物理微環境在腫瘤病程與治療上有相當重要之影響。近年硼中子捕獲治療(BNCT)因具精準靶向腫瘤之優勢，受到廣泛關注；然腫瘤物理微環境對其治療之影響，仍有許多值得探討的空間。本研究中，我們將人類神經膠質母細胞瘤細胞(Gliomablstom)培養於生理病理性硬度範圍為0.1 kPa到120 kPa的基質，進行BNCT及相關實驗。結果顯示，硬基質(≧19 kPa)促使GBM細胞(U87-MG)有較佳的BNCT治療效果；然而，對另一GBM細胞(U251-MG)的效果卻較差。然而，GBM細胞LAT1表現雖然隨基質硬度增加而增加，10B累積濃度卻無明顯改變，且發現硬基質上GBM會有較多的γ-H2AX細胞核表現，可能間接影響低通量中子照射GBM細胞DNA 損傷後的凋亡比例。胞內ROS是細胞生理另一重要評估指標；軟基質(0.08 kPa)使U87-MG細胞核內的Bcl2高度表現，進而負向調節ROS和抑制凋亡作用。有趣的是，我們觀察到機械傳導蛋白YAP1和β-catenin於細胞中的分布受到基質硬度變化影響，使β-catenin於GBM細胞核之高表達分別發生在較軟基質U87-MG細胞，以及較硬基質U251-MG細胞，進而關聯BNCT在GBM細胞類型之間治療效果差異。我們的研究證實機械傳導訊傳會影響BNCT對神經膠質瘤細胞之生物效應，進而探討了基質硬度影響 GBM細胞之BNCT治療效果的可能路徑，研究亦建議在病理性硬度範圍內，機械傳導訊號表達明顯受到GBM細胞亞型影響。我們期待研究成果能對於臨床BNCT有效性提供更多面向之評估參考。

The stiffness of extracellular matrix serves an essential role in regulating cell physiology, however, the influences of microenvironmental stiffness on the tumor re-sponse to radiation therapy is still largely underexplored. Herein, we applied the boron neutron capture therapy (BNCT), a precise targeted particle therapy, to the glioma cells on the substrates with pathophysiological stiffness (ranging from 0.1 kPa to 120 kPa). Our results showed that, in a softer environment, there was higher BNCT efficacy for human glioblastoma cells (U87-MG), but not for another type of gliomablstoma cells (U251-MG). We observed that increasing substrate stiffness upregulate the LAT1 of gli-oma, but the intracellular 10B concentration remains unchanged. Additionally, substrate stiffness alters the dynamics of γ-H2AX DNA repair and modulates the level of reactive oxygen species in glioma cells. Two critical mechanotransduction signals, YAP1 and β-catenin were identified as being correlated to the glioma responses to BNCT. Bcl2, which is involved in modulating mitochondrial function and apoptosis, responds to the alteration of substrates stiffness as well. Our results suggest that substrate stiffness serves as a critical factor for influencing BNCT efficacy through altering the dynamic of DNA repair and intracellular ROS homeostasis. The outcome of this study may sheds light on the essential linkages between the biophysical microenvironment and BNCT efficacy, which further imply the mechanotransduction signaling is vital and provides alternative perspectives for evaluating clinical BNCT effectiveness.

摘要 i
Abstract ii
誌謝 iii
目錄 iv
圖目錄 x
表目錄 xii
Chapter 1 導論 1
1.1 研究動機 1
1.1.1 BNCT臨床適應症 1
1.1.2 BNCT對GBM的治療潛力 1
1.1.3 基質硬度對GBM的BNCT治療效果之潛在影響 1
1.2 文獻回顧 2
1.2.1 基質硬度對神經膠質母細胞瘤 (Glioblastoma multiforme, GBM) 在硼中子捕獲治療(Boron neutron capture therapy, BNCT)的治療效果和影響 2
1.2.1.1 GBM於臨床治療的挑戰 2
1.2.1.2 BNCT治療原理以及對GBM患者的治療潛力 3
1.2.2 硼中子捕獲治療(BNCT)直接與間接對DNA破壞之生物反應 4
1.2.2.1 BNCT高LET帶電粒子對DNA直接損傷與修復機制 4
1.2.2.2 BNCT低LET之伽馬射線(γ-ray) 間接對DNA損傷 5
1.2.3 輻射對DNA的破壞啟動細胞凋亡程序 6
1.2.3.1 細胞凋亡(Apoptisis)途徑的發生與機制 6
1.2.4 活性氧(ROS)與抗凋亡蛋白Bcl2於輻射治療之影響 8
1.2.4.1 過量ROS於臨床輻射治療之優勢與影響 8
1.2.4.2 Bcl2 參與細胞凋亡途徑機制與影響輻射治療抗性 9
1.2.5 細胞外基質硬度(ECM)對GBM進展與臨床治療的潛在影響 10
1.2.5.1 GBM於大腦內之ECM成分與硬度 10
1.2.5.2 ECM的機械特性影響腫瘤細胞行為表現 11
1.2.6 基質硬度調控YAP1 影響輻射治療效果 12
1.2.6.1 基質硬度影響細胞YAP1分佈對輻射治療潛在影響 12
1.2.7 基質硬度影響細胞中β-catenin的分佈與行為調節 15
基質硬度對具有雙重功能的β-catenin蛋白之影響，分為以下2點： 15
1.2.7.1 E-cadherin/β-catenin機械轉導機制與增殖 15
1.2.7.2 Wnt/β-catenin對細胞行為和輻射治療影響潛力 15
1.3 研究主題與實驗流程 17
1.4 研究架構圖 18
Chapter 2 材料與方法 19
2.1 細胞培養 (Cell culture) 19
2.2 聚丙烯醯胺水凝膠 (Polyacrylamide hydrogel, PAGE) 20
2.2.1 清洗蓋玻片 20
2.2.2 蓋玻片表面活化 20
2.2.3 聚丙烯醯胺成膠 21
2.2.4 透明質酸鈉（Hyaluronic acid, HA）塗層 22
2.3 Boronophenylalanine (10B-BPA)溶液配製備 23
2.4 細胞內硼元素(10B)含量測定與細胞之蛋白質定量 23
2.4.1 細胞內硼元素(10B)含量測定 24
2.4.2 細胞之蛋白質萃取 24
2.4.3 細胞之蛋白質定量 24
2.4.4 標準校正線 25
2.5 BNCT 實驗照射前與照射後處理條件與流程 25
2.6 細胞存活分析 (Colony formation assay) 26
2.7 細胞凋亡 (Apoptosis test) 27
2.8 DNA 損傷 (DNA damage) 的γ-H2AX測定 28
2.9 細胞內活性氧 (Reactive oxygen species, ROS)測定 29
2.10 免疫螢光染色 30
2.10.1 免疫螢光染色步驟 30
2.10.2 YAP 1與β-catenin之細胞核轉位免疫螢光染色分析方法 31
2.11 Cell Counting Kit-8 (CCK-8)細胞活力測定 （附錄） 32
2.12 數據統計 32
2.13 實驗藥品、材料與儀器彙整 33
Chapter 3 結果 35
3.1 基質硬度影響GBM細胞在BNCT治療後的效果 35
3.2 探討GBM細胞對10B-BPA累積濃度與基質硬度之影響 38
3.2.1 基質變硬使GBM細胞LAT1表現增加 38
3.2.2 基質硬度變硬使GBM細胞增殖增強 38
3.2.3 GBM細胞對10B累積濃度差異不受基質硬度顯著影響 39
3.3 探討基質硬度影響GBM細胞於BNCT照射的生物反應 41
3.3.1 基質硬度影響GBM細胞於BNCT治療後的凋亡反應 41
3.3.1.1 基質硬度影響GBM細胞的凋亡反應趨勢與中子通量有關.................... 41
3.3.1.2 GBM細胞類型於硬基質表現相異凋亡程度 42
3.3.1.3 GBM細胞類型與BNCT凋亡敏感性有關 42
3.3.2 基質硬度變硬使GBM細胞DNA損傷反應增強 44
3.3.2.1 評估基質硬度GBM 之DNA損傷反應方法 44
3.3.2.2 基質硬度變硬使GBM細胞之γ-H2AX foci 形成數量增加.................... 44
3.3.2.3 基質硬度使GBM細胞類型的DNA 損傷清除延遲表現差異................ 45
3.3.3 基質硬度影響GBM細胞於BNCT治療後的ROS表現 47
3.3.3.1 基質硬度變硬增加GBM細胞的ROS誘導 47
3.3.3.2 較硬的基質使GBM細胞的ROS表現不同 48
3.3.4 基質硬度影響GBM細胞的ROS與Bcl2表現 50
3.3.4.1 較硬的基質增加GBM細胞的ROS表現 50
3.3.4.2 較硬的基質抑制GBM細胞的Bcl2表現 50
3.3.4.3 GBM細胞ROS和Bcl2表現於基質硬度呈負相關 51
3.3.5 基質硬度影響GBM細胞在BNCT治療之ROS與Bcl2表現 53
3.3.5.1 GBM細胞類型(U87-MG/U251-MG)Bcl2表現受基質硬度影響趨勢相反 53
3.3.5.2 GBM(U251-MG)的Bcl2與ROS表現受硬基質影響呈負向調節............ 53
3.3.6 基質硬度影響GBM細胞核在BNCT治療之Bcl2表現 54
3.3.6.1 GBM(U87-MG)細胞核Bcl2表現受軟基質影響而增加 54
3.3.6.2 Bcl2於GBM(U251-MG)細胞核分佈易誘導細胞凋亡 54
3.4 基質硬度之機械轉導影響GBM細胞的表現 58
3.4.1 基質硬度增加使GBM細胞YAP1核轉位增強 58
3.4.2 基質硬度增加使GBM細胞β-catenin核轉位增強 61
3.4.3 觀察基質硬度影響GBM核YAP1和β-catenin總表現 63
3.4.3.1 基質硬度增加使GBM細胞核YAP1總表現降低 63
3.4.3.2 基質硬度使GBM細胞核β-catenin總表現趨勢相反 63
Chapter 4 討論 65
4.1 基質硬度機械轉導途徑影響GBM細胞於BNCT預後 65
4.1.1 GBM細胞的BNCT預後與核β-catenin表現負相關 65
4.1.2 GBM核β-catenin涉及YAP1調節與Bcl2表現正相關 65
4.2 基質硬度不影響GBM細胞的10B-BPA累積濃度 67
4.2.1 基質硬度增加而增強GBM細胞的LAT1表現 67
4.2.1.1 基質硬度影響GBM細胞胺基酸代謝與YAP1有關 67
4.2.1.2 YAP1核轉位發生使GBM細胞LAT1表現增強 67
4.2.1.3 β-catenin核轉位增強GBM細胞的LAT1表現 67
4.2.2 GBM細胞的10B-BPA累積濃度不受基質硬度影響 68
4.3 基質硬度增加而增強GBM細胞的增殖能力 70
4.3.1 YAP1核轉位增強GBM細胞增殖表現 70
4.3.2 β-catenin核轉位增強GBM細胞增殖表現 71
4.4 基質硬度影響GBM細胞對BNCT的生物反應 75
4.4.1 GBM細胞凋亡表現不直接影響BNCT治療後之存活 75
4.4.2 基質硬度上GBM影響對DNA損傷反應 75
4.4.2.1 較硬基質可能增強GBM細胞DNA 修復蛋白定位 75
4.4.2.2 較軟基質增加GBM核(U87-MG)Bcl2表現抑制DNA損傷修復............ 76
4.4.2.3 較硬基質YAP1核轉位促進GBM細胞DNA損傷修復.................... 77
4.4.3 較硬基質GBM細胞類型細胞凋亡與ROS表現相關 77
4.4.4 基質硬度影響GBM細胞類型之Bcl2表現趨勢差異 78
4.4.5 Bcl2於GBM(U251-MG)細胞核中分布易誘導細胞凋亡 78
4.5 基質硬度影響GBM(U87-MG/U251-MG)細胞核的YAP1和β-catenin表現............. 80
4.5.1 基質硬度影響GBM細胞核YAP1總表現 80
4.5.1.1 較硬基質降低GBM細胞核YAP1總表現 80
4.5.1.2 軟基質0.08 kPa使GBM細胞核YAP1總表現降低 80
4.5.2 基質硬度影響GBM(U87-MG)細胞核β-catenin總表現 81
4.5.2.1 較硬基質降低GBM(U87-MG)細胞核β-catenin總表現..................... 81
4.5.2.2 較軟基質增加GBM(U87-MG)細胞核β-catenin總表現.................... 81
4.5.3 基質硬度影響GBM(U251-MG)細胞核β-catenin總表現 82
4.5.3.1 較硬基質硬度增加GBM細胞(U251-MG)β-catenin總表現.................... 82
4.5.3.2 較軟基質降低GBM(U251-MG)細胞核β-catenin總表現.................... 82
Chapter 5 結論 84
Chapter 6 未來發展 86
6.1 評估GBM基質硬度之BNCT臨床治療預後潛力 86
6.2 基質硬度影響GBM細胞類型於BNCT治療之評估 86
6.3 GBM細胞之YAP1機械轉導調控對BNCT治療優化潛力 87
參考文獻 88
附錄一 100
1.1 較硬基質增加GBM細胞核YAP1總表現誘導BNCT治療抗性 100
1.2 較軟基質下調GBM細胞YAP1與其磷酸化削弱BNCT治療抗性............. 103
1.3 建議YAP1總表現不適用於GBM細胞在BNCT之預後指標 104
附錄二、觀察基質硬度細胞活力於GBM之表現 107
附錄三、BNCT照射模式設定與觀察10B-BPA藥物配製方法差異反應 109
附錄四、 BNCT條件選擇 111

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