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dc.contributorChang-Tze Ricky Yuen_US
dc.contributorChing-Han Yuen_US
dc.contributor.advisorHo Linen_US
dc.contributor.authorLien, Chuan-Yuenen_US
dc.identifier.citation1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29. 2. Thill PG, Goswami P, Berchem G, Domon B. Lung cancer statistics in Luxembourg from 1981 to 2008. Bulletin de la Societe des sciences medicales du Grand-Duche de Luxembourg. 2011:43-55. 3. Raine R, Wong W, Scholes S, Ashton C, Obichere A, Ambler G. Social variations in access to hospital care for patients with colorectal, breast, and lung cancer between 1999 and 2006: retrospective analysis of hospital episode statistics. BMJ. 2010;340:b5479. 4. Lababede O, Meziane M, Rice T. Seventh edition of the cancer staging manual and stage grouping of lung cancer: quick reference chart and diagrams. Chest. 2011;139:183-9. 5. Simone CB, 2nd, Friedberg JS, Glatstein E, Stevenson JP, Sterman DH, Hahn SM, et al. Photodynamic therapy for the treatment of non-small cell lung cancer. Journal of thoracic disease. 2012;4:63-75. 6. Barriger RB, Forquer JA, Brabham JG, Andolino DL, Shapiro RH, Henderson MA, et al. A dose-volume analysis of radiation pneumonitis in non-small cell lung cancer patients treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2012;82:457-62. 7. Hoppe BS, Flampouri S, Henderson RH, Pham D, Bajwa AA, D''Agostino H, et al. Proton Therapy With Concurrent Chemotherapy for Non-small-cell Lung Cancer: Technique and Early Results. Clin Lung Cancer. 2012. 8. Targeted therapy in non-small lung cancer. Anticancer research. 2012;32:719. 9. Kelly RJ, Giaccone G. Lung cancer vaccines. Cancer J. 2011;17:302-8. 10. Thomas R, Wolf J. Personalized therapy of lung cancer. Onkologie. 2012;35 Suppl 1:14-9. 11. van der Drift MA, Karim-Kos HE, Siesling S, Groen HJ, Wouters MW, Coebergh JW, et al. Progress in Standard of Care Therapy and Modest Survival Benefits in the Treatment of Non-small Cell Lung Cancer Patients in the Netherlands in the Last 20 Years. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012;7:291-8. 12. Haddadin S, Perry MC. History of small-cell lung cancer. Clin Lung Cancer. 2011;12:87-93. 13. Greaves SM, Brown K, Garon EB, Garon BL. The new staging system for lung cancer: imaging and clinical implications. J Thorac Imaging. 2011;26:119-31. 14. Horne ZD, Landreneau RJ, Luketich JD, Schuchert MJ. Endoluminal management of bronchogenic carcinoma in 2010: diagnosis, staging, and therapy. Minerva Chir. 2010;65:635-54. 15. Rusch V, Klimstra D, Venkatraman E, Pisters PW, Langenfeld J, Dmitrovsky E. Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clinical cancer research : an official journal of the American Association for Cancer Research. 1997;3:515-22. 16. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nature reviews Cancer. 2007;7:778-90. 17. Ayabe T, Matsuzaki Y, Edagawa M, Shimizu T, Hara M, Tomita M, et al. [Primary lung cancer; assessment of the disclosed 5-year survival rate by the Internet website]. Kyobu geka The Japanese journal of thoracic surgery. 2005;58:451-9. 18. Desjardins C. Endocrine regulation of reproductive development and function in the male. Journal of animal science. 1978;47 Suppl 2:56-79. 19. Jost A. Hormonal factors in the sex differentiation of the mammalian foetus. Philosophical transactions of the Royal Society of London Series B, Biological sciences. 1970;259:119-30. 20. Forest MG. Role of androgens in fetal and pubertal development. Hormone research. 1983;18:69-83. 21. Luu-The V, Labrie F. The intracrine sex steroid biosynthesis pathways. Progress in brain research. 2010;181:177-92. 22. Luu-The V, Belanger A, Labrie F. Androgen biosynthetic pathways in the human prostate. Best practice & research Clinical endocrinology & metabolism. 2008;22:207-21. 23. Provost PR, Simard M, Tremblay Y. A link between lung androgen metabolism and the emergence of mature epithelial type II cells. American journal of respiratory and critical care medicine. 2004;170:296-305. 24. Provost PR, Blomquist CH, Godin C, Huang XF, Flamand N, Luu-The V, et al. Androgen formation and metabolism in the pulmonary epithelial cell line A549: expression of 17beta-hydroxysteroid dehydrogenase type 5 and 3alpha-hydroxysteroid dehydrogenase type 3. Endocrinology. 2000;141:2786-94. 25. Diani AR, Mulholland MJ, Shull KL, Kubicek MF, Johnson GA, Schostarez HJ, et al. Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. The Journal of clinical endocrinology and metabolism. 1992;74:345-50. 26. Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, et al. The effect of finasteride, a 5 alpha-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. The Journal of clinical endocrinology and metabolism. 1994;79:703-6. 27. Leyden J, Dunlap F, Miller B, Winters P, Lebwohl M, Hecker D, et al. Finasteride in the treatment of men with frontal male pattern hair loss. Journal of the American Academy of Dermatology. 1999;40:930-7. 28. Rathnayake D, Sinclair R. Male androgenetic alopecia. Expert opinion on pharmacotherapy. 2010;11:1295-304. 29. Hogan DJ, Chamberlain M. Male pattern baldness. Southern medical journal. 2000;93:657-62. 30. Fruzzetti F, de Lorenzo D, Parrini D, Ricci C. Effects of finasteride, a 5 alpha-reductase inhibitor, on circulating androgens and gonadotropin secretion in hirsute women. The Journal of clinical endocrinology and metabolism. 1994;79:831-5. 31. Stout SM, Stumpf JL. Finasteride treatment of hair loss in women. The Annals of pharmacotherapy. 2010;44:1090-7. 32. Tosti A, Piraccini BM, Sisti A, Duque-Estrada B. Hair loss in women. Minerva ginecologica. 2009;61:445-52. 33. McPhaul MJ. Factors that mediate and modulate androgen action. The journal of investigative dermatology Symposium proceedings / the Society for Investigative Dermatology, Inc [and] European Society for Dermatological Research. 2003;8:1-5. 34. Roy AK, Chatterjee B. Androgen action. Critical reviews in eukaryotic gene expression. 1995;5:157-76. 35. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nature reviews Cancer. 2001;1:34-45. 36. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Molecular and cellular endocrinology. 1996;120:51-7. 37. Nielsen HC, Zinman HM, Torday JS. Dihydrotestosterone inhibits fetal rabbit pulmonary surfactant production. The Journal of clinical investigation. 1982;69:611-6. 38. Kimura Y, Suzuki T, Kaneko C, Darnel AD, Akahira J, Ebina M, et al. Expression of androgen receptor and 5alpha-reductase types 1 and 2 in early gestation fetal lung: a possible correlation with branching morphogenesis. Clin Sci (Lond). 2003;105:709-13. 39. Plante J, Simard M, Rantakari P, Cote M, Provost PR, Poutanen M, et al. Epithelial cells are the major site of hydroxysteroid (17beta) dehydrogenase 2 and androgen receptor expression in fetal mouse lungs during the period overlapping the surge of surfactant. The Journal of steroid biochemistry and molecular biology. 2009;117:139-45. 40. Mikkonen L, Pihlajamaa P, Sahu B, Zhang FP, Janne OA. Androgen receptor and androgen-dependent gene expression in lung. Molecular and cellular endocrinology. 2010;317:14-24. 41. Verma MK, Miki Y, Sasano H. Sex steroid receptors in human lung diseases. The Journal of steroid biochemistry and molecular biology. 2011;127:216-22. 42. Fu JB, Kau TY, Severson RK, Kalemkerian GP. Lung cancer in women: analysis of the national Surveillance, Epidemiology, and End Results database. Chest. 2005;127:768-77. 43. Chen KY, Chang CH, Yu CJ, Kuo SH, Yang PC. Distribution according to histologic type and outcome by gender and age group in Taiwanese patients with lung carcinoma. Cancer. 2005;103:2566-74. 44. Ahmad N, Kumar R. Steroid hormone receptors in cancer development: a target for cancer therapeutics. Cancer letters. 2011;300:1-9. 45. Yan M, Chen X, Wang S, Li Y. [Expression of ER and AR in lung cancer.]. Zhongguo fei ai za zhi = Chinese journal of lung cancer. 2008;11:126-9. 46. Rades D, Setter C, Dahl O, Schild SE, Noack F. The prognostic impact of tumor cell expression of estrogen receptor-alpha, progesterone receptor, and androgen receptor in patients irradiated for non-small cell lung cancer. Cancer. 2011. 47. Beattie CW, Hansen NW, Thomas PA. Steroid receptors in human lung cancer. Cancer research. 1985;45:4206-14. 48. Chaudhuri PK, Thomas PA, Walker MJ, Briele HA, Das Gupta TK, Beattie CW. Steroid receptors in human lung cancer cytosols. Cancer letters. 1982;16:327-32. 49. Liao ML, Wang JH, Wang HM, Ou AQ, Wang XJ, You WQ. A study of the association between squamous cell carcinoma and adenocarcinoma in the lung, and history of menstruation in Shanghai women, China. Lung Cancer. 1996;14 Suppl 1:S215-21. 50. Maasberg M, Rotsch M, Jaques G, Enderle-Schmidt U, Weehle R, Havemann K. Androgen receptors, androgen-dependent proliferation, and 5 alpha-reductase activity of small-cell lung cancer cell lines. International journal of cancer Journal international du cancer. 1989;43:685-91. 51. Recchia AG, Musti AM, Lanzino M, Panno ML, Turano E, Zumpano R, et al. A cross-talk between the androgen receptor and the epidermal growth factor receptor leads to p38MAPK-dependent activation of mTOR and cyclinD1 expression in prostate and lung cancer cells. The international journal of biochemistry & cell biology. 2009;41:603-14. 52. Zetterberg AH, Pettersson RF, Lindahl SG. [Hartwell, Hunt and Nurse share the 2001 Nobel Prize in physiology or medicine. CDK and cyclin--molecular motors of cell cycle]. Lakartidningen. 2001;98:4544-50. 53. Etcheverry GJ. [Unraveling the control of life cycle. Nobel Prize of Physiology or Medicine 2001]. Medicina. 2001;61:895-7. 54. Balter M, Vogel G. Nobel prize in physiology or medicine. Cycling toward Stockholm. Science. 2001;294:502-3. 55. Lees E. Cyclin dependent kinase regulation. Current opinion in cell biology. 1995;7:773-80. 56. Akiyama T. [Molecular mechanism of cell cycle control]. Nihon rinsho Japanese journal of clinical medicine. 1996;54:1031-6. 57. Nigg EA. Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. BioEssays : news and reviews in molecular, cellular and developmental biology. 1995;17:471-80. 58. Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science. 1996;274:1664-72. 59. Murray A. Cell cycle checkpoints. Current opinion in cell biology. 1994;6:872-6. 60. Peeper DS, van der Eb AJ, Zantema A. The G1/S cell-cycle checkpoint in eukaryotic cells. Biochimica et biophysica acta. 1994;1198:215-30. 61. Weinert T, Lydall D. Cell cycle checkpoints, genetic instability and cancer. Seminars in cancer biology. 1993;4:129-40. 62. Chiarugi V, Magnelli L, Cinelli M, Basi G. Apoptosis and the cell cycle. Cellular & molecular biology research. 1994;40:603-12. 63. Herber B, Truss M, Beato M, Muller R. Inducible regulatory elements in the human cyclin D1 promoter. Oncogene. 1994;9:2105-7. 64. Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, et al. Fos family members induce cell cycle entry by activating cyclin D1. Molecular and cellular biology. 1998;18:5609-19. 65. Sherr CJ. D-type cyclins. Trends in biochemical sciences. 1995;20:187-90. 66. Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene. 2006;25:1620-8. 67. Das SK, Hashimoto T, Shimizu K, Yoshida T, Sakai T, Sowa Y, et al. Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochimica et biophysica acta. 2005;1726:328-35. 68. Resnitzky D, Reed SI. Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Molecular and cellular biology. 1995;15:3463-9. 69. Pines J, Hunter T. Cyclins A and B1 in the human cell cycle. Ciba Foundation symposium. 1992;170:187-96; discussion 96-204. 70. Marcote MJ, Pagano M, Draetta G. cdc2 protein kinase: structure-function relationships. Ciba Foundation symposium. 1992;170:30-41; discussion -9. 71. Yam CH, Fung TK, Poon RY. Cyclin A in cell cycle control and cancer. Cellular and molecular life sciences : CMLS. 2002;59:1317-26. 72. Biggs JR, Kraft AS. Inhibitors of cyclin-dependent kinase and cancer. J Mol Med (Berl). 1995;73:509-14. 73. Jiang H, Wang YC. [Cyclin-dependent kinase inhibitors in mammal cells]. Sheng li ke xue jin zhan [Progress in physiology]. 1996;27:107-12. 74. Reed SI, Bailly E, Dulic V, Hengst L, Resnitzky D, Slingerland J. G1 control in mammalian cells. Journal of cell science Supplement. 1994;18:69-73. 75. Kobayashi H. [The cell cycle and the tumor suppressor genes]. Rinsho byori The Japanese journal of clinical pathology. 1996;44:3-11. 76. Zetterberg A, Larsson O, Wiman KG. What is the restriction point? Current opinion in cell biology. 1995;7:835-42. 77. Gartel AL, Serfas MS, Tyner AL. p21--negative regulator of the cell cycle. Proc Soc Exp Biol Med. 1996;213:138-49. 78. Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994;78:67-74. 79. Koff A, Polyak K. p27KIP1, an inhibitor of cyclin-dependent kinases. Progress in cell cycle research. 1995;1:141-7. 80. Sudduth SL, Koronkowski MJ. Finasteride: the first 5 alpha-reductase inhibitor. Pharmacotherapy. 1993;13:309-25; discussion 25-9. 81. Stoner E. The clinical development of a 5 alpha-reductase inhibitor, finasteride. The Journal of steroid biochemistry and molecular biology. 1990;37:375-8. 82. Hasinski S, Miller JL, Rose LI. Finasteride for benign prostatic hyperplasia. American family physician. 1992;46:1511-4. 83. Spinucci G, Pasquali R. [Finasteride: a new drug for the treatment of male hirsutism and androgenetic alopecia?]. La Clinica terapeutica. 1996;147:305-15. 84. Festuccia C, Angelucci A, Gravina GL, Muzi P, Vicentini C, Bologna M. Effects of 5 alpha reductase inhibitors on androgen-dependent human prostatic carcinoma cells. Journal of cancer research and clinical oncology. 2005;131:243-54. 85. Festuccia C, Gravina GL, Muzi P, Pomante R, Angelucci A, Vicentini C, et al. Effects of dutasteride on prostate carcinoma primary cultures: a comparative study with finasteride and MK386. J Urol. 2008;180:367-72. 86. Bologna M, Muzi P, Biordi L, Festuccia C, Vicentini C. Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. Urology. 1995;45:282-90. 87. Chen G, Geng J, Zhang YF. [Mechanism of inhibiting the proliferation of prostate cancer by finasteride: a study using cDNA microarray]. Zhonghua yi xue za zhi. 2005;85:1489-92. 88. Golbano JM, Loppez-Aparicio P, Recio MN, Perez-Albarsanz MA. Finasteride induces apoptosis via Bcl-2, Bcl-xL, Bax and caspase-3 proteins in LNCaP human prostate cancer cell line. International journal of oncology. 2008;32:919-24. 89. Gormley GJ. Role of 5 alpha-reductase inhibitors in the treatment of advanced prostatic carcinoma. The Urologic clinics of North America. 1991;18:93-8. 90. Gormley GJ. Chemoprevention strategies for prostate cancer: the role of 5 alpha-reductase inhibitors. Journal of cellular biochemistry Supplement. 1992;16H:113-7. 91. Zhao J, Tenev T, Martins LM, Downward J, Lemoine NR. The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. Journal of cell science. 2000;113 Pt 23:4363-71. 92. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994;78:773-85. 93. Huo LJ, Fan HY, Zhong ZS, Chen DY, Schatten H, Sun QY. Ubiquitin-proteasome pathway modulates mouse oocyte meiotic maturation and fertilization via regulation of MAPK cascade and cyclin B1 degradation. Mechanisms of development. 2004;121:1275-87. 94. Firestein R, Feuerstein N. Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells. The Journal of biological chemistry. 1998;273:5892-902. 95. Motegi A, Murakawa Y, Takeda S. The vital link between the ubiquitin-proteasome pathway and DNA repair: impact on cancer therapy. Cancer letters. 2009;283:1-9. 96. Orlowski RZ. The role of the ubiquitin-proteasome pathway in apoptosis. Cell death and differentiation. 1999;6:303-13. 97. Wojcik C. Regulation of apoptosis by the ubiquitin and proteasome pathway. Journal of cellular and molecular medicine. 2002;6:25-48. 98. Matsuda N, Tanaka K. Does Impairment of the Ubiquitin-Proteasome System or the Autophagy-Lysosome Pathway Predispose Individuals to Neurodegenerative Disorders such as Parkinson''s Disease? Journal of Alzheimer''s disease : JAD. 2009. 99. Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994;79:13-21. 100. Peters JM, Franke WW, Kleinschmidt JA. Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. The Journal of biological chemistry. 1994;269:7709-18. 101. Xiao BY, Li GY. [Ubiquitin-proteasome pathway]. Zhong nan da xue xue bao Yi xue ban = Journal of Central South University Medical sciences. 2004;29:230-2. 102. Haas AL, Warms JV, Hershko A, Rose IA. Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation. The Journal of biological chemistry. 1982;257:2543-8. 103. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM. Recognition of the polyubiquitin proteolytic signal. The EMBO journal. 2000;19:94-102. 104. Corn PG. Role of the ubiquitin proteasome system in renal cell carcinoma. BMC biochemistry. 2007;8 Suppl 1:S4. 105. Risseeuw EP, Daskalchuk TE, Banks TW, Liu E, Cotelesage J, Hellmann H, et al. Protein interaction analysis of SCF ubiquitin E3 ligase subunits from Arabidopsis. The Plant journal : for cell and molecular biology. 2003;34:753-67. 106. Hong H, Kao C, Jeng MH, Eble JN, Koch MO, Gardner TA, et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer. 2004;101:83-9. 107. Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer research. 2002;62:1008-13. 108. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS letters. 1997;420:25-7. 109. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. The Journal of biological chemistry. 2000;275:8945-51. 110. Sengupta S, Wasylyk B. Physiological and pathological consequences of the interactions of the p53 tumor suppressor with the glucocorticoid, androgen, and estrogen receptors. Annals of the New York Academy of Sciences. 2004;1024:54-71. 111. Linn DE, Yang X, Xie Y, Alfano A, Deshmukh D, Wang X, et al. Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. The Journal of biological chemistry. 2012. 112. Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. The EMBO journal. 2002;21:4037-48. 113. Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. Journal of immunological methods. 1995;184:39-51. 114. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. The Journal of cell biology. 1992;119:493-501. 115. Janus F, Albrechtsen N, Dornreiter I, Wiesmuller L, Grosse F, Deppert W. The dual role model for p53 in maintaining genomic integrity. Cellular and molecular life sciences : CMLS. 1999;55:12-27. 116. Albrechtsen N, Dornreiter I, Grosse F, Kim E, Wiesmuller L, Deppert W. Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene. 1999;18:7706-17. 117. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes & development. 1999;13:1899-911. 118. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. Journal of cell science. 2009;122:437-41. 119. Seglen PO, Berg TO, Blankson H, Fengsrud M, Holen I, Stromhaug PE. Structural aspects of autophagy. Advances in experimental medicine and biology. 1996;389:103-11. 120. Stromhaug PE, Klionsky DJ. Approaching the molecular mechanism of autophagy. Traffic. 2001;2:524-31. 121. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672-6. 122. Asanuma K, Tanida I, Shirato I, Ueno T, Takahara H, Nishitani T, et al. MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003;17:1165-7. 123. Watzka SB, Posch F, Hochmair M, Setinek U, Kostler WJ, Muller MR. Resistance to EGFR targeting therapies in lung cancer. Minerva Chir. 2011;66:483-94.en_US
dc.description.abstract流行病學臨床調查研究顯示,性別差異與肺部疾病的發生率呈正相關性,男性比女性更容易得到腫瘤與非腫瘤性的肺部疾病,且肺癌患者中女性生存率明顯高於男性。相較於正常肺部組織,雄性激素受體 (androgen receptor, AR) 在惡性腫瘤中也有較高的表現情況,此證據顯示AR的調節可能涉及了肺癌的發病機制。Finasteride是5α-還原酶 (5α-reductase) 的特異性抑制劑,其有效抑制睪固酮 (dihydrotestosterone, DHT) 的產生,廣泛的應用在不同雄性荷爾蒙過度表現的病灶,在臨床上作為良性前列腺增生症 (benign prostatic hyperplasia, BPH) 患者的第一線口服治療用藥。先前研究結果顯示,前列腺癌細胞株對於finasteride的治療也很敏感,可有效的治療雄性激素依賴性前列腺癌細胞的增生。因此,本論文的研究目的在於探討AR在非小細胞肺癌 (non-small cell lung cancer, NSCLC) 中所扮演的角色以及finasteride調控AR蛋白質表現的相關機制。研究結果發現,透過轉染方式過度表現AR可以刺激非小型細胞肺癌細胞株A549的增生,反之使用shRNA與AR抑制劑可以降低A549的生長,顯示AR在NSCLC的生長中扮演著重要的角色,暗示著在腫瘤和非腫瘤性肺部疾病中,AR具有治療肺病患者潛在應用價值。在此論文中,我們探討finasteride是否透過干擾AR的蛋白穩定性來調控NSCLC的生長。實驗結果顯示finasteride處理會抑制A549生長,且抑制生長效果與finasteride使用劑量與處理時間呈正相關。在A549中發現finasteride會導致AR蛋白量下降,此外亦發現finasteride同時也會減少AR進入細胞核,降低AR的轉錄活性,並對於finateride導致的AR蛋白量下降,排除了finasteride對基因表現影響。進一步我們發現finasteride抑制了AR與熱休克蛋白90 (heat-shock protein 90, HSP 90) 的結合而降低了AR蛋白質穩定性,導致Mdm2與AR鍵結提高而增加ubiquitination,促使AR走向proteasome-dependent的降解路徑。除此之外finasteride透過累積細胞週期導致細胞週期G1阻滯,並發現促凋亡蛋白(Bax)表現增加和抗凋亡蛋白(Bcl-2)表現減少,TUNEL assay結果顯示DNA 斷裂 (DNA fragment) 數量的提高,皆顯示finasteride誘導A549發生細胞凋亡。綜合上述數據,finasteride誘導細胞週期停滯在G1期與增加細胞凋亡,抑制A549的AR蛋白質穩定性與細胞增生。經由以上研究結果,發現 finasteride可能是一個潛在的治療非小細胞肺癌的治療劑,期望這個研究,可以對於未來肺癌的診斷及治療有所貢獻。zh_TW
dc.description.abstractThe previous epidemiological studies have reported that gender differences exist in clinical corroboration in human lung diseases. In particular, men are more probability developed than women both neoplastic and non-neoplastic lung diseases. Female patients with lung cancer survival rate were significantly higher than male patients. Androgen receptors (AR) in malignant tumors have a higher performance compared to normal lung tissue. This gender difference above suggests that regulation of AR may be involved in the pathogenesis of human lung cancer. Finasteride is a specific inhibitor of the 5α-reductase and used as a first-lined medicine for benign prostatic hyperplasia (BPH) patients due to decreasing the conversion of testosterone into dihydroteststosterone, a potent form of androgen. To focus that extensive application excessively expressed in the different male hormone. Previous results indicate that the proliferation of prostate cancer cells is decreased with finasteride treatment. Interestingly, androgen-dependent prostate cancer cell lines are also sensitive to finasteride treatment. In this study, we verify the role of AR in non-small cell lung cancer and the mechanism of finasteride in AR regulation. The cell growth tests results show that AR overexpression by transient transfection increased the cell proliferation of A549 cells. On the other hand, knockdown AR expression by shRNA and AR inhibitor, casodex, could inhibit cell growth of A549 cells. Display AR plays an important role in the growth of NSCLC. It appears the potential roles of AR in both neoplastic and non-neoplastic lung diseases toward improved treatment options for the patients. In this study, we investigated whether finasteride could affect cell viability of NSCLC. Finasteride potently inhibited growth of NSCLC cell line, A549, in a dose- and time-dependent manner. However, finasteride decreased AR protein expression excludes mRNA level in A549, and resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Furthermore, we found that finasteride decreased the complex of AR and heat-shock protein 90 (HSP 90), and reduce the protein stability of AR. Simultaneously, finasteride increased the association of AR and Mdm2, which in turn induced AR degradation through proteasome-mediated pathway, resulting in AR protein expression decreased. Moreover, there was an increase in the number of cells accumulating in the G1 phase of the cell cycle, resulted in cell cycle G1 arrest. In addition, finasteride induced apoptosis of NSCLC which is mediated through up-regulating pro-apoptotic protein expression (Bax) and down-regulating anti-apoptotic protein expression (Bcl-2). It consists with the determination of finasteride-induced DNA fragmentation in A549 through the TUNEL assay. Based on above data, finasteride suppressed AR protein stability and cell proliferation via inducing cell cycle arrest at G1 phase and apoptosis. Taken together, these results suggest that finasteride might be a potential therapeutic agent for treating the NSCLC. We hope these findings in the future can contribute to diagnosis and treatment of lung cancer.en_US
dc.description.tableofcontents目次 第一章、 前言 1 一、 肺癌 1 二、 雄性激素及其受體 3 三、 肺癌與雄性激素受體 6 四、 細胞週期與細胞週期調控蛋白 8 五、 Finasteride 11 六、 泛素化 (ubiquitination) 12 七、 雄性激素受體蛋白質穩定性 (stability) 13 第二章、 材料與方法 15 一、 人類非小型細胞肺癌細胞株A549之培養 (Cell Culture) 15 二、 細胞基因轉殖感染技術 (Plasmid DNA Transfection) 15 三、 細胞生長曲線測定 (Cell Counting) 16 四、 細胞增殖分析法 (MTT Assay) 16 五、 蛋白質萃取 (Protein Extraction) 17 六、 細胞核質分離萃取技術 (Fractionation) 18 七、 西方墨漬法之蛋白質表現檢測 (Western Blotting) 18 (一)、SDS-PAGE電泳法 (SDS-polyacrylamide gel electrophoresis) 18 (二)、全濕式蛋白質轉漬法 (protein transfering,immersion) 19 (三)、抗體標記與螢光呈色 19 八、 免疫沉澱法 (Immunoprecipitation,IP) 20 九、 細胞免疫螢光染色 (Immunofluorescent stain) 20 十、 mRNA 表現分析 21 (一)、Total RNA純化萃取 (Total RNA purification) 21 (二)、RT-PCR (Reverse-transcription Polymerase Chain Reaction) 21 (三)、RT-PCR (Real-Time Polymerase Chain Reaction) 21 (四)、DNA電泳 22 十一、 qRT-PCR (Quantitative Real-Time Polymerase Chain Reaction) 22 十二、 細胞凋亡檢測 (Cell Apoptosis Assay) 22 (一)、Annexin V assay 22 (二)、TUNEL assay 23 十三、 報導基因分析 (Reporter Assay) 23 十四、 細胞週期分析法 (Cell Cycle Assay) 24 十五、 細胞群落形成分析 (Colony Formation Assay) 24 十六、 統計分析 24 第三章、 實驗結果 25 一、 雄性激素受體在不同肺癌細胞株中的表現 25 二、 雄性激素受體對於A549肺癌細胞株生長的影響 25 (一)、雄性激素受體抑制劑會抑制A549肺癌細胞株生長 25 (二)、過度表現雄性激素受體會刺激A549肺癌細胞株生長 26 (三)、阻斷雄性激素受體表現會抑制A549肺癌細胞株生長 27 三、 操縱雄性激素受體表現影響mRNA表達 28 四、 Finasteride抑制A549肺癌細胞的生長 29 五、 Finasteride 對A549的雄性激素受體蛋白表現之影響 30 (一)、不同濃度的finasteride抑制雄性激素受體蛋白質的表現 31 (二)、不同時間點finasteride抑制雄性激素受體蛋白質的表現 31 六、 Finasteride影響雄性激素受體之蛋白質穩定性 (stability) 32 七、 Finasteride干擾雄性激素受體在細胞間的表現與分佈 33 八、 Finasteride 促進了雄性激素受體的ubiquitination 34 九、 Finasteride 促進了雄性激素受體的與Mdm2的鍵結 34 十、 Finasteride 抑制雄性激素受體的轉錄活性 35 十一、 Finasteride不影響雄性激素受體的messenger RNA表現 36 十二、 伴隨MG132處理減緩finasteride抑制A549肺癌細胞生長的效用 37 十三、 Finasteride干擾heat-shock protein 90的表現 37 十四、 Finasteride改變了A549肺癌細胞的細胞週期分佈 38 十五、 Finasteride影響細胞週期調控相關蛋白表現 39 十六、 Finasteride導致A549細胞凋亡 40 十七、 Finasteride影響細胞凋亡相關蛋白表現 41 十八、 Finasteride不會促使A549細胞自體吞噬 (autophagy) 42 十九、 Finasteride與Iressa的複合使用具有加成作用 43 第四章、 討論 44 一、 雄性激素受體在肺癌中的重要性 44 二、 Finasteride降低了A549中雄性激素受體的穩定性 44 三、 Finasteride導致A549的G1 arrest與apoptosis 46 四、 Finasteride與Iressa的複合式使用的加成性 47 第五章、 結論 48 第六章、 參考文獻 80   圖表目次 附圖 附圖一、全球致死原因統計及預測。 1 附圖二、1993~2008年美國男性癌症死亡率 2 附圖三、1930~2008年美國女性癌症死亡率 2 附圖四、癌症預估發生率及癌症預估死亡率 2 附圖五、雄性激素合成途徑 4 附圖六、雄性激素的活化路徑 5 附圖七、雄性激素受體在不同臨床分期肺癌病患中的表現情況 7 附圖八、肺癌病患特性 7 附圖九、細胞週期 8 附圖十、cyclin D1在細胞週期中的調控機制 10 附圖十一、Finasteride的臨床研究 11 附圖十二、蛋白質泛素化 (ubiquitination) 路徑 12 附圖十三、雄性激素受體蛋白降解路徑 13 附圖十四、研究動機示意圖。 14 實驗結果 圖一、非小型細胞肺癌細胞株A549之細胞型態 49 圖二、不同肺癌細胞株之雄性激素受體的表現情況 50 圖三、雄性激素受體抑制劑會抑制A549肺癌細胞株生長 51 圖四、過度表現雄性激素受體會刺激A549肺癌細胞株生長 52 圖五、阻斷表現雄性激素受體會抑制A549肺癌細胞株生長 53 圖六、操縱雄性激素受體表現影響mRNA表達 55 圖七、Finasteride 對A549的細胞型態影響 56 圖八、Finasteride抑制A549肺癌細胞的生長 57 圖九、Finasteride 對A549的雄性激素受體蛋白表現之影響 59 圖十、Finasteride影響雄性激素受體之蛋白質穩定性 60 圖十一、Finasteride干擾雄性激素受體在細胞間的表現與分佈 62 圖十二、Finasteride 促進了雄性激素受體的ubiquitination 63 圖十三、Finasteride 增加了雄性激素受體與Mdm2的鍵結 64 圖十四、Finasteride 抑制雄性激素受體的轉錄活性 (transcriptional activity) 65 圖十五、Finasteride不影響雄性激素受體的mRNA表現 66 圖十六、伴隨MG132處理減緩Finasteride抑制A549肺癌細胞生長的作用 67 圖十七、Finasteride干擾heat-shock protein 90的表現 68 圖十八、Finasteride改變了A549肺癌細胞的細胞週期分佈 70 圖十九、Finasteride影響細胞週期調控相關蛋白表現 71 圖二十、Finasteride處理導致A549肺癌凋亡 73 圖二十一、Finasteride處理導致A549肺癌凋亡 74 圖二十二、Finasteride影響細胞凋亡相關蛋白表現 75 圖二十三、Finasteride不影響細胞的autophagy 77 圖二十四、Finasteride與Iressa的複合使用具有加成作用 78 圖二十五、Finasteride經由降低AR穩定性進而抑制非小型細胞肺癌之細胞生長的機制示意圖 79zh_TW
dc.subjectlung canceren_US
dc.subjectandrogen receptoren_US
dc.titleFinasteride Suppresses Proliferation of A549 Cells through Interfering Androgen Receptor Protein Stabilityen_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.fulltextno fulltext-
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