淋巴癌發生率自二十世紀末急劇上升，為全球十大惡性腫瘤之一，已知淋巴癌致病原因與免疫能力下降有關，主要危險因子為暴露環境或職業中化學物質。雙酚A (bisphenol A; BPA)是廣泛用於製造聚碳酸酯塑料或環氧樹脂等材料之塑化劑。有研究指出BPA會藉由擾亂基因調控而導致疾病和癌症發生。已發現BPA會影響免疫反應，當免疫系統異常會增加淋巴癌發生機會，推測BPA可能干擾免疫系統誘發淋巴細胞癌化。由於暴露BPA可能誘發淋巴細胞癌化之分子機制並不清楚，因此本研究目的為探討BPA暴露是否藉由影響基因調控，誘發人類淋巴細胞癌化。
本研究利用巨量資料分析(meta-analysis)方法，匯集309片人類非何杰金氏淋巴癌(non-Hodgkin lymphoma; NHL)與正常組織基因晶片及98片BPA暴露與對照組之人類細胞株基因晶片，分別找出罹患NHL和暴露BPA之差異表現基因(differentially expressed genes; DEGs)。接著利用加權基因關聯性分析(weighted gene co-expression network analysis; WGCNA)建立對應BPA和NHL之基因模組，再利用Cytoscape分析各基因模組之基因網絡，並整合建構出BPA暴露可能導致NHL癌化之基因調控路徑。由基因網絡分析結果顯示，BPA暴露可能影響CTNNB1 (catenin beta 1)-NFKB1 (nuclear factor kappa B subunit 1)-AR (androgen receptor)-IGF1 (insulin like growth factor 1)-TWIST1 (twist family BHLH transcription factor 1)路徑，導致淋巴細胞癌化。本研究亦利用人類TK6淋巴細胞驗證BPA暴露(10, 103和105 nM)對於淋巴細胞癌化之影響。TK6細胞暴露BPA會上調CTNNB1、NFKB1、AR、IGF1和TWIST1基因表現，造成單股和雙股DNA斷裂，促使細胞週期停滯於G2/M期，以及降低DNA修復基因tumor protein 53 (TP53)和cyclin-dependent kinase inhibitor 1A (CDKN1A)表現量。CTNNB1 siRNA會下調BPA暴露後NFKB1、AR、IGF1和TWIST1基因表現增加量，減少DNA損傷與G2/M期停滯現象，提升TP53和CDKN1A表現量和修復能力。因此，本研究發現BPA暴露會影響CTNNB1-NFKB1-AR-IGF1-TWIST1路徑，導致DNA損傷，促使細胞週期停滯，造成DNA修復功能異常，誘發淋巴細胞癌化發生之可能性。

Lymphoma is the most top 10 cancers in worldwide and the incidence rise strikingly since the last half of the 20th century. Lymphoma is a cancer affecting the immune system, the major risk factor is associated with exposure to occupational or environmental chemicals. Bisphenol A (BPA) is a common manufactory chemical widely used in polycarbonate and epoxy plastic products. BPA can alter gene expression to raise susceptibility of disease and cancer. BPA can interfere with immune reaction, and aberrant immune function has been reported that related to lymphoma incidence. BPA may be considered to induce lymphomagenesis through influencing immune system. However, the molecular effect of BPA exposure on lymphomagenesis has not been declared. Therefore, the purpose of this study was to investigate whether BPA exposure would lead to lymphomagenesis through gene dysregulation.
This study conducted a meta-analysis in 309 microarray datasets of human NHL tissues and 98 microarray datasets of human cells in exposure to BPA. The differentially expressed genes (DEGs) of NHL and BPA exposure were identified individually. This study used weighted gene co-expression network analysis (WGCNA) to explore module genes of NHL and BPA exposure, respectively, and Cytoscape to construct the potential pathway of NHL progression in response to BPA exposure. The results of the gene-network analysis presented that BPA exposure could activate the CTNNB1 (catenin beta 1)-NFKB1 (nuclear factor kappa B subunit 1)-AR (androgen receptor)-IGF1 (insulin like growth factor 1)-TWIST1 (twist family BHLH transcription factor 1) pathway to lead to lymphomagenesis. Moreover, the result of gene-network analysis was validated in human lymphoblastoid TK6 cells. In TK6 cells, BPA exposure induced gene expression of CTNNB1, NFKB1, AR, IGF1 and TWIST1, caused DNA single strand and double strand damage, promoted G2/M cell cycle arrest, and reduced expression of DNA repair genes TP53 (tumor protein P53) and CDKN1A (cyclin-dependent kinase inhibitor 1A). This study demonstrated that transfection of siCTNNB1 attenuated BPA-induced NFKB1, AR, IGF1 and TWIST1 expression, diminished DNA damage and G2/M arrest, and elevated TP53 and CDKN1A expression for repair function. This study found that BPA exposure can cause DNA damage and disrupt cell cycle and DNA repair function potentially for lymphomagenesis underlying CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway.

摘要 II
Abstract IV
Contents VI
Lists of Tables IX
Lists of Figures X
Chapter 1 Introduction 1
Chapter 2 Paper review 3
2.1 Lymphoma 3
2.2 Aberrant gene expression in non-Hodgkin lymphoma 4
2.3 Endocrine disrupting chemicals 6
2.4 Bisphenol A 7
2.5 Aberrant gene expression in exposure to BPA 10
2.6 Weighted gene co-expression network analysis and Cytoscape for gene-network analysis 11
2.7 The role of cell cycle regulation, DNA damage and DNA repair in carcinogenesis 13
Chapter 3 Aim of this study 15
Chapter 4 Materials and methods 17
4.1 Collection of microarray dataset 17
4.2 Preprocessing and normalization of microarray data 20
4.3 Differentially expressed genes analysis 21
4.4 Weighted gene co-expression network analysis 22
4.5 Gene ontology (GO) analysis 23
4.6 Reconstruction of gene network for regulatory pathway identification 24
4.7 Receiver-operator characteristic curve 25
4.8 Cell culture and BPA treatment 26
4.9 Cell viability assay 27
4.10 Total RNA extraction 28
4.11 Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR (qPCR) for mRNA determination 28
4.12 Cell cycle analysis 30
4.13 Comet assay 31
4.14 Transfection of small interfering RNA 33
4.15 Statistical analysis 34
Chapter 5 Results 35
5.1 Identification of differentially expressed genes and module genes 37
5.2 GO term for module genes of NHL and BPA exposure 37
5.3 Ontological network of module genes for NHL and BPA exposure 40
5.4 Sub-network and potential pathways for NHL and BPA exposure 43
5.5 ROC analysis for target genes in exposure to BPA 48
5.6 Viability of TK6 cells in exposure to BPA 51
5.7 Determination of gene expression of CTNNB1, NFKB1, AR, IGF1 and TWIST1 after BPA exposure 52
5.8 Cell cycle distribution in TK6 cells exposure to BPA 57
5.9 DNA single-strand break in TK6 cells exposure to BPA 62
5.10 DNA double-strand break in TK6 cells exposure to BPA 64
5.11 Determination of DNA repair-associated genes TP53 and CDKN1A in TK6 cells exposure to BPA 66
5.12 Dose selection of CTNNB1 siRNA transfection 68
5.13 Expression of downstream genes of CTNNB1 in TK6 cells exposure to BPA after CTNNB1 siRNA transfection 70
5.14 Cell cycle distribution in TK6 cells exposure to BPA after CTNNB1 siRNA transfection 73
5.15 Attenuation of DNA single-strand break in TK6 cells exposure to BPA after CTNNB1 siRNA transfection 77
5.16 Attenuation of DNA double-strand break in TK6 cells exposure to BPA after CTNNB1 siRNA transfection 79
5.17 Expression of DNA repair-associated genes in TK6 cells exposure to BPA after CTNNB1 siRNA transfection 82
Chapter 6 Discussion 85
6.1 An integrated ontological network of BPA exposure and NHL involved in regulation of fibroblast growth factor receptor, aorta development, and immune response 85
6.2 BPA exposure increased gene expression of CTNNB1, NFKB1, AR, IGF1 and TWIST1 potentially for NHL progression 87
6.3 BPA exposure caused cell cycle arrest 92
6.4 BPA exposure caused DNA damage and dysregulation of DNA repair 94
Chapter 7 Conclusion 99
Chapter 8 References 100

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