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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 俞松良(Sung-Liang Yu) | |
| dc.contributor.author | Yen Chun-Lai | en |
| dc.contributor.author | 賴彥君 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:48:08Z | - |
| dc.date.available | 2011-10-07 | |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-24 | |
| dc.identifier.citation | 1. Herbst, R.S., J.V. Heymach, and S.M. Lippman, Lung cancer. N Engl J Med, 2008. 359(13): p. 1367-80.
2. Tsai, M.F., et al., A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst, 2006. 98(12): p. 825-38. 3. Fisseler-Eckhoff, A., [New TNM classification of malignant lung tumors 2009 from a pathology perspective]. Pathologe, 2009. 30 Suppl 2: p. 193-9. 4. Shih, J.Y., et al., Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res, 2005. 11(22): p. 8070-8. 5. Spira, A., et al., Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A, 2004. 101(27): p. 10143-8. 6. Mao, L., et al., Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst, 1997. 89(12): p. 857-62. 7. Sato, M., et al., A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol, 2007. 2(4): p. 327-43. 8. Bianchi, F., et al., Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res, 2004. 10(18 Pt 1): p. 6023-8. 9. Zudaire, I., et al., Molecular characterization of small peripheral lung tumors based on the analysis of fine needle aspirates. Histol Histopathol, 2008. 23(1): p. 33-40. 10. Wistuba, II, et al., Molecular changes in the bronchial epithelium of patients with small cell lung cancer. Clin Cancer Res, 2000. 6(7): p. 2604-10. 11. Beer, D.G., et al., Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med, 2002. 8(8): p. 816-24. 12. Potti, A., et al., A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med, 2006. 355(6): p. 570-80. 13. Gao, J., et al., Expression of Jagged1 and its association with hepatitis B virus X protein in hepatocellular carcinoma. Biochem Biophys Res Commun, 2007. 356(2): p. 341-7. 14. Chen, J.J., et al., Global analysis of gene expression in invasion by a lung cancer model. Cancer Res, 2001. 61(13): p. 5223-30. 15. Puertollano, R. and M.A. Alonso, MAL, an integral element of the apical sorting machinery, is an itinerant protein that cycles between the trans-Golgi network and the plasma membrane. Mol Biol Cell, 1999. 10(10): p. 3435-47. 16. Rancano, C., et al., Genomic structure and subcellular localization of MAL, a human T-cell-specific proteolipid protein. J Biol Chem, 1994. 269(11): p. 8159-64. 17. Alonso, M.A. and J. Millan, The role of lipid rafts in signalling and membrane trafficking in T lymphocytes. J Cell Sci, 2001. 114(Pt 22): p. 3957-65. 18. Liebert, M., et al., Expression of mal is associated with urothelial differentiation in vitro: identification by differential display reverse-transcriptase polymerase chain reaction. Differentiation, 1997. 61(3): p. 177-85. 19. Cheong, K.H., et al., VIP17/MAL, a lipid raft-associated protein, is involved in apical transport in MDCK cells. Proc Natl Acad Sci U S A, 1999. 96(11): p. 6241-8. 20. Beder, L.B., et al., T-lymphocyte maturation-associated protein gene as a candidate metastasis suppressor for head and neck squamous cell carcinomas. Cancer Sci, 2009. 100(5): p. 873-80. 21. Mimori, K., et al., Loss of MAL expression in precancerous lesions of the esophagus. Ann Surg Oncol, 2007. 14(5): p. 1670-7. 22. Koleske, A.J., D. Baltimore, and M.P. Lisanti, Reduction of caveolin and caveolae in oncogenically transformed cells. Proc Natl Acad Sci U S A, 1995. 92(5): p. 1381-5. 23. Engelman, J.A., et al., Recombinant expression of caveolin-1 in oncogenically transformed cells abrogates anchorage-independent growth. J Biol Chem, 1997. 272(26): p. 16374-81. 24. Lee, S.W., et al., Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene, 1998. 16(11): p. 1391-7. 25. Racine, C., et al., Reduction of caveolin 1 gene expression in lung carcinoma cell lines. Biochem Biophys Res Commun, 1999. 255(3): p. 580-6. 26. Bender, F.C., et al., Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity. Cancer Res, 2000. 60(20): p. 5870-8. 27. Couet, J., et al., Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem, 1997. 272(10): p. 6525-33. 28. Li, S., et al., Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem, 1995. 270(26): p. 15693-701. 29. Garcia-Cardena, G., et al., Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem, 1997. 272(41): p. 25437-40. 30. Couet, J., M. Sargiacomo, and M.P. Lisanti, Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem, 1997. 272(48): p. 30429-38. 31. Li, S., J. Couet, and M.P. Lisanti, Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem, 1996. 271(46): p. 29182-90. 32. Engelman, J.A., et al., Reciprocal regulation of neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo. Implications for human breast cancer. J Biol Chem, 1998. 273(32): p. 20448-55. 33. Williams, T.M., et al., Combined loss of INK4a and caveolin-1 synergistically enhances cell proliferation and oncogene-induced tumorigenesis: role of INK4a/CAV-1 in mammary epithelial cell hyperplasia. J Biol Chem, 2004. 279(23): p. 24745-56. 34. Hulit, J., et al., The cyclin D1 gene is transcriptionally repressed by caveolin-1. J Biol Chem, 2000. 275(28): p. 21203-9. 35. Yang, G., et al., Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res, 1998. 4(8): p. 1873-80. 36. Thompson, T.C., Metastasis-related genes in prostate cancer: the role of caveolin-1. Cancer Metastasis Rev, 1998. 17(4): p. 439-42. 37. Timme, T.L., et al., Caveolin-1 is regulated by c-myc and suppresses c-myc-induced apoptosis. Oncogene, 2000. 19(29): p. 3256-65. 38. Yang, G., et al., Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker. Cancer Res, 1999. 59(22): p. 5719-23. 39. Bieche, I., et al., Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin Chem, 1999. 45(8 Pt 1): p. 1148-56. 40. Tsai, M.F., et al., A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst., 2006. 98(12): p. 825-38. 41. de Marco, M.C., et al., BENE, a novel raft-associated protein of the MAL proteolipid family, interacts with caveolin-1 in human endothelial-like ECV304 cells. J Biol Chem, 2001. 276(25): p. 23009-17. 42. Wei, Y., et al., A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol, 1999. 144(6): p. 1285-94. 43. Parkin, A., The Bene-Anthony Family Relations Test revisited: directions in the assessment of children's perceptions of family relations. Br J Med Psychol, 2001. 74(Pt 3): p. 323-49. 44. Horne, H.N., et al., Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy. Mol Cancer Res, 2009. 7(2): p. 199-209. 45. Sunaga, N., et al., Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. Cancer Res, 2004. 64(12): p. 4277-85. 46. Ho, C.C., et al., Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol, 2002. 161(5): p. 1647-56. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45886 | - |
| dc.description.abstract | 背景：先前的研究指出MALL可與Caveolin-1相互作用，至於Caveolin-1是一種已知的致癌基因，它可透過促進絲狀偽足的生成來促進肺腺癌細胞的侵襲能力，因此我們的目標為研究在臨床上MALL在非小細胞肺癌中表現量的高低是否與病人的預後相關，以及MALL是透過何種機制來影響癌症的進程。
方法：我們在MALL表現量較低的肺癌細胞中（CL1-0, NCI-H226, Hop62）過度表現MALL，以及在MALL相對表現量較高的肺癌細胞（CL1-5, A549）中抑制MALL的表現，藉由觀察體外細胞的不依賴支持物生長能力、生長速度、分解膠質能力、移動與侵襲能力，以及觀察老鼠體內的腫瘤生成能力。並且利用DNA微陣列晶片與即時定量聚合酶連鎖反應來探討MALL可能的下游基因，以協助我們釐清MALL主要透過何種訊息傳遞路徑來影響癌細胞的特性改變。另一方面，我們也藉由即時聚合酶連鎖反應來偵測臨床病人癌症組織中MALL的mRNA表現量，利用統計方法分析MALL的mRNA表現量在正常的組織與癌症組織中是否有差異，並且分析MALL m RNA表現量與臨床病人肺癌進展的關聯性。 結果：我們建立了大量表達MALL蛋白的系統來藉以探討此基因的功能，並且發現MALL可以促進肺癌細胞的侵襲能力，同時，無論使用傷口癒合移動實驗或是細胞移動分析皆可發現MALL促進肺癌細胞的移動能力，甚至MALL可以增加細胞不依賴支持物生長的能力，同樣的結果也可在老鼠腫瘤生成模式中得到證實。這些發現都指出MALL可以促進腫瘤的轉移能力以及生成能力。 結論：在我們的實驗中，我們觀察到MALL具有致癌基因的特性，MALL作為一可能的致癌基因，並且可能在臨床用藥及治療上提供嶄新的面向。 | zh_TW |
| dc.description.abstract | Background: Previous study showed that MALL can interact with Caveolin-1, and Caveolin-1 could enhance the invasive capability of lung adenocarcinoma cells by inducing filopodia formation. Therefore, we investigated the clinical significance of MALL expression in non–small-cell lung cancer (NSCLC) patients and its role in cancer progression.
Methods: We enforced the expression of MALL in the cells with lower endogenous MALL expression (CL1-0, NCI-H226 and Hop62) and silenced MALL in those cells with higher endogenous MALL expression (CL1-5 and A549). The cell anchorage-independent growth, proliferation, cell migration, invasion, and in vivo turmorigenesis were analyzed in these transfectants. The potential downstream genes of MALL were identified by oligonucleotide microarray and quantitative reverse transcription–polymerase chain reaction (RT-PCR). In clinical correlation, we measured MALL expression in 90 tumor tissue of NSCLC patients by RT-PCR. Correlation between MALL expression and overall survival was determined by the log-rank test and multivariable Cox proportional hazards regression analysis. All statistical tests were two-sided. Results: We found that MALL can significantly enhance cancer invasiveness by the Boyden chamber matrigel assay (2.12 fold, p<0.01). MALL also promoted cell migration by the transwell assay (1.53 fold, p<0.01) and wound healing assay. Moreover, MALL increased the colonogenesis of lung cancer cells by using an anchorage-independent colony formation assay (1.79 fold, p<0.05) but did not affect the rate of cell proliferation by MTT assay. These findings indicated that MALL can promote tumor metastasis and tumorigenesis. Conclusion: MALL showed an oncogenic characteristic in NSCLC, and MALL might be a potential oncogene which might provide new insights into the future treatment of lung cancer. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:48:08Z (GMT). No. of bitstreams: 1 ntu-100-R98424008-1.pdf: 1786195 bytes, checksum: d3be2b5d8497bdc8b74f0b7a7b291e0a (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 口試委員會審定書……………………………………………………...……………..I
致謝……………………………………………………………......…………..…….....II 中文摘要……………………………………………………………………..………..III 英文摘要………………………………………….…………………............................V 1. Introduction………………………………………………………............................1 1.1 Lung cancer………………………………………………………………………2 1.1.1Population and classification………………………………………… …….2 1.1.2 Non–small-cell lung cancer………………………………………………...2 1.1.3 Clinical staging for lung cancer…………………………………………….3 1.1.4 Metastasis and clinical limit………………………………………………..7 1.1.5 Molecular evolution of lung cancer………………………………….…….7 1.1.6 Molecular-targeted therapy and cancer related gene………………....……8 1.2 MAL protein…………………………………………………………...……...…9 1.2.1 The location of MAL protein………………………………………………9 1.2.2 The relationship between MAL and cancer………………………………10 1.2.3 MAL, BENE and MAL2 interact with Caveolin-1……………………….10 1.2.4 Caveolin-1………………………………………………………………...11 1.2.5 Caveolin-1, tumor suppressors, and oncogenes…………………………..12 2. Flow chart…….…………………………………….…………………………..……14 3. Materials and methods………………………………………………………..16 3.1 Cell culture…………………………………………………………….…...…17 3.2 Microarray analysis…………………………………………………………17 3.3 RNA extraction……………………………………………………………..18 3.4 Construction of expression vector and stable transfection…………………18 3.5 Western Blot……………………………………………………….………..19 3.6 Quantitative real-time RT-PCR……………………………………………20 3.7 Migration and invasion assays……………………………………………20 3.8 Wound healing assay……………………………………………………...20 3.9 In vivo metastasis…………………………………………………………21 3.10 Cell proliferation…………………………………………………………21 3.11 Anchorage-independent growth assay…………………………………...22 3.12 Patients and Tissue Specimens…………………………………………..22 3.13 Statistical analysis………………………………………………………..23 4. Results…………………………………………………………………………...24 4.1 MALL expression is higher in CL1-5 than in CL1-0……………………...25 4.2 Subcellular localization of MALL protein…………………………………25 4.3 MALL promotes wound healing of CL1-0 cells…………………………..26 4.4 MALL enhances invasion and migration of lung cancer cells…………...26 4.5 MALL can promote cell invasion and migration not only in CL1-0 but in other NCI-60 lung cancer cell lines……………………………….…………...27 4.6 MALL enhances lung cancer cell anchorage-independent growth but not proliferation…………………………………………………….…….…27 4.7 MALL promoting cell invasion/migration ability not through FAK pathway……………………………………………………………….....28 4.8 MALL mRNA expression is not correlated with NSCLC survival ………….28 5. Discussion……………………………………………………………………….30 6. References……………………………………………………………………….35 7. Figures…………………………………………………………………………41 8. Tables……………………………………..………………………………...…...…53 9. Appendix………………………….………………………………………...……. .60 | |
| dc.language.iso | en | |
| dc.title | 探討致癌基因MALL在非小細胞肺癌中扮演的角色 | zh_TW |
| dc.title | The Oncogenic Role of MALL in NSCLC | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊雅倩(Ya-Chien Yang),林亮音(Liang-Yin Lin),林淑萍(Shwu-Bin Lin) | |
| dc.subject.keyword | MALL,侵襲,轉移,致癌基因,非小細胞肺癌, | zh_TW |
| dc.subject.keyword | MALL,Invasion,Migration,Oncogene,NSCLC, | en |
| dc.relation.page | 64 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-08-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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