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研究生(外文):Shu-Ching Liang
論文名稱:肺癌細胞 ABCG2 蛋白分布於細胞核中並調控CDH1基因表現之研究
論文名稱(外文):ABCG2 localizes to the nucleus and modulates CDH1expression in lung cancer cells
指導教授(外文):Chi-Hung Lin
外文關鍵詞:Lung cancerABCG2CDH1EMTmetastasis
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ABCG2蛋白屬於ATP-binding cassette 運送家族成員之一,主要分佈在細胞膜上,普遍存在於各種不同的人類腫瘤細胞中,例如肺癌細胞。此基因的功能可使細胞具有多重抗藥性有關,以及可藉由篩選側邉細胞群的方式來找尋肺癌癌症幹細胞。此篇研究利用免疫螢光染色法、細胞核質分離法以及免疫組織化學染色法証實在肺癌細胞及臨床肺癌組織中,ABCG2 蛋白不僅僅表現在細胞膜上也存在於細胞
核內。進一步發現細胞核內的ABCG2 蛋白可藉由與CDH1 基因上游E-box 序列
的結合,進而調控CDH1 基因的表現。CDH1 基因可轉譯出E-cadherin 蛋白,其表現量的高低影響腫瘤細胞轉移能力。當細胞中的ABCG2 大量表達時會使
E-cadherin 表現也隨之增加,而促使細胞移動能力減緩;相反的,若降低ABCG2表達量時,E-cadherin 表現減少而導致細胞移動能力增加。此外,在小鼠動物實驗模式中利用皮下注射的方式,將ABCG2 不同表現量的肺癌細胞株A549 植入免疫不全的小鼠腹部使之形成腫瘤,發現ABCG2 低表現量的細胞有較強的轉移能力,可於肺部或大腸組織中發現有腫瘤形成。然而,若利用尾靜脈注射方式使肺癌細胞株透過血液循環至全身器官,實驗結果發現ABCG2 高表現量的肺癌細胞較易於遠端處聚落增生而形成轉移腫瘤。因此,本研究提出細胞核內ABCG2
蛋白扮演一個全新的角色,具轉錄因子調控功能影響E-cadherin 表現,進而參與癌症轉移的調控。
Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette (ABC) transporter family. The presence of ABCG2 on the plasma membrane in many kinds of human cancer cells contributes to multidrug-resistance during chemotherapy, and it has been used as the side population marker for identifying cancer stem cells in lung cancers. We report here that, in addition to the membranous
form, ABCG2 proteins are also found inside the nucleus, where they bind to the E-box of CDH1 (E-cadherin) promoter and regulate transcription of this gene. Increased expression of ABCG2 causes an increase of E-cadherin and attenuates cell migration, whereas knockdown of ABCG2 down-regulates E-cadherin and enhances cell motility.
In mice, xenografted A549 cells that have less ABCG2 are more likely to metastasize from the subcutaneous inoculation site to the internal organs. However, for the cancer cells that have already entered the blood circulation, an increased level of ABCG2, and correspondingly increased E-cadherin, may facilitate circulating cancer cells to colonize at a distant site and form a metastatic tumor. We propose a novel role for
nuclear ABCG2 that functions as a transcription regulator and participates in modulation of cancer metastasis.
誌謝 i
中文摘要 ii
英文摘要 iii
目錄 iv
圖目錄 vii
表目錄 ix
縮寫表 x
Introduction 1
Lung cancer 1
ABCG2 and side population/cancer stem cells 3
Epithelial–mesenchymal transition (EMT) or mesenchymal–epithelial transition (MET) 5
ABCG2 localization 6
Specific Aims 7
Significance 7
Material and Methods 9
Cells and Cell Culture 9
Immunofluorescence Staining 9
Extraction of Subcellular Fractions 10
Western Blotting 11
Immunohistochemistry 12
Wound Healing Migration Assay, Trans-Well Migration, and Invasion Assay 13
Plasmid Construction 14
Lentivirus Production and Transduction 15
Expression Microarray Analysis 15
Reverse Transcription and Quantitative Real-Time PCR Analysis (Q-RT-PCR) 16
Growth Curve of A549 Variant Cells 16
Flow Cytometry 17
Generation of the Reporter Construct and Luciferase Assay 17
Chromatin Immunoprecipitation Assay (ChIP) 18
Electrophoretic Mobility Shift Assay (EMSA) 18
Experimental Mouse Metastasis Model 19
Colony Formation Assay 20
Statistical Analysis 20
Results 21
1. Nuclear Distributions of ABCG2 Proteins 21
1.1 Nuclear localization of ABCG2 in lung cancer cells 21
1.2 Nuclear distributions of ABCG2 proteins in lung tissues and nuclear staining cells associated with clinical stage 23
2. Additional Biological Activities of ABCG2 24
2.1 ABCG2 affects the percentage of side population in A549 cells 24
2.2 ABCG2 affects cell morphology and inhibits cell migration in lung cancer cells 25
3. Expression Level of ABCG2 is Correlated with Genes Related to Cell Adhesion and Motility 27
3.1 To identify ABCG2 affects the expression of adhesion molecules, such as E-cadherin 27
3.2 ABCG2 affects other epithelial or mesenchymal molecules 29
4. ABCG2 is Involved in Transcriptional Regulation of CDH1 29
4.1 ABCG2 regulates CDH1 transcription through the CDH1 promoter 29
4.2 ABCG2 regulates CDH1 transcription by binding to E-box motif of CDH1 promoter 30
5. ABCG2 Attenuates Invasiveness, but Promotes Colonization of Circulating Cancer Cells 32
5.1 ABCG2 attenuates invasiveness in vivo and in vitro 32
5.2 ABCG2 promotes lung colonization in vivo and in vitro 33
Discussion 35
References 42
Figure 1. The localization of endogenous ABCG2 in A549 cells 50
Figure 2. Subcellular distribution of ABCG2 in A549 cells 51
Figure 3. Subcellular distribution of ABCG2 in A549 cells 52
Figure 4. The localization and expression of ABCG2 in CL1/TPT cells 53
Figure 5. The ABCG2 expression patterns in lung tissues and clinical survival analysis 54
Figure 6. ABCG2 affects side population (SP) percentage, cell morphology and motility in A549 cells 55
Figure 7. The flowchart shows how to identify the candidate molecules were affected by ABCG2 in microarray analysis 57
Figure 8. The ABCG2 expression levels of variant A549 stable cell lines (Vec-ctrl, ABCG2, shGFP, or shABCG2) in microarray experiments 58
Figure 9. ABCG2 affects expression of epithelial–mesenchymal transition (EMT) or mesenchymal–epithelial transition (MET) markers in A549 cells 59
Figure 10. The cytoplasmic and nuclear ABCG2 expression levels were compared among four A549 stable cell lines 60
Figure 11. ABCG2 enhances CDH1 transcription through the E-boxes of the CDH1 promoter 61
Figure 12. ABCG2 enhances CDH1 transcription by binding to the E-boxes of the CDH1 promoter 62
Figure 13. ABCG2 attenuates invasiveness in vivo and in vitro 64
Figure 14. ABCG2 promotes lung colonization in vivo and in vitro 65
Figure 15. Proposed metastasis model summarizing the role played by nuclear ABCG2 in up-regulating CDH1 transcription and trending MET progression in this study 66
Figure 16. The variant deletion clones of ABCG2 67
Figure 17. The expression of Snail and MMP9 in A549 stable cells 68
Table 1: Clinicopathological characteristics of the 27 lung cancer patients in ABCG2 staining patterns 69
Table 2-1: The comparison between the clinical stage and ABCG2-Nuclear pattern 70
Table 2-2: The comparison between the clinical stage and the percentage of ABCG2-Nuclear staining cells 70
Table 3: Probe set was selected from top 100 positively/negatively correlated probes 71
Table 4: Selected genes (135) were enriched in 41 gene ontology terms 74
Table 5: Total 13 selected genes were involved in cell adhesion 75

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