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系統識別號 U0026-1602201621224700
論文名稱(中文) 蛋白酶體抑制劑Bortezomib增強口腔癌放射線治療敏感性
論文名稱(英文) Bortezomib, a proteasome inhibitor, enhances radiosensitivity in oral cancer
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 104
學期 1
出版年 105
研究生(中文) 吳玟萱
研究生(英文) Wun-Syuan Wu
學號 s76024086
學位類別 碩士
語文別 中文
論文頁數 63頁
口試委員 指導教授-王應然
口試委員-郭靜娟
口試委員-何元順
口試委員-張嘉哲
口試委員-邱惠雯
中文關鍵字 口腔癌  蛋白酶體抑制劑  放射線治療  自體吞噬  泛素化 
英文關鍵字 oral cancer  protrasome inhibitor  radiotherapy  autophagy  ubiquitination 
學科別分類
中文摘要 口腔鱗狀細胞癌是癌症中最常見的類型之一。大多數口腔癌患者早期有很好的生存率,但是晚期或復發的患者沒有更有效的治療效果。蛋白酶體的主要作用是將接上泛素鏈的蛋白質分解,並且在人體中會調控細胞週期、細胞增生、細胞凋亡、血管新生、轉移、化療和放射治療的抗性;因此近年來有學者將蛋白酶體抑制劑合併放射治療希望在癌症治療上有更好的效果。Bortezomib 是第一個批准用於臨床治療的蛋白酶體抑制劑,目前可用於治療多發性骨髓癌。最近的研究指出,TRAF6 會調節 Akt 泛素化以及活化,並且 TRAF6 活化 NF-κB 的路徑在癌症發展中扮演重要的角色。先前研究也發現在口腔癌細胞中 TRAF6 和 NF-κB 有過度表現的現象。在目前的研究發現抗癌藥物會引起第一型(細胞凋亡)和第二型(自體吞噬)計畫性細胞死亡。本篇的研究目的是合併處理蛋白酶體抑制劑 Bortezomib 與放射線在體外細胞實驗、動物實驗和分析臨床檢體,進一步分析其可能的相關作用機制。在體外試驗中利用 trypan blue 分析細胞存活率,並利用 CalcuSyn 軟體計算其 combination index (CI);以流式細胞儀分析細胞週期和早期細胞凋亡;西方墨點法來測定細胞凋亡和自體吞噬相關蛋白之表現量變化;蛋白質之間的交互作用及泛素作用使用免疫沉澱法分析。在動物實驗中,採用皮下異種移植模式,以量尺量測的方式觀察腫瘤生長的情形,並利用組織切片染色法觀察口腔癌的病理變化,最後利用免疫組織化學染色法和西方墨點法分析相關蛋白的表現量。此外,使用免疫組織化學染色法分析口腔癌病人和相對的正常組織檢體 TRAF6 的表現量。在體外試驗的結果顯示,我們利用人類口腔癌細胞株 SCC-9、SAS 與 SCC-25 在合併處理放射線與蛋白酶抑制劑 Bortezomib 後,抑制效果較單獨處理藥物組別顯著,利用細胞群落分布實驗也發現合併處理的組別比單獨藥物組的細胞形成群落的數目更少,並且顯著提高自體吞噬與早期細胞凋亡的百分比。我們發現在 SAS 細胞中單獨處理放射線或 Bortezomib 與合併處理的組別明顯增加自體吞噬指標 p62 的表現,而在另一個自體吞噬指標 LC3-II 的表現量結果顯示單獨給予 Bortezomib 與合併處理的組別均有增加的情形。探討單獨處理放射線對於 SAS 細胞所誘發的相關機制以及合併處理Bortezomib 所造成的影響,從結果顯示 Bortezomib 可以明顯的抑制放射線所誘發 NFκB 的活化和口腔癌細胞存活能力。SAS 細胞在 Bortezomib 合併處理之下,TRAF6與磷酸化 Akt(T308) 的表現量都有顯著降低;進一步利用免疫沉澱法發現合併處理會降低 Akt 蛋白的多泛素化,除此之外我們可以發現蛋白酶體抑制劑 Bortezomib 合併放射線治療口腔癌的機轉是透過增強 autophagy-dependent TRAF6 degradation。在口腔癌皮下異種移植動物模式,合併處理放射線與蛋白酶體抑制劑Bortezomib 可有效抑制口腔腫瘤的生長,SAS 細胞在 Bortezomib 合併處理之下,TRAF6 和磷酸化 Akt(T308) 的表現量都有顯著降低。另外在 Knockdown SAS 細胞株的 TRAF6 基因動物模式中,也明顯的降低口腔腫瘤生長的體積,因此 TRAF6 可能會影響到腫瘤生長情形。此外,TRAF6 於4個隨機取樣的口腔鱗狀細胞癌臨床檢體中都有過度表現的現象,利用免疫組織化學染色法的結果也顯示 TRAF6 在人類口腔癌組織中有過度的表現。另外經由 Kaplan-Meier 生存分析結果顯示,有 TRAF6 表達的患者比沒有 TRAF6 表達的患者存活率相對較低。綜合以上結果可知,合併處理蛋白酶體抑制劑可經由抑制 TRAF6 訊息傳遞路徑而誘發自體吞噬和細胞凋亡而增加放射線對於口腔癌細胞抗癌效果。
英文摘要 Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world. The advances in treatment modalities; like chemotherapy, radiation and surgery, failed to significantly improve the prognosis and respond to standard therapies of patients with OSCC. In this study, we intented to investigate the synergistic anti-cancer effects of ionizing radiation (IR) combined with bortezomib in human oral cancer cells, and to examine the mechanisms of these effects in vitro and in vivo, focusing on the expression pattern of TRAF6 in OSCC samples. The current results indicated that combined treatment increased the therapeutic efficacy of oral cancer cell lines (SCC-9, SAS, SCC-25) through the induction of apoptosis and autophagy. Furthermore, there was a significant increase of TRAF6 expression in oral cancer cell line. The expression level of TRAF6 and phosphorylation of Akt T308 was significantly decreased in SAS cells treated with combined treatment, and the combined treatment also led to decreased Akt poly-ubiquitination level detected by using immunoprecipitation. In a xenograft model of oral cancer, we found that the combined treatment group and the two stable TRAF6 knockdown oral cells group had lower tumorigenic potential than control cells and the expression of TRAF6 and phosphorylation of Akt T308 were significantly decreased in the combination of IR and Bortezomib. Thus, TRAF6 appeared to influence tumorigenesis in those animal models. In clinical results, significant increased TRAF6 expression was found in randomly selected OSCC tissues. Kaplan-Meier survival curve also showed that positive TRAF6 expression was significantly associated with poor overall survival. Taken together, our results demonstrated that the combined treatment of IR and Bortezomib, at least in part, suppressing TRAF6 expression would increase anti-cancer effect in humor oral cancers.
論文目次 第一章、 序論 1
第二章、 文獻回顧 2
第一節、口腔癌(Oral cancer)及其治療方式 2
第二節、放射線治療(Radiation therapy)合併化學藥物 2
第三節、蛋白酶體抑制劑(Proteasome inhibitor) 4
第四節、癌症和泛素化(Ubuquitination)作用之相關性 6
第五節、Tumor necrosis factor receptor associated factor 6 (TRAF6) 7
第六節、細胞凋亡與自體吞噬(Apoptosis and Autophagy) 9
第三章、 研究目的 12
第四章、 研究架構 13
第一節、In vitro study 13
第二節、In vivo study 14
第三節、Clinical sample study 16
第五章、 研究材料與方法 17
第一節、研究材料 17
第二節、研究方法與實驗步驟 21
一、細胞培養 (Cell culture) 21
二、細胞解凍 21
三、細胞冷凍 21
四、細胞存活率 (Cell viability) 21
五、協同效應分析 (Synergistic interaction) 21
六、細胞群落分析 (Clonogenic assay) 22
七、早期細胞凋亡 (Early apoptosis) 分析 22
八、Acridine orange(AO) 分析 22
九、免疫螢光染色 (Immunofluorescence) 22
十、西方墨點法 (Western blotting) 22
十一、免疫沉澱 (Immunoprecipitation, IP) 23
十二、挑選穩定致弱基因表現細胞株 (Stable knockdown clone selection) 23
十三、定量即時聚合酶連鎖反應 (real-time PCR, qPCR) 23
十四、口腔癌皮下異種移植動物模式 (Subcutaneous xenograft in vivo model) 24
十五、臨床檢體: 26
第六章、實驗結果 28
第一節、放射線和蛋白酶體抑制劑Bortezomib對SCC-9、SAS與SCC-25細胞之毒性的劑量效應關係 28
第二節、分析合併處理放射線與蛋白酶體抑制劑Bortezomib影響SAS細胞之細胞凋亡與自體吞噬的變化 29
第三節、探討合併處理放射線合併蛋白酶體抑制劑Bortezomib對SAS細胞誘發自體吞噬現象 29
第四節、放射線引起 DNA 損傷並且誘導 NF-κB 活化主要透過 TRAF6 介導的泛素化30
第五節、合併處理放射線與蛋白酶體抑制劑Bortezomib透過抑制TRAF6-Akt訊息傳遞路徑對SAS細胞誘發計畫性死亡 30
第六節、口腔癌皮下異種移植動物模式 31
第七節、臨床檢體分析 32
第七章、討論 33
第八章、結論與建議 36
第九章、參考文獻 37
表 43
圖 46
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