNA) 和HIF-1α & EGFR siRNA組合治療組 (LCP HIF-1α & EGFR siRNA),在第 0、1、2、5、6 和7天注射LCP藥物,其間隔為每24小時一次。每天持續觀察生理狀況,並每日量測腫瘤體積大小和體重,在第13天結束實驗犧牲動物。第13天的結果,PBS組腫瘤體積為500 mm3;LCP Control siRNA組腫瘤體積為542 mm3;LCP HIF-1α siRNA組腫瘤體積為526 mm3;LCP EGFR siRNA組腫瘤體積為532 mm3;LCP HIF-1α & EGFR siRNA組腫瘤體積為379 mm3。受到LCP藥物治療後,LCP HIF-1α & EGFR siRNA組比較PBS組減少121 mm3的腫瘤體積 (P<0.05)。LCP HIF-1α & EGFR siRNA組比較LCP Control siRNA組、LCP HIF-1α siRNA組與LCP EGFR siRNA組的腫瘤體積都有達到顯著的抑制 (P<0.01)。

蘇木精-伊紅染色 (hematoxylin and eosin stain, H&E stain) 觀察動物肝、腎和腫瘤切片,LCP藥物對動物的肝腎組織是沒有毒性,腫瘤切片觀察LCP HIF-1α & EGFR siRNA組有較多凋亡細胞的產生,用Mitotic Figure方法分析確認LCP HIF-1α & EGFR siRNA治療可以減少細胞有絲分裂的發生。LCP HIF-1α & EGFR siRNA在免疫組織染色中與PBS組相比Ki-67細胞增生因子和CD31血管新生因子的表現都有顯著減少,Caspase 3細胞凋亡因子的表現也比PBS組高出71%,代表LCP HIF-1α & EGFR siRNA可以抑制細胞增生,使癌細胞凋亡,並阻止腫瘤繼續生長。免疫組織染色HIF-1α和EGFR的切片染色分析證實LCP包覆HIF-1α與EGFR siRNA可以抑制HIF-1α和EGFR蛋白質表現的效果 (P<0.001)。血液生化分析分析15項與肝、腎和心肌有關的生化因子,數據顯示使用LCP HIF-1α & EGFR siRNA治療的動物,沒有出現與肝、腎和心肌功能相關的毒性產生。總體而言,LCP組合HIF-1α siRNA和EGFR siRNA可以比單獨使用HIF-1α siRNA或EGFR siRNA能更有效的抑制SAS口腔癌腫瘤的生長,並能抑制腫瘤中蛋白質的表現,且不會對動物有毒性產生副作用發生。
Cancer is most of the people cause of death in Taiwanese, accounting for 27.7% of deaths. About one day have 130 people die from cancer. The incidence of oral cancer in Taiwan is the highest in the world. The main reason is related to the behavior of chewing areca. Lipid calcium phosphate (LCP) compose of DOPA (1,2-dioleoyl-sn-glycero-3-phosphate, sodium salt)、DOTAP (1,2-dioleoyl-3-trimethylammonium-propane, chloride salt)、DSPE–PEG-2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000], ammonium salt). The LCP technology encapsulated of hypoxia-inducible factors-1α (HIF-1α) and epidermal growth factor receptor (EGFR) small interfering RNA (siRNA). LCP HIF-1α & EGFR siRNA liposome average size was 38.6 ± 7.4 nm, zeta potential was 50.2 ± 0.8 mV. In vitro cell experiments confirmed that siRNA sequences can effectively inhibit the expression of 60% HIF-1α protein and inhibit the expression of 81% EGFR protein.

In vivo animal study used xenograft SAS oral cancer cell animal model. The animal used BALB/cAnN.Cg-Foxn1nu/CrlNarl mice. Inject the SAS oral cancer cell under the mice back skin, and waited tumor growth to 180-201 mm3. The animal group had PBS group, LCP Control siRNA group, LCP HIF-1α siRNA group, LCP EGFR siRNA group and LCP HIF-1α & EGFR siRNA. LCP drugs were injected on days 0, 1, 2, 5, 6 and 7 at intervals of 24 hours. The physiological condition was continuously observed every day, and the tumor volume and body weight were measured daily, and the animals were sacrificed on the 13th day. The day 13th result, PBS group tumor volume was 500 mm3;LCP Control siRNA group tumor volume was 542 mm3;LCP HIF-1α siRNA group tumor volume was 526 mm3;LCP EGFR siRNA group tumor volume was 532 mm3;LCP HIF-1α & EGFR siRNA group tumor volume was 379 mm3。After being treated with LCP drug, LCP HIF-1α & EGFR siRNA group tumor volume was smaller than PBS group 121 mm3 (P<0.05). LCP HIF-1α & EGFR siRNA group tumor volume compares to LCP Control siRNA group, LCP HIF-1α siRNA group and LCP EGFR siRNA group tumor volume had been inhibited (P<0.01).

H&E stain (hematoxylin and eosin stain) slice about the animal liver and kidney was showing no toxicity of LCP drug. The tumor H&E stain slice LCP HIF-1α & EGFR siRNA group had apoptosis more than other groups. Mitotic figure data show LCP HIF-1α & EGFR siRNA can reduce mitosis. The expression of Ki-67 and CD31 was significantly decreased in LCP HIF-1α & EGFR siRNA groups compared with PBS group. The LCP HIF-1α & EGFR siRNA group expression of caspase 3 was higher than the PBS groups. The LCP HIF-1α & EGFR siRNA can inhibit cell proliferation, causes apoptosis, and prevents tumor growth. IHC staining of HIF-1α and EGFR protein analysis confirmed that LCP encapsulated HIF-1α and EGFR siRNA could inhibit the expression of HIF-1α and EGFR proteins (P<0.001). Biochemical analysis analyzed 15 biochemical factors related to liver, kidney and heart muscle. The data showed that animals treated with LCP HIF-1α & EGFR siRNA did not develop toxicity associated with liver, kidney and heart.

Overall, LCP combined with HIF-1α siRNA and EGFR siRNA can inhibit the growth of SAS oral cancer tumors more effectively than HIF-1α siRNA or EGFR siRNA alone, and can inhibit the expression of proteins in tumors, and not to animals. LCP will not cause side effects.
口試委員會審定書………………………………………………………………………i
中文摘要…………………………………………………………………………………ii
英文摘要……………………………………………………………………………iiii
致謝………………………………………………………………………………...…...vi
目錄……………………………………………………………………………...……..vii
圖目錄………………………………………………………………………………......xi
表目錄…………………………………………………………………………...…….xiii
第一章 研究介紹………………………………...……………………………………..1
1-1 研究背景…………………………………………………………………………1
1-2 研究動機及目的…………………………………………………………………7
第二章 實驗設計規劃流程…………………………………………………………….9
2-1 動物實驗流程設計………………………………………………………………9
2-2 LCP毒理實驗設計流程………………………………………………………...11
第三章 文獻探討……………………………………………………………………...12
3-1 口腔癌生成機制………………………………………………………………..12
3-2 口腔癌的生長………………………………………………………………......14
3-3 口腔癌的治療…………………………………………………………………..18
3-4 Small interference RAN介紹與機制…………………………………………....19
3-5 缺氧誘導因子(Hypoxia-inducible factors, HIFs) 介紹與機制………………..21
3-6 表皮生長因子受器 (Epidermal growth factor receptor, EGFR) 介紹與機制.24
3-7 奈米藥物 (Nanomedicine)……………………………………………………..30
第四章 材料與方法……………………………………………………………..…….36
4-1 口腔癌細胞株介紹……………………………………………………………..36
4-2動物模型介紹……………………………………………………………….......36
4-3 微脂體磷酸鈣 (Lipid calcium phosphate, LCP) 包覆藥物傳遞……………...37
4-4 siRNA序列………………………………………………………………………39
4-5 siRNA轉染細胞株實驗………………………………………………………....39
4-6 西方點墨法 (Western Blot)……………………………………………………40
4-6-1 蛋白質萃取………………………………………………………………...40
4-6-2 BCA protein assay…………………………………………………………..40
4-6-3 蛋白質電泳………………………………………………………………...41
4-6-4 西方點墨法………………………………………………………………...42
4-6-5 專一性抗體檢測…………………………………………………………...42
4-7 動物實驗………………………………………………………………..............43
4-8 血液生化分析………………………………………………………………......44
4-9 組織包埋與化學染色切片分析………………………………………………..45
4-11 免疫組織染色分析……………………………………………………………46
4-12微血管密度評估 (Microvessel density, MVD) ……………………….47
4-13 細胞存活率分析 (MTT assay) ……………………………………………….47
4-14 實驗統計資料分析……………………………………………………………48
第五章 實驗結果………………………..…..………………………………………...49
5-1 CoCl2細胞毒殺劑量與誘發HIF-1α蛋白質表現免疫分析……………...49
5-1-1 CoCl2細胞毒殺劑量…………………………………………..................49
5-1-2 CoCl2誘發HIF-1α蛋白質表現免疫分析……………………….…….......50
5-2 siRNA於SAS口腔癌細胞的細胞毒殺劑量測試……………………………...51
5-3 siRNA轉染SAS口腔癌細胞蛋白質西方點墨法分析實驗…………………..52
5-4 LCP微脂體包覆藥物粒徑與表面膜電位測定分析結果……………………..54
5-4-1 LCP微脂體包覆Control siRNA粒徑與表面膜電位測定分析結果………54
5-4-2 LCP微脂體包覆HIF-1α siRNA粒徑與表面膜電位測定分析結果.....55
5-4-3 LCP微脂體包覆EGFR siRNA粒徑與表面膜電位測定分析結果……56
5-4-4 LCP微脂體包覆HIF-1α & EGFR siRNA粒徑與表面膜電位測定分析結果…57
5-5 異種移植SAS口腔癌細胞之裸鼠腫瘤體積……………………………..…....58
5-6 異種移植SAS口腔癌細胞之裸鼠體重………………………….…...........60
5-7 異種移植SAS口腔癌細胞之裸鼠之肝、腎和腫瘤病理染色切片……61
5-8 異種移植SAS口腔癌細胞之裸鼠腫瘤免疫組織染色切片…………………63
5-8-1異種移植SAS口腔癌細胞之裸鼠腫瘤Ki-67免疫組織染色切片……......63
5-8-2異種移植SAS口腔癌細胞之裸鼠腫瘤Caspase 3免疫組織染色切片.....65
5-8-3異種移植SAS口腔癌細胞之裸鼠腫瘤CD31免疫組織染色切片...67
5-8-4異種移植SAS口腔癌細胞之裸鼠腫瘤HIF-1α免疫組織染色切片…69
5-8-5異種移植SAS口腔癌細胞之裸鼠腫瘤EGFR免疫組織染色切片………71
5-9 臨床血液生化分析……………………………………..…………………..........73
5-9-1 肝功能指數分析…………………………………………..………….........73
5-9-2 腎功能指數分析………………………………………………..…….........74
5-9-3 肝腎功能指數分析……………………………………………..…….........76
5-9-4 心肌功能指數分析…………………………………..…………………….78
第六章 結果討論……………………………………… ….......…………..………….79
6-1 LCP微脂體包覆藥物粒徑與表面膜電位測定分析結果……………….79
6-2 CoCl2細胞毒殺劑量與誘發HIF-1α蛋白質表現免疫分析………….80
6-3 siRNA於SAS口腔癌細胞的細胞毒殺劑量測試…………………….80
6-4 siRNA轉染SAS口腔癌細胞蛋白質西方點墨法分析實驗……………….81
6-5 異種移植SAS口腔癌細胞之裸鼠腫瘤體積…………………....82
6-6 異種移植SAS口腔癌細胞之裸鼠體重…………...…………..………….....83
6-7 異種移植SAS口腔癌細胞之裸鼠之肝、腎和腫瘤病理染色切片………83
6-8 異種移植SAS口腔癌細胞之裸鼠腫瘤免疫組織染色切片………….…….84
6-9 臨床血液生化分析………………………………………….………........…….84
第七章 結論……....…………..…………………....…………..………..……….……86
參考資料.……………………..……………....……………………………………87
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