瀰漫性大B細胞淋巴瘤(diffuse large B-cell lymphoma; DLBCL)為常見的非霍奇金淋巴瘤(non-Hodgkin lymphoma; NHL)。DLBCL可分為生髮中心B細胞(germinal center B cell)淋巴瘤、活化B細胞(activated B cell; ABC)淋巴瘤及原發縱隔大B細胞(primary mediastinal B-cell)淋巴瘤，其中ABC DLBCL具有較差預後和復發之情形。長時間持續給予同一藥物易使癌細胞產生抗藥性(drug-resistance)，是影響治療效果和腫瘤轉移之主要關鍵。近年發展合併療法(combination therapy)為能有效治療抗藥性腫瘤。有研究指出DLBCL中ALDH1A1表現為癌細胞產生抗藥性原因之一，因此，本研究目的為探究阿黴素(Doxorubicin; DOX)與蘿蔔硫素(sulforaphane; SFN)合併療法是否能藉由調控ALDH1A1介導之目標基因表現以有效治療ABC DLBCL。
本研究從ArrayExpress和Gene Expression Omnibus網站蒐集100個ABC DLBCL臨床組織樣本、175個人類細胞株經DOX處理及39個人類細胞株經SFN處理之微陣列資料，以NetworkAnalyst網站進行巨量資料分析，並使用Cytoscape軟體構建ABC DLBCL接受DOX與SFN治療相關之潛在基因網路圖與基因調控路徑。分析結果表示，ABC DLBCL接受DOX與SFN治療可能藉由潛在路徑F2R-GNAQ-GNAI1-KRAS-IL-1-EGFR-CCL2-STAT1-MYC-PLK1-CDKN1A-CASP3之基因調控，調控ABC DLBCL抗藥性。後續使用ABC DLBCL型細胞株進行驗證，顯示合併DOX與SFN處理能下降細胞存活率，降低ALDH1A1表現進而減少G0/G1期細胞，誘導Caspase-3和促使細胞程序性死亡。因此，本研究發現暴露DOX與SFN並降低ALDH1A1表現能逆轉ABC DLBCL抗藥性並有助於誘導細胞死亡，在臨床運用上具有治療潛力。

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). DLBCL is classified into germinal center B cell (GCB), activated B cell (ABC) and primary mediastinal B-cell (PMBL) lymphoma. ABC DLBCL has poor prognosis and recurrence when administrated with conventional chemotherapy. Continuous treatment of the same drug for a long time may make cancer cells develop drug resistance, which is the key to affect the therapeutic effect and tumor metastasis. In recent years, combination therapy has been developed to effectively treat drug-resistant tumors. Some studies have pointed out that ALDH1A1 in DLBCL is one of the reasons for the drug-resistance of cancer cells. Therefore, the purpose of this study was to investigate whether the combination treatment of doxorubicin (DOX) and sulforaphane (SFN) could modulate the expression of ALDH1A1 mediated target genes to improve the treatment of ABC DLBCL.
This study gathered microarray datasets of 100 clinical human tissue of ABC DLBCL, 175 human cell lines treated with DOX and 39 human cell lines treated with SFN from ArrayExpress and Gene Expression Omnibus (GEO), and further performed meta-analysis using NetworkAnalyst website to identify differential expression genes (DEGs) and module genes of ABC DLBCL, DOX and SFN. Cytoscape was applied to construct the gene-network and potential pathway of ABC DLBCL receiving DOX and SFN treatment. The results indicated that DOX and SFN treatment of ABC DLBCL may regulate the drug resistance of ABC DLBCL through the potential pathway F2R-GNAQ-GNAI1-KRAS-IL-1-EGFR-CCL2-STAT1-MYC-PLK1-CDKN1A-CASP3. This study subsequently validated using ABC DLBCL-like SU-DHL-2 cells, which showed that combined treatment with DOX and SFN decreased cell viability, diminished ALDH1A1 expression, reduced G0/G1 phase cells, attenuated cell proliferation, induced Caspase-3 and promoted programmed cell death. This study suggested that the combined treatment of DOX and SFN can reduce ALDH1A1 expression and assist the process of apoptosis and cell programmed cell death to reverse the drug-resistance of ABC DLBCL, which has the potential for clinical application.

摘要----I
ABSTRACT----III
圖目錄----VIII
ㄧ、前言----1
二、文獻回顧----2
2.1 淋巴癌----2
2.2 瀰漫性大B細胞淋巴癌----6
2.3活化型B細胞癌臨床治療----7
2.4 阿黴素----9
2.5 蘿蔔硫素----10
2.6 細胞週期對化療的影響----12
2.7細胞凋亡之癌症療法----14
三、研究目的----16
四、研究材料與方法----17
4.1基因網絡分析尋找目標基因----17
4.1.1蒐集微陣列數據庫資料----17
4.1.2 微陣列數據資料的處理與標準化----19
4.1.3 差異表現基因的分析與基因模塊提取----19
4.1.4 建構基因網絡以探究潛在基因路徑----19
4.2細胞實驗----20
4.2.1 細胞培養與暴露處理----20
4.2.2 偵測細胞存活----21
4.2.3 RNA萃取----21
4.2.4 反轉錄聚合酶連鎖反應(RT-PCR)與即時聚合酶連鎖反應定量(QPCR)----22
4.2.5 SU-DHL-2細胞轉染ALDH1A1質體----23
4.2.6 細胞凋亡驗證----24
4.2.7 細胞週期分析----24
4.2.8 統計分析----25
五、結果----26
5.1 ABC DLBCL與DOX治療樣本及SFN治療樣本之差異表現基因(DEGS)與基因模組----27
5.2 ABC DLBCL與DOX治療樣本及SFN治療樣本之基因模塊功能分類----29
5.3 ABC DLBCL與DOX治療樣本及SFN治療樣本之模組基因功能網絡構建----34
5.4 ABC DLBCL與DOX治療樣本及SFN治療樣本之模組基因與基因調控網絡----35
5.5 ABC DLBCL與DOX治療樣本及SFN治療樣本之樞紐基因子網路圖----36
5.6 ABC DLBCL與DOX治療樣本及SFN治療樣本之潛在基因路徑----37
5.7 潛在路徑中預測目標基因準確性之ROC曲線分析----38
5.8 暴露DOX或SFN之細胞存活率----44
5.9.1 ABC DLBCL細胞經DOX和SFN處理後目標基因之表現量----45
5.9.2 ABC DLBCL細胞經DOX和SFN處理後之細胞週期分佈----47
5.9.3 ABC DLBCL細胞經DOX和SFN處理後之細胞凋亡情況----49
5.10細胞轉染ALDH1A1質體----51
5.11.1 SU-DHL-2暴露DOX和SFN之目標基因表現量----51
5.11.2 轉染組別暴露DOX與SFN之細胞週期----54
5.11.3 暴露DOX與SFN之細胞凋亡情況----56
5.13.1 A37處理細胞----58
5.13.2 SU-DHL-2轉染組別經A37處理之目標基因----60
5.13.3 SU-DHL-2轉染組別經A37處理之細胞週期----62
5.13.4 SU-DHL-2轉染組別經A37處理之細胞凋亡情況----65
六、討論----68
6.1 DOX和SFN藉由調控ABC DLBCL細胞週期與程序性死亡功能減緩癌化過程----70
6.2 DOX和SFN透過調控細胞週期與凋亡反應相關之目標基因減緩ABC DLBCL癌化過程----71
6.3 ALDH1A1上調與細胞增生功能相關之目標基因表現量使細胞產生抗藥性----73
6.4 DOX和SFN藉由提昇CDKN1A表現量造成ABC DLBCL細胞週期停滯並導致DNA損傷----74
6.5暴露DOX和SFN提升CASP3表現量並誘導ABC DLBCL細胞程序性死亡----75
七、結論----76

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