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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85246完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學(Ming-Shyue Lee) | |
| dc.contributor.author | Hsin-Ying Lin | en |
| dc.contributor.author | 林心瀅 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:52:41Z | - |
| dc.date.copyright | 2022-10-05 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-08-02 | |
| dc.identifier.citation | 1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2020. CA Cancer J Clin, 2020. 70(1): p. 7-30. 2. Agarwal, R., Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem Pharmacol, 2000. 60(8): p.1051-9. 3. Saraon, P., K. Jarvi, and E.P. Diamandis, Molecular alterations during progression of prostate cancer to androgen independence. Clin Chem, 2011. 57(10): p. 1366-75. 4. Clarke, N.W., C.A. Hart, and M.D. Brown, Molecular mechanisms of metastasis in prostate cancer. Asian J Androl, 2009. 11(1): p. 57-67. 5. Nguyen, D.X., P.D. Bos, and J. Massague, Metastasis: from dissemination to organ- specific colonization. Nat Rev Cancer, 2009. 9(4): p. 274-84. 6. Wang, G., et al., Genetics and biology of prostate cancer. Genes Dev, 2018. 32(17- 18): p. 1105-1140. 7. Ferlay, J., et al., Estimating the global cancer incidence and mortality in 2018:GLOBOCAN sources and methods. Int J Cancer, 2019. 144(8): p. 1941-1953. 8. Joyce, J.A. and J.W. Pollard, Microenvironmental regulation of metastasis. Nat Rev Cancer, 2009. 9(4): p. 239-52. 9. Lopez-Otin, C. and J.S. Bond, Proteases: multifunctional enzymes in life and disease. J Biol Chem, 2008. 283(45): p. 30433-7. 10. Park, K.C., M. Dharmasivam, and D.R. Richardson, The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity. Int J Mol Sci, 2020. 21(18). 11. Valastyan, S. and R.A. Weinberg, Tumor metastasis: molecular insights and evolving paradigms. Cell, 2011. 147(2): p. 275-92. 12. Lopez-Otin, C. and L.M. Matrisian, Emerging roles of proteases in tumour suppression. Nat Rev Cancer, 2007. 7(10): p. 800-8. 13. Spill, F., et al., Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol, 2016. 40: p. 41-48. 14. Sevenich, L. and J.A. Joyce, Pericellular proteolysis in cancer. Genes Dev, 2014. 28(21): p. 2331-47. 15. Baghban, R., et al., Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal, 2020. 18(1): p. 59. 16. Wang, M., et al., Role of tumor microenvironment in tumorigenesis. J Cancer, 2017. 8(5): p. 761-773. 17. Pickup, M., S. Novitskiy, and H.L. Moses, The roles of TGFbeta in the tumourmicroenvironment. Nat Rev Cancer, 2013. 13(11): p. 788-99. 18. Chen, G., C. Deng, and Y.P. Li, TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci, 2012. 8(2): p. 272-88. 19. Tang, B., et al., TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest, 2003. 112(7): p. 1116-24. 20. Slabakova, E., et al., TGF-beta1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug. Prostate, 2011. 71(12): p. 1332-43. 21. Mani, S.A., et al., The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008. 133(4): p. 704-15. 22. De Wever, O. and M. Mareel, Role of tissue stroma in cancer cell invasion. J Pathol, 2003. 200(4): p. 429-47. 23. Thomas, D.A. and J. Massague, TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell, 2005. 8(5): p. 369-80. 24. Gkretsi, V., et al., Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy. Front Oncol, 2015. 5: p. 214. 25. Schwartz, M.K., Role of trace elements in cancer. Cancer Res, 1975. 35(11 Pt. 2): p. 3481-7. 26. Rosner, M.H. and A.C. Dalkin, Electrolyte disorders associated with cancer. Adv Chronic Kidney Dis, 2014. 21(1): p. 7-17. 27. Pedersen, S.F. and C. Stock, Ion channels and transporters in cancer: pathophysiology, regulation, and clinical potential. Cancer Res, 2013. 73(6): p.1658-61. 28. Boedtkjer, E., et al., Contribution of Na+,HCO3(-)-cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int J Cancer, 2013. 132(6): p. 1288-99. 29. Chen, Y., et al., Disordered signaling governing ferroportin transcription favors breast cancer growth. Cell Signal, 2015. 27(1): p. 168-76. 30. Gordon, K.J. and G.C. Blobe, Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008. 1782(4): p. 197-228. 31. Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003. 425(6958): p. 577-84. 32. Heldin, C.H. and A. Moustakas, Signaling Receptors for TGF-beta Family Members. Cold Spring Harb Perspect Biol, 2016. 8(8). 33. Xu, L., Regulation of Smad activities. Biochim Biophys Acta, 2006. 1759(11-12):p. 503-13. 34. Massague, J., J. Seoane, and D. Wotton, Smad transcription factors. Genes Dev, 2005. 19(23): p. 2783-810. 35. Massague, J., TGFbeta in Cancer. Cell, 2008. 134(2): p. 215-30. 36. Ikushima, H. and K. Miyazono, TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer, 2010. 10(6): p. 415-24. 37. Snoek-van Beurden, P.A. and J.W. Von den Hoff, Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. Biotechniques, 2005. 38(1): p. 73-83. 38. Shi, Y. and J. Massague, Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003. 113(6): p. 685-700. 39. Matsuzaki, K., Smad phosphoisoform signaling specificity: the right place at the right time. Carcinogenesis, 2011. 32(11): p. 1578-88. 40. Kretzschmar, M., et al., A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev, 1999. 13(7): p. 804-16. 41. Kubiczkova, L., et al., TGF-beta - an excellent servant but a bad master. J Transl Med, 2012. 10: p. 183. 42. Massague, J., TGFbeta signalling in context. Nat Rev Mol Cell Biol, 2012. 13(10): p. 616-30. 43. Dennler, S., et al., Direct binding of Smad3 and Smad4 to critical TGF beta inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J, 1998. 17(11): p. 3091-100. 44. Lu, T., et al., Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways. Proc Natl Acad Sci U S A, 2007. 104(11): p. 4365-70. 45. Zhang, Y.E., Non-Smad pathways in TGF-beta signaling. Cell Res, 2009. 19(1): p. 128-39. 46. Kiyono, K., et al., c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma. Cancer Sci, 2009. 100(10): p. 1809-16. 47. Liu, S., S. Chen, and J. Zeng, TGFbeta signaling: A complex role in tumorigenesis (Review). Mol Med Rep, 2018. 17(1): p. 699-704. 48. Wakefield, L.M. and A.B. Roberts, TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev, 2002. 12(1): p. 22-9. 49. Gorelik, L. and R.A. Flavell, Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity, 2000. 12(2): p. 171-81. 50. Letterio, J.J. and A.B. Roberts, Regulation of immune responses by TGF-beta. Annu Rev Immunol, 1998. 16: p. 137-61. 51. Scandura, J.M., et al., Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc Natl Acad Sci U S A, 2004. 101(42): p. 15231-6. 52. Yeh, H.W., et al., A New Switch for TGFbeta in Cancer. Cancer Res, 2019. 79(15): p. 3797-3805. 53. Feng, X.H., et al., The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev, 1998. 12(14): p. 2153-63. 54. Krimpenfort, P., et al., p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature, 2007. 448(7156): p. 943-6. 55. Buck, A., et al., The tumor suppressor KLF11 mediates a novel mechanism in transforming growth factor beta-induced growth inhibition that is inactivated in pancreatic cancer. Mol Cancer Res, 2006. 4(11): p. 861-72. 56. Xu, J., et al., 14-3-3zeta turns TGF-beta's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2. Cancer Cell, 2015. 27(2): p. 177-92. 57. ten Dijke, P. and H. van Dam, 14-3-3zeta turns TGF-beta to the dark side. Cancer Cell, 2015. 27(2): p. 151-3. 58. Yeh, H.W., et al., PSPC1 mediates TGF-beta1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis. Nat Cell Biol, 2018. 20(4): p. 479-491. 59. Andrews, N.C., Iron homeostasis: insights from genetics and animal models. Nat Rev Genet, 2000. 1(3): p. 208-17. 60. Wessling-Resnick, M., Iron homeostasis and the inflammatory response. Annu Rev Nutr, 2010. 30: p. 105-22. 61. Winter, W.E., L.A. Bazydlo, and N.S. Harris, The molecular biology of human iron metabolism. Lab Med, 2014. 45(2): p. 92-102. 62. De Domenico, I., D. McVey Ward, and J. Kaplan, Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol, 2008. 9(1): p. 72-81. 63. Le Blanc, S., M.D. Garrick, and M. Arredondo, Heme carrier protein 1 transports heme and is involved in heme-Fe metabolism. Am J Physiol Cell Physiol, 2012. 302(12): p. C1780-5. 64. Rouault, T.A., The intestinal heme transporter revealed. Cell, 2005. 122(5): p. 649-51. 65. Crielaard, B.J., T. Lammers, and S. Rivella, Targeting iron metabolism in drug discovery and delivery. Nat Rev Drug Discov, 2017. 16(6): p. 400-423. 66. Cheng, Y., et al., Structure of the human transferrin receptor-transferrin complex. Cell, 2004. 116(4): p. 565-76. 67. Bali, P.K., O. Zak, and P. Aisen, A new role for the transferrin receptor in the release of iron from transferrin. Biochemistry, 1991. 30(2): p. 324-8. 68. Dautry-Varsat, A., A. Ciechanover, and H.F. Lodish, pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci U S A, 1983. 80(8): p. 2258-62. 69. MacKenzie, E.L., K. Iwasaki, and Y. Tsuji, Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal, 2008. 10(6): p. 997-1030. 70. Staubli, A. and U.A. Boelsterli, The labile iron pool in hepatocytes: prooxidant- induced increase in free iron precedes oxidative cell injury. Am J Physiol, 1998. 274(6): p. G1031-7. 71. Dixon, S.J., et al., Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012. 149(5): p. 1060-72. 72. Li, J., et al., Ferroptosis: past, present and future. Cell Death Dis, 2020. 11(2): p. 88. 73. Hentze, M.W., et al., Two to tango: regulation of Mammalian iron metabolism. Cell, 2010. 142(1): p. 24-38. 74. Nemeth, E., et al., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 2004. 306(5704): p. 2090-3. 75. Torti, S.V. and F.M. Torti, Iron and cancer: more ore to be mined. Nat Rev Cancer, 2013. 13(5): p. 342-55. 76. van Asperen, I.A., et al., Body iron stores and mortality due to cancer and ischaemic heart disease: a 17-year follow-up study of elderly men and women. Int J Epidemiol, 1995. 24(4): p. 665-70. 77. Knekt, P., et al., Body iron stores and risk of cancer. Int J Cancer, 1994. 56(3): p. 379-82. 78. Wu, T., et al., Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol, 2004. 14(3): p. 195-201. 79. Ganz, T. and E. Nemeth, Hepcidin and disorders of iron metabolism. Annu Rev Med, 2011. 62: p. 347-60. 80. Ferguson, L.R., et al., Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol, 2015. 35 Suppl: p. S5-S24. 81. Liou, G.Y. and P. Storz, Reactive oxygen species in cancer. Free Radic Res, 2010. 44(5): p. 479-96. 82. Madeddu, C., et al., Pathogenesis and Treatment Options of Cancer Related Anemia: Perspective for a Targeted Mechanism-Based Approach. Front Physiol, 2018. 9: p. 1294. 83. Means, R.T., Jr., Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia. Stem Cells, 1995. 13(1): p. 32-7. 84. Shu, T., et al., Hepcidin in tumor-related iron deficiency anemia and tumor-related anemia of chronic disease: pathogenic mechanisms and diagnosis. Eur J Haematol, 2015. 94(1): p. 67-73. 85. Basseri, R.J., et al., Hepcidin is a key mediator of anemia of inflammation in Crohn's disease. J Crohns Colitis, 2013. 7(8): p. e286-91. 86. Rawlings, N.D., A.J. Barrett, and R. Finn, Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res, 2016. 44(D1): p. D343-50. 87. Liyanage, C., A. Fernando, and J. Batra, Differential roles of protease isoforms in the tumor microenvironment. Cancer Metastasis Rev, 2019. 38(3): p. 389-415. 88. Martin, C.E. and K. List, Cell surface-anchored serine proteases in cancer progression and metastasis. Cancer Metastasis Rev, 2019. 38(3): p. 357-387. 89. Noel, A., et al., Membrane associated proteases and their inhibitors in tumour angiogenesis. J Clin Pathol, 2004. 57(6): p. 577-84. 90. Thiery, J.P., Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2002. 2(6): p. 442-54. 91. Netzel-Arnett, S., et al., Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Rev, 2003. 22(2-3): p. 237-58. 92. Woessner, J.F., Jr., The family of matrix metalloproteinases. Ann N Y Acad Sci, 1994. 732: p. 11-21. 93. Otlewski, J., et al., The many faces of protease-protein inhibitor interaction. EMBO J, 2005. 24(7): p. 1303-10. 94. Krowarsch, D., et al., Canonical protein inhibitors of serine proteases. Cell Mol Life Sci, 2003. 60(11): p. 2427-44. 95. Grutter, M.G., et al., Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J, 1990. 9(8): p. 2361-5. 96. Murphy, G., et al., The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity. Biochemistry, 1991. 30(33): p. 8097-102. 97. Graham, C.H., Effect of transforming growth factor-beta on the plasminogen activator system in cultured first trimester human cytotrophoblasts. Placenta, 108 1997. 18(2-3): p. 137-43. 98. Duffy, M.J., The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des, 2004. 10(1): p. 39-49. 99. Duffy, M.J., et al., uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies. Breast Cancer Res, 2014. 16(4): p. 428. 100. Kwaan, H.C., A.P. Mazar, and B.J. McMahon, The apparent uPA/PAI-1 paradox in cancer: more than meets the eye. Semin Thromb Hemost, 2013. 39(4): p. 382-91. 101. Dong-Le Bourhis, X., V. Lambrecht, and B. Boilly, Transforming growth factor beta 1 and sodium butyrate differentially modulate urokinase plasminogen activator and plasminogen activator inhibitor-1 in human breast normal and cancer cells. Br J Cancer, 1998. 77(3): p. 396-403. 102. Bohm, L., et al., uPA/PAI-1 ratios distinguish benign prostatic hyperplasia and prostate cancer. J Cancer Res Clin Oncol, 2013. 139(7): p. 1221-8. 103. Velasco, G., et al., Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J Biol Chem, 2002. 277(40): p. 37637-46. 104. Ramsay, A.J., et al., The type II transmembrane serine protease matriptase-2--identification, structural features, enzymology, expression pattern and potential roles. Front Biosci, 2008. 13: p. 569-79. 105. Altamura, S., et al., A novel TMPRSS6 mutation that prevents protease auto- activation causes IRIDA. Biochem J, 2010. 431(3): p. 363-71. 106. Beliveau, F., A. Desilets, and R. Leduc, Probing the substrate specificities of matriptase, matriptase-2, hepsin and DESC1 with internally quenched fluorescent peptides. FEBS J, 2009. 276(8): p. 2213-26. 107. Folgueras, A.R., et al., Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood, 2008. 112(6): p. 2539-45. 108. Meynard, D., et al., Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood, 2011. 118(3): p. 747-56. 109. Babitt, J.L., et al., Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet, 2006. 38(5): p. 531-9. 110. Corradini, E., J.L. Babitt, and H.Y. Lin, The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev, 2009. 20(5-6): p. 389-98. 111. Silvestri, L., et al., The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab, 2008. 8(6): p. 502-11. 112. Finberg, K.E., et al., Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood, 2010. 115(18): p. 3817-26. 113. Finberg, K.E., et al., Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet, 2008. 40(5): p. 569-71. 114. Chambers, J.C., et al., Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet, 2009. 41(11): p. 1170-2. 115. Benyamin, B., et al., Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet, 2009. 41(11): p. 1173-5. 116. Parr, C., et al., Matriptase-2 inhibits breast tumor growth and invasion and correlates with favorable prognosis for breast cancer patients. Clin Cancer Res, 2007. 13(12): p. 3568-76. 117. Hartikainen, J.M., et al., Refinement of the 22q12-q13 breast cancer--associated region: evidence of TMPRSS6 as a candidate gene in an eastern Finnish population. Clin Cancer Res, 2006. 12(5): p. 1454-62. 118. Sanders, A.J., et al., The type II transmembrane serine protease, matriptase-2: Possible links to cancer? Anticancer Agents Med Chem, 2010. 10(1): p. 64-9. 119. Cheng, M.F., et al., Downexpression of Matriptase-2 Correlates With Tumor Progression and Clinical Prognosis in Oral Squamous-Cell Carcinoma. Appl Immunohistochem Mol Morphol, 2017. 25(7): p. 481-488. 120. Webb, S.L., et al., The influence of matriptase-2 on prostate cancer in vitro: a possible role for beta-catenin. Oncol Rep, 2012. 28(4): p. 1491-7. 121. Sanders, A.J., et al., Genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. J Cell Physiol, 2008. 216(3): p. 780-9. 122. Maxwell, M.A. and G.E. Muscat, The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal, 2006. 4: p. e002. 123. Safe, S., et al., Nuclear receptor 4A (NR4A) family - orphans no more. J Steroid Biochem Mol Biol, 2016. 157: p. 48-60. 124. Ranhotra, H.S., The NR4A orphan nuclear receptors: mediators in metabolism and diseases. J Recept Signal Transduct Res, 2015. 35(2): p. 184-8. 125. Crean, D. and E.P. Murphy, Targeting NR4A Nuclear Receptors to Control Stromal Cell Inflammation, Metabolism, Angiogenesis, and Tumorigenesis. Front Cell Dev Biol, 2021. 9: p. 589770. 126. Weikum, E.R., X. Liu, and E.A. Ortlund, The nuclear receptor superfamily: A structural perspective. Protein Sci, 2018. 27(11): p. 1876-1892. 127. Odagiu, L., et al., Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology. Front Endocrinol (Lausanne), 2020. 11: p. 624122. 128. Mullican, S.E., et al., Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med, 2007. 13(6): p. 730-5. 129. Deutsch, A.J., et al., The nuclear orphan receptors NR4A as therapeutic target in cancer therapy. Anticancer Agents Med Chem, 2012. 12(9): p. 1001-14. 130. Ramirez-Herrick, A.M., et al., Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Blood, 2011. 117(9): p. 2681-90. 131. Deutsch, A.J.A., et al., NR4A3 Suppresses Lymphomagenesis through Induction of Proapoptotic Genes. Cancer Res, 2017. 77(9): p. 2375-2386. 132. Nie, X., et al., Cloning, expression, and mutation analysis of NOR1, a novel human gene down-regulated in HNE1 nasopharyngeal carcinoma cell line. J Cancer Res Clin Oncol, 2003. 129(7): p. 410-4. 133. Li, W., et al., NOR1 is an HSF1- and NRF1-regulated putative tumor suppressor inactivated by promoter hypermethylation in nasopharyngeal carcinoma. Carcinogenesis, 2011. 32(9): p. 1305-14. 134. Yeh, C.M., et al., Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer. Sci Rep, 2016. 6: p. 31690. 135. Zhao, X.G., et al., miR-665 expression predicts poor survival and promotes tumor metastasis by targeting NR4A3 in breast cancer. Cell Death Dis, 2019. 10(7): p. 479. 136. Fedorova, O., et al., Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. Oncogene, 2019. 38(12): p. 2108-2122. 137. Palumbo-Zerr, K., et al., Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis. Nat Med, 2015. 21(2): p. 150-8. 138. Filion, C., et al., The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene. J Pathol, 2009. 217(1): p. 83-93. 139. Beard, J.A., A. Tenga, and T. Chen, The interplay of NR4A receptors and the oncogene-tumor suppressor networks in cancer. Cell Signal, 2015. 27(2): p. 257-66. 140. Koinuma, D., et al., Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor beta signaling. Mol Cell Biol, 2009. 29(1): p. 172-86. 141. Stillfried, G.E., D.N. Saunders, and M. Ranson, Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res, 2007. 9(1): p. R14. 142. Kaighn, M.E., et al., Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol, 1979. 17(1): p. 16-23. 143. Stone, K.R., et al., Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer, 1978. 21(3): p. 274-81. 144. Perlmutter, M.A. and H. Lepor, Androgen deprivation therapy in the treatment of advanced prostate cancer. Rev Urol, 2007. 9 Suppl 1: p. S3-8. 145. Igawa, T., et al., Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate, 2002. 50(4): p. 222-35. 146. Moustakas, A. and D. Kardassis, Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc Natl Acad Sci U S A, 1998. 95(12): p. 6733-8. 147. Taylor, B.S., et al., Integrative genomic profiling of human prostate cancer. Cancer Cell, 2010. 18(1): p. 11-22. 148. Guo, B., et al., Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem, 1995. 270(37): p. 21645-51. 149. Sanchez, M., et al., Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins. Blood, 2011. 118(22): p. e168-79. 150. Wu, S.R., et al., Matriptase is involved in ErbB-2-induced prostate cancer cell invasion. Am J Pathol, 2010. 177(6): p. 3145-58. 151. Ko, C.J., et al., Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis. Cancer Res, 2015. 75(14): p. 2949-60. 152. Kosa, P., et al., Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis. Oncogene, 2012. 31(32): p. 3679-95. 153. Cheng, M.F., et al., Expression of EMMPRIN and matriptase in esophageal squamous cell carcinoma: correlation with clinicopathological parameters. Dis Esophagus, 2006. 19(6): p. 482-6. 154. Chou, F.P., et al., Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas. Am J Pathol, 2013. 183(4): p. 1306-17. 155. Riggins, G.J., et al., Frequency of Smad gene mutations in human cancers. Cancer Res, 1997. 57(13): p. 2578-80. 156. Rodriguez-Calvo, R., M. Tajes, and M. Vazquez-Carrera, The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases. Expert Opin Ther Targets, 2017. 21(3): p. 291-304. 157. Safe, S., et al., Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol Endocrinol, 2014. 28(2): p. 157-72. 158. Petersen, M., et al., Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene, 2010. 29(9): p. 1351-61. 159. Ying, Z., et al., CCT6A suppresses SMAD2 and promotes prometastatic TGF-beta signaling. J Clin Invest, 2017. 127(5): p. 1725-1740. 160. Tu, W.H., et al., The loss of TGF-beta signaling promotes prostate cancer metastasis. Neoplasia, 2003. 5(3): p. 267-77. 161. Perttu, M.C., et al., Altered levels of Smad2 and Smad4 are associated with human prostate carcinogenesis. Prostate Cancer Prostatic Dis, 2006. 9(2): p. 185-9. 162. Huynh, L.K., C.J. Hipolito, and P. Ten Dijke, A Perspective on the Development of TGF-beta Inhibitors for Cancer Treatment. Biomolecules, 2019. 9(11). 163. Vela, D. and Z. Vela-Gaxha, Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. Exp Mol Med, 2018. 50(2): p. e436. 164. Santibanez, J.F., JNK mediates TGF-beta1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes. FEBS Lett, 2006. 580(22): p. 5385-91. 165. Akudugu, J., A. Serafin, and L. Bohm, Further evaluation of uPA and PAI-1 as biomarkers for prostatic diseases. J Cancer Res Clin Oncol, 2015. 141(4): p. 627-31. 166. Czekay, R.P., et al., PAI-1: An Integrator of Cell Signaling and Migration. Int J Cell Biol, 2011. 2011: p. 562481. 167. Isogai, C., et al., Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res, 2001. 61(14): p. 5587-94. 168. Degryse, B., et al., The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem, 2004. 279(21): p. 22595-604. 169. Garg, N., et al., Plasminogen activator inhibitor-1 and vitronectin expression level and stoichiometry regulate vascular smooth muscle cell migration through physiological collagen matrices. J Thromb Haemost, 2010. 8(8): p. 1847-54. 170. Hou, S.X., et al., The Jak/STAT pathway in model organisms: emerging roles in cell movement. Dev Cell, 2002. 3(6): p. 765-78. 171. Burgos-Panadero, R., et al., Vitronectin as a molecular player of the tumor microenvironment in neuroblastoma. BMC Cancer, 2019. 19(1): p. 479. 172. Kamikubo, Y., J.G. Neels, and B. Degryse, Vitronectin inhibits plasminogen activator inhibitor-1-induced signalling and chemotaxis by blocking plasminogen activator inhibitor-1 binding to the low-density lipoprotein receptor-related protein. Int J Biochem Cell Biol, 2009. 41(3): p. 578-85. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85246 | - |
| dc.description.abstract | 攝護腺癌(Prostate cancer, PCa)為已開發國家男性好發癌症之一，且癌症轉移與否與病人預後不佳及死亡上升呈正相關。蛋白酶活性失調已被報導高度與癌症轉移相關，高度轉移是癌症惡化原因之一，進而導致死亡。細胞周圍蛋白酶活性失調被指出和癌症細胞轉移能力有正相關，且會影響其周圍微環境。第二型細胞間質蛋白酶(Matriptase-2, MT-2)，為近期發現之絲胺酸蛋白酶，主要在肝臟表達且調控鐵的代謝。然而在癌症中，研究顯示MT-2可能為抑制者且其機制仍尚未明瞭。實驗結果顯示MT-2表現量和攝護腺癌進程成負相關，且MT-2表達能抑制具轉移特性PCa細胞株(PC3與DU-145)侵襲能力，證實其抑制者角色。乙型轉化生長因子(Transforming growth factor-beta1, TGF-beta1)為一多功能的生長因子，且已被報導在癌症進程具有雙面影響，在初期抑制生長為抑制者，但隨疾病演進累積且轉為腫瘤促進者。我們發現MT-2會藉由調控癌細胞鐵代謝來促進NR4A3 (Nuclear Receptor Subfamily 4 Group A Member 3)表現量上升，讓PCa細胞對於TGF-beta1刺激反應從腫瘤促進者趨向抑制作用。NR4A3降底由TGF-β引起細胞間質轉型[Epithelial-mesenchymal transition (EMT)]程度，且促進由TGF-beta引起細胞周期抑制蛋白p21與PAI-1[第一型胞漿素原活化抑制蛋白(Plasminogen Activator Inhibitor-1)]的表現，此外上升之PAI-1可抑制尿激酶型胞漿素原活化劑uPA (Urokinase Plasminogen Activator)活性，進而抑制細胞增生與侵襲移動能力。透過共免疫沉澱法進一步發現NR4A3藉由和TGF-beta下游Smad2蛋白結合，進而促進p21與PAI-1表達。此外上升之PAI-1導致PAI-1與uPA下降。最後在臨床資料庫TCGA中也顯示MT-2與NR4A3表現量與病人復發率為負相關。本篇研究指出MT-2和NR4A3兩者在攝護腺癌中均為抑癌因子，且讓PAI-1/uPA比例上升，顯示三者可能為未來用來檢視病症是否惡化的指標因子。由於NR4A3參與癌細胞如何反應TGF-beta刺激，顯示其表達量的高低可做且具潛能做為篩選病人是否適合使用TGF-beta抑制劑的生物標記。 | zh_TW |
| dc.description.abstract | Dysregulation of pericellular proteolysis is strongly implicated in cancer metastasis through alteration of cell invasion and the microenvironment. Matriptase-2 (MT-2) is a membrane-anchored serine protease which can suppress prostate cancer (PCa) cell invasion. In this study, we showed that MT-2 was down-regulated in PCa and could suppress PCa cell motility, tumor growth, and metastasis. Using microarray and biochemical analysis, we found that MT-2 shifted TGF-β action towards its tumor suppressor function by repressing epithelial-to-mesenchymal transition (EMT) and promoting Smad2 phosphorylation and nuclear accumulation to up-regulate two TGF-β1 downstream effectors (p21 and PAI-1), culminating in hindrance of PCa cell motility and malignant growth. Mechanistically, MT-2 could dramatically up-regulate the expression of nuclear receptor NR4A3 via iron metabolism in PCa cells. MT-2-induced NR4A3 further coactivated Smad2 to activate p21 and PAI-1 expression. In addition, NR4A3 functioned as a suppressor of PCa and mediated MT-2 signaling to inhibit PCa tumorigenesis and metastasis. These results together indicate that NR4A3 sustains MT-2 signaling to suppress PCa cell invasion, tumor growth, and metastasis, and serves as a contextual factor for the TGF-β/Smad2 signaling pathway in favor of tumor suppression via promoting p21 and PAI-1 expression. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T22:52:41Z (GMT). No. of bitstreams: 1 U0001-0208202211300100.pdf: 5950632 bytes, checksum: ebf0b0cc8bd1e6bcdad8fe1c8a21b715 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 口試委員會審定書 ..................... I 致謝................................ II 中文摘要............................ III Abstract ........................... V Lists of abbreviations.............. VI Introduction ....................... 1 Prostate cancer .....1 Prostate cancer metastasis .....1 Tumor microenvironment (TME) .....2 Transforming Growth Factor β (TGF-β) superfamily..... 3 Canonical signal and non-canonical pathway of Transforming Growth Factor β (TGF-β) .....5 Paradoxical role of TGF-β in human cancers .....6 Iron metabolism .....8 Iron metabolism in cancers .....11 Cancer-related anemia (CRA) .....12 Pericellular proteolysis .....13 PAI-1 and uPA .....15 Matriptase-2/TMPRSS6 .....16 Matriptase-2 function in hepatocyte: iron metabolism .....17 Matriptase-2 and cancer progression .....18 Nuclear receptor subfamily 4 group A member 3 (NR4A3)..... 18 NR4A3 in human cancers .....20 Research motivation..... 21 Material and Methods ..... 23 Cell culture ..... 23 cDNA preparation ..... 23 Real-Time RT-PCR ..... 25 Tissue array qPCR analysis ..... 26 cDNA Microarray assay ..... 27 Western Blot ..... 28 Lentiviral infection for shRNA interference ..... 30 Lipofectamine Transfection ..... 31 Transwell assay ..... 32 Immunoprecipitation and ChIP assay ..... 33 Plasmin activity assay ..... 34 TCGA data analysis ..... 34 Colony formation assay .... 35 Cytoplasmic and nuclear extract preparation ..... 35 Zymography assay ..... 36 Immunohistochemistry (IHC) ..... 37 Tumor xenograft...... 38 Statistical analysis ..... 38 Results ..... 40 Downregulation of Matriptase-2 (MT-2) in prostate cancer ...... 40 Matriptase-2 (MT-2) suppressed PCa cell motility ..... 41 Inhibitory role of MT-2 in TGF-β-mediated PCa cell invasion by suppressing EMT phenomenon ..... 42 Inhibitory role of MT-2 in the effect of paracrine TGF-β1 on PCa cell 1 on PCa cell invasion ...... 43 Role of MT-2 in Smad1-4 phosphorylation and the expression of uPA, PAI-1 and p21 in PCa cells. ...... 44 Role of MT-2 in alteration of TGF-β1 function toward tumor suppressor by 1 function toward tumor suppressor by elevating p21 and PAI-1 expression ...... 46 Involvement of PAI-1 in MT-2 suppression of TGF-β1-induced PC3 cell invasion ..... 48 MT-2 suppressed PCa tumorigenicity ...... 49 NR4A3 mediated the MT-2 suppression on TGF-β-modulated PCa malignance ..... 49 Inhibitory role of MT-2 in PCa colony formation and cell invasion by elevating p21 and PAI-1 expression ..... 51 NR4A3 mediated TGF-β1-induced nuclear Smad2 phosphorylation and PAI-1 expression ..... 52 Involvement of iron metabolism in MT-2-mediated NR4A3 expression and invasion suppression ...... 54 Involvement of NR4A3 in MT-2-suppressed PCa tumor growth and metastasis ..... 57 Discussion..... 59 Matriptase-2 functions as a tumor suppressor in PCa ..... 59 NR4A3 is a contexture factor for TGF-β signaling in PCa cells ..... 60 MT-2 is involved in PC iron metabolism....... 64 The ratio of uPA to PAI-1 may employ as a prognosis marker for prostate cancer ... 65 Downregulation of MT-2 and NR4A3 in prostate cancer is not due to genomic alteration ...... 68 Figures ...... 70 Figure 1. Matriptase-2 is down-regulated in human prostate cancer. ...... 70 Figure 2. Suppression role of Matriptase-2 in PCa cell mobility. ....... 72 Figure 3. MT-2 suppressed TGF-β 1 induced EMT and PC3 cell invasion....... 74 Figure 4. MT-2 could suppress PC3 cell invasion which was induced by paracrine TGF-β from myofibroblast stromal cells. ......76 Figure 5. MT-2 was involved in TGF-β--signaling to increase Smad2 signaling to increase Smad2 phosphorylation and up-regulate the expression of p21 and PAI-1. .. 77 Figure 6. MT-2 altered the effect of TGF-β1 on Smad2 phosphorylation, PCa cell colony formation and invasion, as well as the expression of p21 and PAI-1. ...... 78 Figure 7. PAI-1 was involved in MT-2 suppression of TGF-β1--induced PC3 induced PC3 cell invasion..... 82 Figure 8. MT-2 suppressed PCa tumor growth and metastasis in orthotopic prostate cancer xenograft mouse model...... 84 Figure 9. Involvement of NR4A3 in MT-2 suppression on TGF-β1--induced induced EMT phenomena. ...... 86 Figure 10. Involvement of NR4A3 in MT-2 signaling to shift the effect of TGF-β1 on Smad2 phosphorylation, p21 induction, PCa cell colony formation, and invasion. ....... 89 Figure 11. NR4A3 enhanced the phosphorylation levels of nuclear Smad2 and TGF-β1-induced p21 and PAI-1 expression. ...... 92 Figure 12. Involvement of MT-2 in prostate cancer cell iron homeostasis. ...... 94 Figure 13. Involvement of iron in MT-2 action on NR4A3 expression and PCa cell invasion. ...... 96 Figure 14. NR4A3 mediated MT-2-suppressed PCa tumor growth and metastasis. ..... 98 Figure 15. The clinical relevance of MT-2 and NR4A3 in prostate cancer....... 100 Figure 16. MT-2 regulates iron metabolism to induce NR4A3 expression, which switches TGF-β function from tumor promotion to suppression function from tumor promotion to suppression via Smad2/p21/PAI-1 axis. ...... 101 References ................................................................... 102 | |
| dc.language.iso | en | |
| dc.title | 探討第二型間質蛋白酶在人類攝護腺癌細胞轉移中所扮演的角色 | zh_TW |
| dc.title | The role of matriptase-2 in prostate cancer cell invasion, tumor growth, and metastasis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳瑞華(Ruey-Hwa Chen),林淑華(Shu-Wha Lin),陳美州(Mei-Jou Chen),黃娟娟(Jiuan-Jiuan Hwang),黃祥博(Hsiang-Po Huang) | |
| dc.subject.keyword | 第二型細胞間質蛋白酶,攝護腺癌細胞,癌症轉移,乙型轉化生長因子,NR4A3孤兒核受體,第一型胞漿素原活化抑制劑, | zh_TW |
| dc.subject.keyword | Matriptase-2,PCa,Metastasis,TGF-beta1,NR4A3,PAI-1, | en |
| dc.relation.page | 113 | |
| dc.identifier.doi | 10.6342/NTU202201963 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-08-02 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| dc.date.embargo-lift | 2022-10-05 | - |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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