跳到主要內容

臺灣博碩士論文加值系統

(100.26.196.222) 您好!臺灣時間:2024/02/23 09:43
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:李秉蓁
研究生(外文):Ping-Chen Lee
論文名稱:探討FOXA2基因表現與食道鱗狀上皮細胞癌遷移的相關性
論文名稱(外文):Study of the relationship between FOXA2 gene expression and cell migration in esophageal squamous cell carcinoma
指導教授:李瑞年
指導教授(外文):Ruei-Nian Li
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:生物醫學暨環境生物學系碩士班
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:79
中文關鍵詞:食道癌基因甲基化細胞遷移
外文關鍵詞:Esophageal cancergene methylationcell migration
相關次數:
  • 被引用被引用:0
  • 點閱點閱:180
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
食道鱗狀上皮細胞癌是食道癌中最主要的類型,佔總病例的90%,上皮-間質轉化是造成食道癌病患癌細胞轉移的原因之一,其中,上皮-間質轉化的關鍵基因CDH1,是主要調控細胞間黏附的相關因子。根據之前文獻報導指出,在CDH1的啟動子區域有4個FOXA2的轉錄結合位,且FOXA2可以直接上調控CDH1的表現並抑制細胞遷移。由先前的實驗結果證實,經由甲基化抑制劑 (5-aza-dC)處理食道癌細胞株後,FOXA2的表現回升,確實也增加CDH1的表現量,進而抑制癌細胞的遷移,在未來對於食道癌遷移的研究具有很大的潛力。然而,FOXA2的基因表現與食道鱗狀上皮細胞癌遷移的相關性尚未明瞭,因此,本研究為了更進一步探討,分別以三種不同的調控方式進行檢測:以TGFβ1處理使FOXA2基因達到高度甲基化狀態、將FOXA2基因表現默化、將FOXA2蛋白過表現。在未經任何藥物處理前,我們利用甲基化特異性聚合&;#37238;連鎖反應 (Methylation-specific polymerase chain reaction, MSP)以及西方點墨法先了解FOXA2及CDH1的甲基化狀態及蛋白表現,結果發現在TE-2、81T、81T-4及146T四株食道癌細胞株,FOXA2基因啟動子均為高度甲基化狀態,CDH1則均為未甲基化狀態;而FOXA2蛋白除了在146T有大量表現外,TE-2、81T及81T-4細胞株均呈低下。有文獻指出,轉化生長因子-β1 (TGFβ1)可以刺激DNA甲基轉移&;#37238; (DNMTs)的活性,並促使基因發生甲基化。146T細胞株經由TGFβ1處理後,FOXA2甲基化程度回升,且FOXA2及CDH1的蛋白表現均下降。此外,在細胞遷移能力方面,146T細胞株經由TGFβ1處理後,在傷口癒合分析實驗 (Wound-healing assay)中,能夠誘導細胞遷移,但在細胞遷移能力分析實驗 (Transwell migration assay)中,遷移能力沒有顯著差異。接著,我們建立一個包含FOXA2轉錄結合位的CDH1啟動子序列冷光載體,證實CDH1啟動子的轉錄活性是由FOXA2所調控,結果顯示,81T、81T-4及146T細胞株經由TGFβ1處理後,81T及81T-4細胞株的CDH1啟動子轉錄活性有劑量依賴性的遞減,但146T細胞株卻沒有差異。此外,81T及81T-4細胞株經由5-aza-dC恢復FOXA2的表現後,能夠被FOXA2-human siRNA抑制其蛋白表現量,且CDH1的蛋白表現也同時被抑制。最後,我們將81T-4細胞株轉染pcDNA3.1-FOXA2使FOXA2蛋白過表現,發現CDH1的表現也跟著回升。根據以上結果證實,在食道癌中,FOXA2的基因表現可藉由DNA甲基化修飾所調控,進而影響CDH1的表現,最後影響癌細胞的遷移能力。期望FOXA2可以成為未來食道癌診斷與治療的生物標靶。

Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer, it is about 90%. Epithelial-mesenchymal transition (EMT) contributes to cancer cell migration in patients with ESCC. E-cadherin (CDH1), an EMT marker, is one of the genes which regulates the cell-cell adhesion. Previous study indicated that there are four FOXA2 transcription binding sites on CDH1 promoter, and FOXA2 can upregulate CDH1 expression directly and inhibits cell migration. According to the previous results, when the ESCC cell lines were treated with 5-Aza-2’-deoxycytidine (5-aza-dC), which could cause gene demethylation, FOXA2 expression was reexpressed. Upregulation of CDH1 expression increases the potential to cell migration in esophageal cancer. However, the relationship between FOXA2 gene expression and cell migration in ESCC cell lines is still unclear. Therefore, in this study, we want to investigate further mechanism. We detected the FOXA2 expression by three different ways: restore the methylation level by treated with transforming growth factor beta 1 (TGFβ1), silencing the transcription of FOXA2, and overexpression of FOXA2 protein. By methylation-specific polymerase chain reaction (MS-PCR) and Western blot, we had found that FOXA2 was hypermethylated and CDH1 was demethylated. The protein expression of FOXA2 was not expressed in TE-2, 81T and 81T-4 cell lines, but 146T expressed in high amount. In previous studies, TGFβ1 has been reported that would increase the expression of DNA methyltransferase (DNMTs) and caused gene methylation. After treated 146T cell line with TGFβ1, FOXA2 was methylated. The protein expression of FOXA2 and CDH1 were decreased with the addition of TGFβ1. Besides, cell migration of 146T cell line was induced after treated with TGFβ1 by wound-healing assay, but it was not significant different in transwell migration assay. We contructed CDH1 promoter luciferase reporter system to confirm CDH1 promoter activity was influenced by FOXA2. The data showed that after treated ESCC cell lines with TGFβ1, the CDH1 promoter activity was decreased in a dose dependent manner in 81T and 81T-4 cell lines, but 146T was not changed. Besides, the reexpression of FOXA2 which induced by 5-aza-dC, was inhibited by FOXA2-human siRNA and the expression of CDH1 was also inhibited in 81T and 81T-4 cell lines. Finally, we transfected the pcDNA3.1-FOXA2 to overexpress the FOXA2 protein, the expression of CDH1 was also increased in 81T-4 cell lines. Our findings indicate that FOXA2 gene expression could be regulated by DNA methylation, and influence the CDH1 expression, finally cause the cell migration. In the future, FOXA2 will be a novel biomarker for targeted therapy in esophageal cancer.

致謝.............................................................................................................I
中文摘要…………………………………..………………………........III
英文摘要...................................................................................................V
目錄.........................................................................................................VII
附表目錄...............................................................................................VIII
附圖目錄..................................................................................................IX
第一章 緒論..............................................................................................1
第一節 食道癌概論...........................................................................1
第二節 上皮-間質轉化 (Epithelial-Mesenchymal Transition, EMT)....5
第三節 DNA甲基化 (DNA methylation).........................................7
第四節 腫瘤抑制基因 (Tumor Suppressor Gene)..........................10
第五節 轉化生長因子-β (Transforming growth factor beta, TGFβ)....12
第六節 研究問題與目的..................................................................15
第二章 材料與方法................................................................................16
第三章 結果............................................................................................29
第四章 討論與結論................................................................................35
第一節 本篇研究發現及相關文獻探討..........................................35
第二節 未來研究方向與潛力..........................................................41
第三節 結論......................................................................................42
第五章 參考文獻....................................................................................43
附表..........................................................................................................52
附圖..........................................................................................................57

附表目錄
表一、甲基化特異性聚合&;#37238;連鎖反應 (Methylation-specific PCR)
引子 (Primer)序列列表...........................................................................53

表二、GoTaq&;#174; Hot Start Polymerase (Promega, USA)...........................54

表三、西方點墨法分析(Western blot analysis)抗體列表......................55

表四、FOXA2-human siRNA及Scrambled siRNA序列列表................56

附圖目錄
圖一、上皮-間質轉化 (Epithelial-Mesenchymal Transition, EMT).......58

圖二、上皮-間質轉化 (EMT)參與癌症發展與癌細胞轉移及侵襲......59

圖三、DNA 甲基化修飾 (DNA methylation)........................................60

圖四、DNA甲基化在正常細胞與腫瘤細胞的差異...............................61

圖五、DNA甲基化抑制啟動子 (Promoter)的轉錄作用.......................62

圖六、FOXA2在E-cadherin的啟動子 (-1000 bp至+1 bp)上的轉錄結合位..........................................................................................................63

圖七、轉化生長因子-β (Transforming growth factor beta, TGFβ)訊號傳遞路徑......................................................................................................64

圖八、Sodium bisulfite conversion及甲基化特異性聚合&;#37238;連鎖反應 (Methylation-specific PCR)......................................................................65

圖九、利用MethPrimer網站進行CDH1啟動子及FOXA2啟動子CpG小島偵測..................................................................................................66

圖十、CDH1啟動子片段序列 (612 bp)..................................................67
圖十一、pGL4.14[luc2/Hygro] vector (Promega, USA)及pGL4.14-CDH1........................................................................................68

圖十二、pcDNA3.1 (+) vector及FOXA2-human in pcDNA3.1 (+) (pcDNA3.1-FOXA2)................................................................................69

圖十三、食道癌細胞株未經藥物處理前CDH1啟動子及FOXA2啟動子甲基化狀態..........................................................................................70

圖十四、食道癌細胞株未經藥物處理前CDH1及FOXA2的蛋白表現量..............................................................................................................71

圖十五、146T食道癌細胞株經由TGFβ1處理後CDH1啟動子及FOXA2啟動子甲基化狀態.....................................................................72

圖十六、146T食道癌細胞株經由TGFβ1處理後CDH1及FOXA2的蛋白表現量..............................................................................................73

圖十七、146T食道癌細胞株經由TGFβ1處理後利用傷口癒合分析 (Wound-healing assay)觀察細胞遷移之能力.........................................74

圖十八、81T-4食道癌細胞株經由TGFβ1處理後利用傷口癒合分析 (Wound-healing assay)觀察細胞遷移之能力:.......................................75

圖十九、食道癌細胞株經由TGFβ1處理後利用細胞遷移能力分析 (Transwell migration assay)觀察細胞遷移之能力.................................76

圖二十、食道癌細胞株經由TGFβ1處理後轉染pGL4.14-CDH1並偵測CDH1啟動子活性...............................................................................77

圖二十一、食道癌細胞株經由5-aza-dC甲基化抑制劑處理48小時後轉染FOXA2-human siRNA及Scrambled siRNA並偵測CDH1及FOXA2的蛋白表現量.............................................................................78

圖二十二、81T-4食道癌細胞株轉染pcDNA3.1-FOXA2及pcDNA3.1 (+) vector後,偵測CDH1及FOXA2的蛋白表現量..............................79


1.EA. M: World Cancer Report 2014: World Health Organization; 2014.
2.Siegel R, Ma J, Zou Z, Jemal A: Cancer statistics, 2014. CA: a cancer journal for clinicians 2014, 64(1):9-29.
3.中華民國100年癌症登記報告. In.: Health promotion administration, Ministry of Health and Welfare; 2011.
4.Lee CH, Lee JM, Wu DC, Hsu HK, Kao EL, Huang HL, Wang TN, Huang MC, Wu MT: Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan. International journal of cancer Journal international du cancer 2005, 113(3):475-482.
5.Daly JM, Fry WA, Little AG, Winchester DP, McKee RF, Stewart AK, Fremgen AM: Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study. Journal of the American College of Surgeons 2000, 190(5):562-572; discussion 572-563.
6.Siewert JR, Stein HJ, Feith M, Bruecher BL, Bartels H, Fink U: Histologic tumor type is an independent prognostic parameter in esophageal cancer: lessons from more than 1,000 consecutive resections at a single center in the Western world. Annals of surgery 2001, 234(3):360-367; discussion 368-369.
7.Parkin DM, Bray F, Ferlay J, Pisani P: Estimating the world cancer burden: Globocan 2000. International journal of cancer Journal international du cancer 2001, 94(2):153-156.
8.Stahl M, Mariette C, Haustermans K, Cervantes A, Arnold D, Group EGW: Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2013, 24 Suppl 6:vi51-56.
9.Williams CD: Antioxidants and prevention of gastrointestinal cancers. Current opinion in gastroenterology 2013, 29(2):195-200.
10.Pennathur A, Gibson MK, Jobe BA, Luketich JD: Oesophageal carcinoma. Lancet 2013, 381(9864):400-412.
11.Huang Q, Luo K, Yang H, Wen J, Zhang S, Li J, Ela Bella A, Liu Q, Yang F, Zheng Y et al: Impact of alcohol consumption on survival in patients with esophageal carcinoma: a large cohort with long-term follow-up. Cancer science 2014, 105(12):1638-1646.
12.Lin S, Wang X, Huang C, Liu X, Zhao J, Yu IT, Christiani DC: Consumption of salted meat and its interactions with alcohol drinking and tobacco smoking on esophageal squamous-cell carcinoma. International journal of cancer Journal international du cancer 2015, 137(3):582-589.
13.Rice TW, Rusch VW, Ishwaran H, Blackstone EH, Worldwide Esophageal Cancer C: Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer Cancer Staging Manuals. Cancer 2010, 116(16):3763-3773.
14.Roth MJ, Hu N, Emmert-Buck MR, Wang QH, Dawsey SM, Li G, Guo WJ, Zhang YZ, Taylor PR: Genetic progression and heterogeneity associated with the development of esophageal squamous cell carcinoma. Cancer research 2001, 61(10):4098-4104.
15.Baylin SB, Herman JG: DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends in genetics : TIG 2000, 16(4):168-174.
16.Wu DL, Sui FY, Jiang XM, Jiang XH: Methylation in esophageal carcinogenesis. World journal of gastroenterology : WJG 2006, 12(43):6933-6940.
17.Kuo IY, Chang JM, Jiang SS, Chen CH, Chang IS, Sheu BS, Lu PJ, Chang WL, Lai WW, Wang YC: Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients. International journal of medical sciences 2014, 11(8):779-787.
18.Lima SC, Hernandez-Vargas H, Simao T, Durand G, Kruel CD, Le Calvez-Kelm F, Ribeiro Pinto LF, Herceg Z: Identification of a DNA methylome signature of esophageal squamous cell carcinoma and potential epigenetic biomarkers. Epigenetics : official journal of the DNA Methylation Society 2011, 6(10):1217-1227.
19.Kalluri R, Weinberg RA: The basics of epithelial-mesenchymal transition. The Journal of clinical investigation 2009, 119(6):1420-1428.
20.Gurzu S, Turdean S, Kovecsi A, Contac AO, Jung I: Epithelial-mesenchymal, mesenchymal-epithelial, and endothelial-mesenchymal transitions in malignant tumors: An update. World journal of clinical cases 2015, 3(5):393-404.
21.Nakaya Y, Sheng G: Epithelial to mesenchymal transition during gastrulation: an embryological view. Development, growth &; differentiation 2008, 50(9):755-766.
22.Bataille F, Rohrmeier C, Bates R, Weber A, Rieder F, Brenmoehl J, Strauch U, Farkas S, Furst A, Hofstadter F et al: Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn''s disease. Inflammatory bowel diseases 2008, 14(11):1514-1527.
23.Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nature reviews Cancer 2002, 2(6):442-454.
24.Brackenbury R, Rutishauser U, Edelman GM: Distinct calcium-independent and calcium-dependent adhesion systems of chicken embryo cells. Proceedings of the National Academy of Sciences of the United States of America 1981, 78(1):387-391.
25.Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de Water B, Cornelisse CJ et al: E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. British journal of cancer 2006, 94(5):661-671.
26.Yates CC, Shepard CR, Stolz DB, Wells A: Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. British journal of cancer 2007, 96(8):1246-1252.
27.Peinado H, Marin F, Cubillo E, Stark HJ, Fusenig N, Nieto MA, Cano A: Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. Journal of cell science 2004, 117(Pt 13):2827-2839.
28.Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK et al: An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 2013, 19(1):279-290.
29.Polyak K, Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature reviews Cancer 2009, 9(4):265-273.
30.Singh A, Settleman J: EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010, 29(34):4741-4751.
31.Pang L, Li Q, Wei C, Zou H, Li S, Cao W, He J, Zhou Y, Ju X, Lan J et al: TGF-beta1/Smad signaling pathway regulates epithelial-to-mesenchymal transition in esophageal squamous cell carcinoma: in vitro and clinical analyses of cell lines and nomadic Kazakh patients from northwest Xinjiang, China. PloS one 2014, 9(12):e112300.
32.Iacobuzio-Donahue CA: Epigenetic changes in cancer. Annual review of pathology 2009, 4:229-249.
33.Smith ZD, Meissner A: DNA methylation: roles in mammalian development. Nature reviews Genetics 2013, 14(3):204-220.
34.Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S: Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. The EMBO journal 2002, 21(15):4183-4195.
35.Bird A: DNA methylation patterns and epigenetic memory. Genes &; development 2002, 16(1):6-21.
36.Suzuki MM, Bird A: DNA methylation landscapes: provocative insights from epigenomics. Nature reviews Genetics 2008, 9(6):465-476.
37.Jabbari K, Bernardi G: Cytosine methylation and CpG, TpG (CpA) and TpA frequencies. Gene 2004, 333:143-149.
38.Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100(1):57-70.
39.Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144(5):646-674.
40.Herman JG, Baylin SB: Promoter-region hypermethylation and gene silencing in human cancer. Current topics in microbiology and immunology 2000, 249:35-54.
41.Eden A, Gaudet F, Waghmare A, Jaenisch R: Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003, 300(5618):455.
42.SB B: Stem cells, cancer, and epigenetics.: Cambridge (MA): Harvard Stem Cell Institute; 2008-2009.
43.Hermann A, Gowher H, Jeltsch A: Biochemistry and biology of mammalian DNA methyltransferases. Cellular and molecular life sciences : CMLS 2004, 61(19-20):2571-2587.
44.Daniel FI, Cherubini K, Yurgel LS, de Figueiredo MA, Salum FG: The role of epigenetic transcription repression and DNA methyltransferases in cancer. Cancer 2011, 117(4):677-687.
45.Robertson KD: DNA methylation, methyltransferases, and cancer. Oncogene 2001, 20(24):3139-3155.
46.Feinberg AP, Vogelstein B: Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983, 301(5895):89-92.
47.Sherr CJ: Principles of tumor suppression. Cell 2004, 116(2):235-246.
48.Hirohashi S, Kanai Y: Cell adhesion system and human cancer morphogenesis. Cancer science 2003, 94(7):575-581.
49.Kaestner KH, Knochel W, Martinez DE: Unified nomenclature for the winged helix/forkhead transcription factors. Genes &; development 2000, 14(2):142-146.
50.Friedman JR, Kaestner KH: The Foxa family of transcription factors in development and metabolism. Cellular and molecular life sciences : CMLS 2006, 63(19-20):2317-2328.
51.Lee CS, Friedman JR, Fulmer JT, Kaestner KH: The initiation of liver development is dependent on Foxa transcription factors. Nature 2005, 435(7044):944-947.
52.Lee CS, Sund NJ, Behr R, Herrera PL, Kaestner KH: Foxa2 is required for the differentiation of pancreatic alpha-cells. Developmental biology 2005, 278(2):484-495.
53.Wan H, Kaestner KH, Ang SL, Ikegami M, Finkelman FD, Stahlman MT, Fulkerson PC, Rothenberg ME, Whitsett JA: Foxa2 regulates alveolarization and goblet cell hyperplasia. Development 2004, 131(4):953-964.
54.Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH: Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 2005, 24(56):8277-8290.
55.Song Y, Washington MK, Crawford HC: Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer research 2010, 70(5):2115-2125.
56.Tang Y, Shu G, Yuan X, Jing N, Song J: FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell research 2011, 21(2):316-326.
57.Lehner F, Kulik U, Klempnauer J, Borlak J: The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2007, 21(7):1445-1462.
58.Mirosevich J, Gao N, Gupta A, Shappell SB, Jove R, Matusik RJ: Expression and role of Foxa proteins in prostate cancer. The Prostate 2006, 66(10):1013-1028.
59.Halmos B, Basseres DS, Monti S, D''Alo F, Dayaram T, Ferenczi K, Wouters BJ, Huettner CS, Golub TR, Tenen DG: A transcriptional profiling study of CCAAT/enhancer binding protein targets identifies hepatocyte nuclear factor 3 beta as a novel tumor suppressor in lung cancer. Cancer research 2004, 64(12):4137-4147.
60.Basseres DS, D''Alo F, Yeap BY, Lowenberg EC, Gonzalez DA, Yasuda H, Dayaram T, Kocher ON, Godleski JJ, Richards WG et al: Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing. Lung cancer 2012, 77(1):31-37.
61.Correction: Role of Transforming Growth Factor (beta) in Human Disease. The New England journal of medicine 2000, 343(3):228.
62.Akhurst RJ, Lehnert SA, Faissner A, Duffie E: TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis. Development 1990, 108(4):645-656.
63.Penn JW, Grobbelaar AO, Rolfe KJ: The role of the TGF-beta family in wound healing, burns and scarring: a review. International journal of burns and trauma 2012, 2(1):18-28.
64.Pepper MS: Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine &; growth factor reviews 1997, 8(1):21-43.
65.Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA: Transforming growth factor-beta regulation of immune responses. Annual review of immunology 2006, 24:99-146.
66.Jang CW, Chen CH, Chen CC, Chen JY, Su YH, Chen RH: TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nature cell biology 2002, 4(1):51-58.
67.Sinha S, Nevett C, Shuttleworth CA, Kielty CM: Cellular and extracellular biology of the latent transforming growth factor-beta binding proteins. Matrix biology : journal of the International Society for Matrix Biology 1998, 17(8-9):529-545.
68.Xu J, Lamouille S, Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell research 2009, 19(2):156-172.
69.Pardali K, Moustakas A: Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochimica et biophysica acta 2007, 1775(1):21-62.
70.Fukushima T, Mashiko M, Takita K, Otake T, Endo Y, Sekikawa K, Takenoshita S: Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer. Journal of experimental &; clinical cancer research : CR 2003, 22(2):315-320.
71.Lee JD, Hempel N, Lee NY, Blobe GC: The type III TGF-beta receptor suppresses breast cancer progression through GIPC-mediated inhibition of TGF-beta signaling. Carcinogenesis 2010, 31(2):175-183.
72.Derynck R, Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003, 425(6958):577-584.
73.Jung SM, Lee JH, Park J, Oh YS, Lee SK, Park JS, Lee YS, Kim JH, Lee JY, Bae YS et al: Smad6 inhibits non-canonical TGF-beta1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nature communications 2013, 4:2562.
74.Piek E, Heldin CH, Ten Dijke P: Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999, 13(15):2105-2124.
75.Lee C, Zhang Q, Zi X, Dash A, Soares MB, Rahmatpanah F, Jia Z, McClelland M, Mercola D: TGF-beta mediated DNA methylation in prostate cancer. Translational andrology and urology 2012, 1(2):78-88.
76.Lu R, Wang X, Chen ZF, Sun DF, Tian XQ, Fang JY: Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells. The Journal of biological chemistry 2007, 282(16):12249-12259.
77.Bu F, Liu X, Li J, Chen S, Tong X, Ma C, Mao H, Pan F, Li X, Chen B et al: TGF-beta1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma. Oncotarget 2015, 6(4):2120-2133.
78.Geback T, Schulz MM, Koumoutsakos P, Detmar M: TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays. BioTechniques 2009, 46(4):265-274.
79.Si HX, Tsao SW, Lam KY, Srivastava G, Liu Y, Wong YC, Shen ZY, Cheung AL: E-cadherin expression is commonly downregulated by CpG island hypermethylation in esophageal carcinoma cells. Cancer letters 2001, 173(1):71-78.
80.Zhang Y, Handley D, Kaplan T, Yu H, Bais AS, Richards T, Pandit KV, Zeng Q, Benos PV, Friedman N et al: High throughput determination of TGFbeta1/SMAD3 targets in A549 lung epithelial cells. PloS one 2011, 6(5):e20319.
81.Lin CS, Lee HT, Lee SY, Shen YA, Wang LS, Chen YJ, Wei YH: High mitochondrial DNA copy number and bioenergetic function are associated with tumor invasion of esophageal squamous cell carcinoma cell lines. International journal of molecular sciences 2012, 13(9):11228-11246.
82.Schuster N, Krieglstein K: Mechanisms of TGF-beta-mediated apoptosis. Cell and tissue research 2002, 307(1):1-14.
83.Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature cell biology 2000, 2(2):84-89.
84.Hajra KM, Chen DY, Fearon ER: The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer research 2002, 62(6):1613-1618.
85.Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117(7):927-939.
86.Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, Muller CA, Kalluri R, Zeisberg M: Methylation determines fibroblast activation and fibrogenesis in the kidney. Nature medicine 2010, 16(5):544-550.
87.You H, Ding W, Rountree CB: Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology 2010, 51(5):1635-1644.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top