Epithelial-mesenchymal transition: From molecular mechanisms, redox regulation to implications in human health and disease

Antioxidants and Redox Signaling

Volumn 12, Issue 12, 2010, Pages 1383-1430

  Cannito, Stefania ^a   Novo, Erica ^a   Di Bonzo, Lorenzo Valfrè ^a   Busletta, Chiara ^a   Colombatto, Sebastiano ^a   Parola, Maurizio ^a  

^a UNIVERSITY OF TURIN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; CADHERIN; GROWTH FACTOR; MICRORNA; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR SNAI1; TRANSFORMING GROWTH FACTOR BETA; TYROSINE KINASE RECEPTOR; UNCLASSIFIED DRUG; WNT PROTEIN;

CANCER GROWTH; CELL HYPOXIA; CHRONIC INFLAMMATION; DOWN REGULATION; EMBRYO DEVELOPMENT; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIZATION; EXTRACELLULAR MATRIX; FIBROGENESIS; FIBROSIS; HUMAN; METASTASIS; MOLECULAR MECHANICS; NONHUMAN; OXIDATION REDUCTION REACTION; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PLASTICITY; PRIORITY JOURNAL; PROTEIN FUNCTION; REGULATORY MECHANISM; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION; WOUND HEALING;

CELL DEDIFFERENTIATION; CELL HYPOXIA; CELL POLARITY; CYTOSKELETON; EMBRYONIC DEVELOPMENT; ENDOTHELIAL CELLS; EPITHELIAL CELLS; EXTRACELLULAR MATRIX PROTEINS; FIBROSIS; GENE EXPRESSION REGULATION; HUMANS; MESODERM; MICRORNAS; NEOPLASMS; OXIDATION-REDUCTION; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; WOUND HEALING;

EID: 77951953778     PISSN: 15230864     EISSN: None     Source Type: Journal    
DOI: 10.1089/ars.2009.2737     Document Type: Review

References (307)

1. Abe R, Donnelly SC, Peng T, Bucala R, and Metz CN. Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites. J Immunol 166: 7556-7562, 2001.
2. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, and Nieto MA. Epithelial-mesenchymal transitions: The importance of changing cell state in development and disease. J Clin Invest 119: 1438-1449, 2009.
3. Albano E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 65: 278-280, 2006.
4. Arnoux V, Come C, Kusewitt D, Hudson L, and Savagner P. Cutaneous wound re-riepithellalization: A partial and reversible EMT. In: Rise and Fall of Epithelial Phenotype: Concepts of Epithelial-Mesenchymal Transition, edited by Sa-vagner P. Berlin: Springer, 2005, pp. 11-134.
5. Arnoux V, Nassour M, L'Helgoualc'h A, Hipskind RA, and Savagner P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol Biol Cell 19: 4738-4749, 2008.
6. Avizienyte E and Frame MC. Src and FAK signaling control adhesion fate and the epithelial-to-mesenchymal transition. Curr Opin Cell Biol 17: 542-547, 2005.
7. Babior BM. NADPH oxidase: An update. Blood 93: 1464-1476, 1999.
8. Bachelder RE, Yoon S-O, Franci C, Garcia de Herreros A, and Mercurio A. Glycogen synthase kinase 3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol 168: 29-33, 2005.
9. Bagnato A and Rosanò L. Epithelial-mesenchymal transition in ovarian cancer progression: A crucial role for the endothelin axis. Cells Tissues Organs 185: 85-94, 2007.
10. Bailey JM, Singh PK, and Hollingsworth MA. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J Cell Biochem 102: 829-839, 2007.
11. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, and Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 275: 36803-36810, 2000.
12. Barberà MJ, Puig I, Doḿ?nguez D, Julien-Grille S, Guaita-Esteruelas S, Peiró S, Baulida J, Franć? C, Dedhar S, Larue L, and Garć?a de Herreros A. Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23: 7345-7354, 2004.
13. Barr S, Thomson S, Buck E, Russo S, Petti F, Sujka-Kwok I, Eyzaguirre A, Rosenfeld-Franklin M, Gibson NW, Mi-glarese M, Epstein D, Iwata KK, and Haley JD. Bypassing cellular EGF receptor dependence through epithelial-to- mesenchymal-like transitions. Clin Exp Metastasis 25: 685-693, 2008.
14. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, and Garcia De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2: 84-89, 2000.
15. Baum B, Settleman J, and Quinlan MP. Transitions between epithelial and mesenchymal states in development and disease. Sem Cell Dev Biol 19: 294-308, 2008.
16. Becker KF, Rosivatz E, Blechschmidt K, Kremmer E, Sarbia M, and Höfler H. Analysis of the E-cadherin repressor Snail in primary human cancers. Cells Tissues Organs 185: 204-212, 2007.
17. Benitah SA, Valerón PF, Rui H, and Lacal JC. STAT5a activation mediates the epithelial to mesenchymal transition induced by oncogenic RhoA. Mol Biol Cell 14: 40-53, 2003.
18. Berndt C, Lillig CH, and Holmgren A. Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: Implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol 292: 1227-1236, 2007.
19. Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, and Moses HL. Transforming factor-b1 mediates epithelial to mesenchymal trans-differentiation through a RhoA-dependent mechanism. Mol Biol Cell 12: 27-36, 2001.
20. Birchmeier C, Birchmeier W, and Brand-Saberi B. Epithe-lial-mesenchymal transitions in cancer progression. Acta Anat (Basel) 156: 217-226, 1996.
21. Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, and Nieto MA. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21: 3241-3246, 2002.
22. Bloushtain-Qimron N, Yao J, Snyder EL, Shipitsin M, Campbell LL, Mani SA, Hu M, Chen H, Ustyansky V, Antosiewicz JE, Argani P, Halushka MK, Thomson JA, Pharoah P, Porgador A, Sukumar S, Parsons R, Richardson AL, Stampfer MR, Gelman RS, Nikolskaya T, Nikolsky Y, and Polyak K. Cell type-specific DNA methylation patterns in the human breast. Proc Natl Acad Sci USA 105: 14076-14081, 2008.
23. Bonizzi G and Karin M. The two NF-kappaB activation pathways and their role in innate and adaptative immunity. Trends Immunol 25: 280-288, 2004.
24. Boyer B, Dufour S, and Thiery JP. E-cadherin expression during the acidic FGF-induced dispersion of a rat bladder carcinoma cell line. Exp Cell Res 201: 347-357, 1992.
25. Boyer B, Roche S, Denoyelle M, and Thiery JP. Src and Ras are involved in separate pathways in epithelial cell scattering. EMBO J 16: 5904-5913, 1997.
26. Boyer B and Thiery JP. Epithelium-mesenchyme intercon-version as example of epithelial plasticity. APMIS 101: 257-268, 1993.
27. Boyer B, Vallés AM, and Edme N. Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol 60: 1091-1099, 2000.
28. Brabletz S, Schmalhofer O, and Brabletz T. Gastrointestinal stem cells in development and cancer. J Pathol 217: 307-317, 2009.
29. Brabletz T, Jung A, Spaderna S, Hlubek F, and Kirchner T. Migrating cancer stem cells. An integrated concept of malignant tumour progression. Nature Rev Cancer 5: 744-749, 2005.
30. Brahimi-Horn MC, Chiche J, and Pouysségur J. Hypoxia and cancer. J Mol Med 85: 1301-1307, 2007.
31. Cadenas E and Davies KJ. Mitochondrial free radical generation, oxidative stress and aging. Free Radic Biol Med 29: 222-230, 2000.
32. Cadenas E. Biochemistry of oxygen toxicity. Ann Rev Bio-chem 58: 79-110, 1989.
33. Cannito S, Novo E, Compagnone A, Valfrè di Bonzo L, Busletta C, Zamara E, Paternostro C, Povero D, Bandino A, Bozzo F, Cravanzola C, Bravoco V, Colombatto S, and Parola M. Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. Carcinogenesis 29: 2267-2278, 2008.
34. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, and Nieto MA. The transcription factor snail controls epithelial-esenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2: 76-83, 2000.
35. Chaffer CL, Thompson EW, and Williams EM. Mesenchy-mal to epithelial transition in development and disease. Cells Tissues Organs 185: 7-19, 2007.
36. Chagraoui J, Lepage-Noll A, Anjo A, Uzan G, and Char-bord P. Fetal liver stroma consists of cells in epithelial-to-mesenchymal transition. Blood 101: 2973-2982, 2003.
37. Chen F, Lu Y, Castranova V, Li Z, and Karin M. Loss of Ikkbeta promotes migration and proliferation of mouse embryo fibroblast cells. J Biol Chem 281: 37142-37149, 2006.
38. Chiarugi P and Fiaschi T. Redox signaling in anchorage-dependent cell growth. Cell Signal 19: 672-682, 2007.
39. Chiarugi P and Cirri P. Redox regulation of protein tyro-sine phosphatases during receptor tyrosine kinase signal transduction. Trends Biochem Sci 28: 509-514, 2003.
40. Cho HY, Reddy SP, and Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 8: 76-87, 2006.
41. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, and Nakshatri H. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: Potential involvement of ZEB-1 and ZEB-2. Oncogene 26: 711-724, 2007.
42. Cicchini C, Laudadio I, Citarella F, Corazzari M, Steindler C, Conigliaro A, Fantoni A, Amicone L, and Tripodi M. TGFbeta-induced EMT requires focal adhesion kinase (FAK) signaling. Exp Cell Res 314: 143-152, 2008.
43. Côme C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, and Savagner P. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 12: 5395-5402, 2006.
44. Commoner B, Townsend J, and Pake GE. Free radicals in biological materials. Nature 174: 689-691, 1954.
45. Comporti M, Signorini C, Arezzini B, Vecchio D, Monaco B, and Gardi C. F2-isoprostanes are not just markers of oxi-dative stress. Free Radic Biol Med 44: 247-256, 2008.
46. Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, and Ben-Ze'ev A. Autoregulation of E-cadherin expression by cadherin-cadherin interactions: The roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 163: 847-957, 2003.
47. Corvol H, Flamein F, Epaud R, Clement A, and Guillot L. Lung alveolar epithelium and interstitial lung disease. Int J Biochem Cell Biol 41: 1643-1651, 2009.
48. D'Autrèaux B and Toledano MB. ROS as signaling molecules: Mechanisms that generate specificity in ROS ho-meostasis. Nat Rev Mol Cell Biol. 8: 813-824, 2007.
49. Davies M, Robinson M, Smith E, Huntley S, Prime S, and Paterson I. Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signaling pathways. J Cell Biochem 95: 918-931, 2005.
50. Davies JA. Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat 156: 187-51.201, 1996.
51. Den Hertog J, Groen A, and Van der Wijk T. Redox regulation of protein-tyrosine phosphatases. Arch Biochem Bio-phys 434: 11-15, 2005.
52. Dewhirst MW, Cao Y, and Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8: 425-437, 2008.
53. Dhawan P, Singh AB, Deane NG, No Y, Shiou SR, Schmidt C, Neff J, Washington MK, and Beauchamp RD. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest 115: 1765-1776, 2005.
54. D́az R, Kim JW, Hui JJ, Li Z, Swain GP, Fong KS, Csiszar K, Russo PA, Rand EB, Furth EE, and Wells RG. Evidence for the epithelial to mesenchymal transition in biliary atresia fibrosis. Hum Pathol 39: 102-115, 2008.
55. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholo-meusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, and Hung MC. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19: 159-170, 2005.
56. Djamali A, Reese S, Yracheta J, Oberley T, Hullett D, and Becker B. Epithelial-to-mesenchymal transition and oxida-tive stress in chronic allograft nephropathy. Am J Transplant 5: 500-509, 2005.
57. Djamali A, Vidyasagar A, Adulla M, Hullett D, and Reese S. Nox-2 is a modulator of fibrogenesis in kidney allografts. Am J Transplant 9: 74-82, 2009.
58. Donato R. S100: A multigenic family of calcium modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33: 637-668, 2001.
59. Dong R, Lu JG, Wang Q, He XL, Chu YK, and Ma QJ. Stabilization of Snail by HuR in the process of hydrogen peroxideinducedcellmigration. BiochemBiophysResCommun 356: 318-321, 2007.
60. Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, Ueberham E, Gebhardt R, Kanzler S, Geier A, Breitkopf K, Weng H, and Mertens PR. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology 135: 642-659, 2008.
61. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 82: 47-95, 2002.
62. Duband JL, Monier F, Delannet M, and Newgreen D. Epithelium mesenchyme transition during neural crest development. Acta Anat 154: 63-78, 1995.
63. duBois RM and Wells AU. Cryptogenic fibrosing alveolitis= idiopathic pulmonary fibrosis. Eur Respir J Suppl 32: 43s-55s, 2001.
64. Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, and Tlsty TD. Sustained induction of epithelial to mesenchymal transition activates DNA methyla-tion of genes silenced in basal-like breast cancers. Proc Natl Acad Sci USA 105: 14867-14872, 2008.
65. Edme N, Downward J, Thiery JP, and Boyer B. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways. J Cell Sci 115: 2591-2601, 2002.
66. Esquela-Kerscher A and Slack FJ. Oncomirs\microRNAs with a role in cancer. Nat Rev Cancer 6: 259-269, 2006.
67. Esterbauer H, Schaur RJ, and Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11: 81-128, 1991.
68. Evans JL, Goldfine ID, Maddux BA, and Grodsky GM. Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocr Rev 23: 599-622, 2003.
69. Farrell GC and Larter CZ. Nonalcoholic fatty liver diseases: From steatosis to cirrhosis. Hepatology Suppl 1: S99-S112, 2006
70. Fausto N. Liver regeneration and repair: Hepatocytes, progenitor cells, and stem cells. Hepatology 39: 1477-1487, 2004.
71. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, and Bosch J. Angiogenesis in liver disease. J Hepatol 50: 604-620, 2009.
72. Fitchett JE and Hay ED. Medial edge epithelium transforms to mesenchyme after embryonic palatal shelves fuse. Dev Biol 131: 455-474, 1989.
73. Frame S and Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359: 1-16, 2001.
74. Friedl P. Prespecification and plasticity: Shifting mechanisms of cell migration. Curr Opin Cell Biol 16: 14-23, 2004.
75. Friedman SL. Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88: 125-172, 2008.
76. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastro-enterology 134: 1655-1669, 2008.
77. Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, Sommer T, and Birchmeier W. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol 4: 222-231, 2002.
78. Funato Y, Michiue T, Asashima M, and Miki H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signaling through dishevelled. Nat Cell Biol 8: 501-508, 2006.
79. Galliher AJ and Schiemann WP. Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res 8: R42, 2006.
80. Gebeshuber CA, Zatloukal K, and Martinez J. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep 10: 400-405, 2009.
81. Giancotti FG and Ruoslahti E. Integrin signaling. Science 285: 1028-1032, 1999.
82. Gloire G, Legrand-Poels S, and Piette J. NF-kB activation by reactive oxygen species: Fifteen years later. Biochem Pharmacol 72: 1493-1505, 2006.
83. Gordon KJ, Kirkbride KC, How T, and Blobe GC. Bone morphogenetic proteins induce pancreatic cancer cell in-vasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2. Carcinogenesis 30: 238-248, 2009.
84. Gort EH, Groot AJ, van der Wall E, van Diest PJ, and Vooijs MA. Hypoxic regulation of metastasis via hypoxia-induc-ible factors. Curr Mol Med 8: 60-67, 2008.
85. Gotoh Y and Cooper JA. Reactive oxygen species-and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-a signal transduction. J Biol Chem 273: 17477-17482, 1998.
86. Greenburg G and Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 95: 333-339, 1982.
87. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, and Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10: 593-601, 2008.
88. Guarino M, Rubino B, and Ballabio G. The role of epithelial to mesenchymal transition in cancer pathology. Pathology 39: 305-318, 2007.
89. Guarino M. Epithelial-to-mesenchymal change of differentiation. From embryogenetic mechanism to pathological patterns. Histol Histopathol 10: 171-184,1995.
90. Guilford P. E-cadherin down-regulation in cancer: Fuel on the fire? Mol Med Today 5: 172-177; 1999.
91. th edition, Oxford, U.K.: Clarendon Press, 2006, pp. 79-185.
92. Halliwell B and Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: How should you do it and what do the results mean? Br J Pharmacol 142: 231-255, 2004.
93. Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol 11: 298-300, 1956.
94. Harman D. The aging process. Proc Natl Acad Sci USA 78: 7124-7128, 1981.
95. Harrison D, Griendling KK, Landmesser U, Hornig B, and Drexler H. Role of oxidative stress in atherosclerosis. Am J Cardiol 91: 7A-11A, 2003.
96. Hay ED. Organization and fine structure of epithelium and mesenchyme in the developing chick embryo. In: Epithelial-Mesenchymal Interactions; 18th Hahnemann Symposium, edited by Fleischmajer R and Billingham RE. Baltimore, MD: Williams & Wilkins Co 1968, pp. 31-55.
97. Hay ED. The mesenchymal cell: Its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233: 706-720, 2005.
98. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, and Haase VH. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117: 3810-3820, 2007.
99. Higgins DF, Kimura K, Iwano M, and Haase VH. Hypoxia-inducible factor signaling in the development of tissue fi-brosis. Cell Cycle 7: 1128-1132, 2008.
100. Hill RP, Marie-Egyptienne DT, and Hedley DW. Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol 19: 106-111, 2009.
101. Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancer. Am J Pathol 153: 333-339, 1999.
102. Hou Z, Peng H, Ayyanathan K, Yan KP, Langer EM, Longmore GD, and Rauscher FJ 3rd. The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression. Mol Cell Biol 28: 3198-3207, 2008.
103. Hsu T, Trojanowska M, and Watson DK. Ets proteins in biological control and cancer. J Cell Biochem 91: 896-903, 2004.
104. Huber MA, Kraut N, and Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17: 1-11, 2005.
105. Hutvágner G, McLachlan J, Pasquinelli AE, Bálint E, Tuschl T, and Zamore PD. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293: 834-838, 2001.
106. Ignarro LJ and Kadowitz PJ. The pharmacological and physiological role of cGMP in vascular smooth muscle relaxation. Ann Pharmacol Toxicol 25: 171-191, 1985.
107. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, and Konishi I. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 163: 1437-1447, 2003.
108. Iredale JP. Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organism. J Clin Invest 117: 539-548, 2007.
109. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, and Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110: 341-350, 2002.
110. Jain R, Shaul PW, Borok Z, and Willis BC. Endothelin-1 induces alveolar epithelial-mesenchymal transition through endothelin type A receptor-mediated production of TGF-beta1. Am J Respir Cell Mol Biol 37: 38-47, 2007.
111. Jung Y, Brown KD, Witek RP, Omenetti A, Yang L, Vandongen M, Milton RJ, Hines IN, Rippe RA, Spahr L, Rubbia-Brandt L, and Diehl AM. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 134: 1532-1543, 2008.
112. Jung Y, McCall SJ, Li YX, and Diehl AM. Bile ductules and stromal cells express hedgehog ligands and=or hedgehog target genes in primary biliary cirrhosis. Hepatology 45: 1091-1096, 2007.
113. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, and Koteish A. Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepa-tocytes in vitro. J Biol Chem 282: 22089-22101, 2007.
114. Kalluri K and Weinberg RA. The basics of epithelia-mesenchymal transition. J Clin Invest 119: 1420-1428, 2009.
115. Kalluri R and Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112: 1776-1784, 2003.
116. Kamata H, Honda S, Maeda S, Chang L, Hirata H, and Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120: 649-661, 2005.
117. Kaneto H, Katakami N, Kawamori D, Miyatsuka T, Sakamoto K, Matsuoka TA, Matsuhisa M, and Yamasaki Y. Involvement of oxidative stress in the pathogenesis of diabetes. Antioxid Redox Signal 9: 355-366, 2007.
118. Keely PJ. Rho GTPases as early markers of tumour progression. Lancet 358: 1744-1745, 2001.
119. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, and Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 103: 13180-13185, 2006.
120. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA, Chapman HA. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest 119: 213-224, 2009.
121. Kimelman D. Mesoderm induction: from caps to chips. Nat Rev Genet 7:360-372, 2006.
122. Kimura K, Iwano M, Higgins DF, Yamaguchi Y, Nakatani K, Harada K, Kubo A, Akai Y, Rankin EB, Neilson EG, Haase VH, and Saito Y. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol 295: F1023-1029, 2008.
123. Kirby JA, Robertson H, Marshall HL, Rygiel KA, Hudson M, Jones DE, and Burt AD. Epithelial to mesenchymal transition in primary sclerosing cholangitis. Liver Int 28: 1176-1177, 2008.
124. Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, and Brenner DA. Bone marrow-derived fibrocytes participate in pathogenesis of liver fi-brosis. J Hepatol 45: 429-438, 2006.
125. Klein JA and Ackerman SL. Oxidative stress, cell cycle and neurodegeneration. J Clin Invest 111: 785-793, 2003.
126. Klymkowsky MW and Savagner P. Epithelial-mesenchymal transition: A cancer researcher's conceptual friend and foe. Am J Pathol 174: 1588-1593, 2009.
127. Koivisto L, Jiang G, Häkkinen L, Chan B, and Larjava H. HaCaT keratinocyte migration is dependent on epidermal growth factor receptor signaling and glycogen synthase kinase-3alpha. Exp Cell Res 312: 2791-2805, 2006.
128. Kondo M, Cubillo E, Tobiume K, Shirakihara T, Fukuda N, Suzuki H, Shimizu K, Takehara K, Cano A, Saitoh M, and Miyazono K. A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation. Cell Death Differ 11: 1092-1101, 2004.
129. Kong D, Wang Z, Sarkar SH, Li Y, Banerjee S, Saliganan A, Kim HR, Cher ML, and Sarkar FH. Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells 26: 1425-1435, 2008.
130. Kong D, Li Y, Wang Z, Banerjee S, Ahmad A, Kim HR and Sarkar FH. miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells 27: 1712-1721, 2009.
131. Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, and Cheng JQ. MicroRNA-155 is regulated by the transforming growth factor beta=Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28: 6773-6784, 2008.
132. Korpal M, Lee ES, Hu G, and Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional re-pressors ZEB1 and ZEB2. J Biol Chem 283: 14910-14914, 2008.
133. Kusewitt DF, Choi C, Newkirk KM, Leroy P, Li Y, Chavez MG, and Hudson LG. Slug=Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated re-epithelialization. J Invest Dermatol 129: 491-495, 2009.
134. Labbé E, Letamendia A, and Attisano L. Association of Smads with lymphoid enhancer binding factor 1=T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci USA 97: 8358-8363, 2000.
135. Labbé E, Lock L, Letamendia A, Gorska AE, Gryfe R, Gallinger S, Moses HL, and Attisano L. Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumori-genesis. Cancer Res 67: 75-84, 2007.
136. Lama VN and Phan SH. The extrapulmonary origin of fi-broblasts: stem=progenitor cells and beyond. Proc Am Thorac Soc 3: 373-376, 2006.
137. Lambeth JD. Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy. Free Radic Biol Med 43: 332-347, 2007.
138. Larue L and Bellacosa A. Epithelial-mesenchymal transition in development and cancer: Role of phosphatidyli-nositol 3 kinase=AKT pathways. Oncogene 24: 7443-7454, 2005.
139. Lee JM, Dedhar S, Kalluri R, and Thompson EW. The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol 172: 973-981, 2006.
140. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Ra?dmark O, Kim S, and Kim VN. The nuclear RNase III Drosha initiates microRNA processing. Nature 425: 415-419, 2003.
141. Lester RD, Jo M, Montel V, Takimoto S, and Gonias SL. uPAR induces epithelial mesenchymal transition in hyp-oxic breast cancer cells. J Cell Biol 178: 425-436, 2007.
142. Lewis CE, De Palma M, and Naldini L. Tie2-expressing monocytes and tumor angiogenesis: Regulation by hypoxia and angiopoietin-2. Cancer Res 67: 8429-8432, 2007. (Pubitemid 47437413)
143. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, and Chang JC. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100: 672-679, 2008.
144. Li Y, Yang J, Dai C, Wu C, and Liu Y. Role for integrin-linked kinase in mediating tubular epithelial to mesen-chymal transition and renal interstitial fibrogenesis. J Clin Invest 112: 503-516, 2003.
145. Lim SO, Gu JM, Kim MS, Kim HS, Park YN, Park CK, Cho JW, Park YM, and Jung G. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 135: 2128-2140, 2008.
146. Liu H, Colavitti R, Rovira II, and Finkel T. Redox-dependent transcriptional regulation. Circ Res 97: 967-974, 2005.
147. Liu H, Nishitoh H, Ichijo H, and Kyriakis JM. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol 20: 2198-2208, 2000.
148. Liu Y. Epithelial to mesenchymal transition in renal fibro-genesis: Pathological significance, molecular mechanisms and therapeutic intervention. J Am Soc Nephrol 15: 1-12, 2004.
149. Liu Y. Hepatocyte growth factor in kidney fibrosis: Therapeutic potential and mechanisms of action. Am J Physiol Renal Physiol 287: F7-16, 2004.
150. Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, and Bissell MJ. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 139: 1861-1872, 1997.
151. Lu J, Landerholm TE, Wei JS, Dong XR, Wu SP, Liu X, Nagata K, Inagaki M and Majesky MW. Coronary smooth muscle differentiation from proepicardial cells requires rhoA-mediated actin reorganization and p160 rho-kinase activity. Dev Biol 240: 404-418, 2001.
152. Ma L, Teruya-Feldstein J, and Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449: 682-688, 2007.
153. Malumbres M and Pellicer A. Ras pathways to cell cycle and cell transformation. Front Biosci 3: d887-912, 1998.
154. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, and Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704-715, 2008.
155. Mareel M and Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 83: 337-376, 2003.
156. Marnett LJ, Riggins JN, and West JD. Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J Clin Invest 111: 583-593, 2003.
157. Massagué J, Seoane J, and Wotton D. Smad transcription factors. Genes Dev 19: 2783-2810, 2005.
158. Mattson MP. Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal 8: 1997-2006, 2006.
159. McCord JM and Fridovich I. Superoxide dismutase: An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244: 6049-6055, 1969.
160. Menke A, Philippi C, Vogelmann R, Seidel B, Lutz MP, Adler G, and Wedlich D. Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res 61: 3508-3517, 2001.
161. Mittal CK and Murad F. Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3',5'-monophosphate formation. Proc Natl Acad Sci USA 74: 4360-4364, 1977.
162. Mjaatvedt CH and Markwald RR. Induction of an epithelial-mesenchymal transition by an in vivo adheron-like complex. Dev Biol 136: 118-128, 1989.
163. Montesano R, Soriano JV, Hosseini G, Pepper MS, and Schramek H. Constitutively active mitogen-activated protein kinase kinase MEK1 disrupts morphogenesis and induces an invasive phenotype in Madin-Darby canine kidney epithelial cells. Cell Growth Differ 10: 317-332, 1999.
164. Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, and Chodosh LA. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8:197-209, 2005.
165. Morel AP, Lièvre M, Thomas C, Hinkal G, Ansieau S, and Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 3: e2888, 2008.
166. Mori K, Shibanuma M, and Nose K. Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res 64: 7464-7472, 2004.
167. Morrow JD, Awad JA, Kato T, Takahashi K, Badr KF, Roberts II LJ, and Burk RF. Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. J Clin Invest 92: 2502-2507, 1992.
168. Moustakas A and Heldin C-H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 98: 1512-1520, 2007.
169. Moustakas A, Pardali K, Gaal A, and Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett 82: 85-91, 2002.
170. Murray NR, Davidson LA, Chapkin RS, Clay Gustafson W, Schattenberg DG, and Fields AP. Overexpression of protein kinase C betaII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis. J Cell Biol 145: 699-711, 1999.
171. Nakaya Y and Sheng G. Epithelial to mesenchymal transition during gastrulation: An embryological view. Develop Growth Differ 50: 755-766, 2008.
172. Nawshad A, LaGamba D,and Hay ED. Transforming growth factor beta (TGFbeta) signaling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 49: 675-689, 2004.
173. Nawshad A, Lagamba D, Polad A, and Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymaltransformation: Implications forembryogenesis and tumor metastasis. Cells Tissues Organs 179: 11-23, 2005.
174. Nelson WJ and Nusse R. Convergence of Wnt, b-catenin, and cadherin pathways. Science 303: 1483-1487, 2004.
175. Ng YY, Fan JM, Mu W, Nikolic-Paterson DJ, Yang WC, Huang TP, Atkins RC, and Lan HY. Glomerular epithelial-myofibroblast transdifferentiation in the evolution of glomerular crescent formation. Nephrol Dial Transplant 14: 2860-2872, 1999.
176. Ng YY, Huang TP, Yang WC, Chen ZP, Yang AH, Mu W, Nikolic-Paterson DJ, Atkins RC, and Lan HY. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5=6 nephrectomized rats. Kidney Int 54: 864-876, 1998.
177. Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, and Karsan A. Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol 182: 315-325, 2008.
178. Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R, Roskelley C, Grosschedl R, and Dedhar S. Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc Natl Acad Sci USA 95: 4374-4379, 1998.
179. Novo E and Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1: 5, 2008.
180. Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, and Parola M. Proangiogenic cytokines as-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 170: 1942-1953, 2007.
181. Novo E, Marra F, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cannito S, Antonaci C, Colombatto S, Pinzani M, and Parola M. Dose dependent and divergent effects of super-oxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells. Gut 55: 90-97, 2006.
182. Okada H, Danoff TM, Kalluri R, and Neilson EG. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273: F563-574, 1997.
183. Oloumi A, McPhee T, and Dedhar S. Regulation of E-cadherin expression and beta-catenin=Tcf transcriptional activity by the integrin-linked kinase. Biochim Biophys Acta 1691: 1-15, 2004.
184. Omenetti A, Popov Y, Jung Y, Choi SS, Witek RP, Yang L, Brown KD, Schuppan D, and Diehl AM. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 57: 1275-1282, 2008.
185. Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, Syn WK, Baroni GS, Benedetti A, Schuppan D, and Diehl AM. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118: 3331-3342, 2008.
186. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, and Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307: 1603-1609, 2005.
187. Pacher P, Beckman JS, and Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87: 315-424, 2007.
188. Pagan R, Llobera M, and Vilaró S. Epithelial-mesenchymal transition in cultured neonatal hepatocytes. Hepatology 21: 820-831, 1995.
189. Pagan R, Sánchez A, Martin I, Llobera M, Fabregat I, and Vilaró S. Effects of growth and differentiation factors on the epithelial-mesenchymal transition in cultured neonatal rat hepatocytes. J Hepatol 31: 895-904, 1999.
190. Palacios F, Price L, Schweitzer J, Collard JG, and D'Souza-Schorey C. An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration. EMBO J 20: 4973-4986, 2001.
191. Papaharalambus CA and Griendling KK. Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. Trends Cardiovasc Med 17: 48-54, 2007.
192. Papkoff J and Aikawa M. WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells. Biochem Biophys Res Commun 247: 851-858, 1998.
193. Park SM, Gaur AB, Lengyel E, and Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22: 894-907, 2008.
194. Parola M and Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol 35: 297-306, 2001.
195. Parola M, Bellomo G, Robino G, Barrera G, and Dianzani MU. 4-Hydroxynonenal as a biological signal: Molecular bases and pathophysiological implication. Antioxid Redox Signal 1: 255-284 1999.
196. Parola M, Marra F, and Pinzani M. Myofibroblast-like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. Mol Asp Med 29: 58-66, 2008.
197. Pasca di Magliano M and Hebrok M. Hedgehog signaling in cancer formation and maintenance. Nat Rev Cancer 3: 903-911, 2003.
198. Peinado H, Ballestar E, Esteller M, and Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A=histone deacetylase 1 (HDAC1)=HDAC2 complex. Mol Cell Biol 24: 306-319, 2004.
199. Peinado H, Olmeda D, and Cano A. Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer 7: 415-428, 2007.
200. Peinado H, Portillo F, and Cano A. Switching on-off Snail. LOXL2 versus GSK3 beta. Cell Cycle 4: 1749-1752, 2005.
201. Peinado H, Portillo F, and Cano A. Transcriptional regulation of cadherins during development and carcinogene-sis. Int J Dev Biol 48: 365-375, 2004.
202. Peinado H, Quintanilla M, and Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: Mechanisms for epithelial mesenchy-mal transitions. J Biol Chem 278: 21113-21123, 2003.
203. Pennathur S and Heinecke JW. Oxidative stress and en-dothelial dysfunction in vascular disease. Curr Diab Rep 7: 257-264, 2007. (Pubitemid 47249084)
204. Person AD, Klewer SE, and Runyan RB. Cell biology of cardiac cushion development. Int Rev Cytol 243: 287-335, 2005.
205. Poelmann RE, Gittenberger-de Groot AC, Mentink MM, Delpech B, Girard N, and Christ B. The extracellular matrix during neural crest formation and migration in rat embryos. Anat Embryol 182: 29-39, 1990.
206. Poli G and Schaur RJ. 4-Hydroxynonenal in the phato-mechanisms of oxidative stress. IUBMB Life 50: 315-321, 2000.
207. Polyak K and Weinberg RA. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer 9: 265-273, 2009.
208. Potenta S, Zeisberg E, and Kalluri R. The role of endothelial-to- mesenchymal transition in cancer progression. Br J Cancer 99: 1375-1379, 2008.
209. Przybylo JA and Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition: Tumor progression at Snail's pace. Int J Biochem Cell Biol 39: 1082-1088, 2007.
210. Radisky DC, Kenny PA, and Bissell MJ. Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101: 830-839, 2007.
211. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, and Bissell MJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436: 123-127, 2005.
212. Radomski MW, Palmer RMJ, and Moncada S: The anti-aggregating properties of vascular endothelium: Interactions between prostacyclin and nitric oxide. Br J Pharmacol 92: 639-646, 1987.
213. Rahman I, Biswas SK, and Kode A. Oxidant and antioxi-dant balance in the airways and airway diseases. Eur J Pharmacol 533: 222-239, 2006.
214. RahmanI,YangSR,and BiswasSK.Currentconceptsofredox signaling in the lungs. Antioxid Redox Signal 8: 681-689, 2006.
215. Rankin EB and Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Diff 15: 678-685, 2008.
216. Rastaldi MP, Ferrario F, Giardino L, Dell'Antonio G, Grillo C, Grillo P, Strutz F, Müller GA, Colasanti G, and D'Amico G. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 62: 137-146, 2002.
217. Rezaee M, Isokawa K, Halligan N, Markwald RR, and Krug EL. Identification of an extracellular 130-kDa protein involved in early cardiac morphogenesis. J Biol Chem 268: 4404-4411, 1993.
218. Rhyu DY, Yang Y, Ha H, Lee GT, Song JS, Uh ST, and Lee HB. Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol 16: 667-675, 2005.
219. Robertson H, Kirby JA, Yip WW, Jones DE, and Burt AD. Biliary epithelial-mesenchymal transition in post-transplantation recurrence of primary biliary cirrhosis. Hepatology 45: 977-981, 2007.
220. Robson EJ, Khaled WT, Abell K, and Watson CJ. Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines. Differentiation 74: 254-264, 2006.
221. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, and Forbes SJ. The bone marrow functionally contributes to liver fi-brosis. Gastroenterology 130: 1807-1821, 2006.
222. Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DE, Burt AD, and Kirby JA. Epithelial-mesenchymal transition contributes to portal tract fibro-genesis during human chronic liver disease. Lab Invest 88: 112-123, 2008.
223. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, and Len-dahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105: 6392-6397, 2008.
224. Santamaria-Kisiel L, Rintala-Dempsey AC, and Shaw GS. Calcium-dependent and-independent interactions of the S100 protein family. Biochem J 396: 201-214, 2006.
225. Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, and Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like pheno-type. Cancer Res 68: 989-997, 2008.
226. Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, and Hudson LG. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202: 858-866, 2005.
227. Savagner P. Leaving the neighborhood: Molecular mechanisms involved during epithelial-mesenchymal transition. BioEssays 23: 912-923, 2001.
228. Schmalhofer O, Brabletz S, and Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 28: 151-166, 2009.
229. Schneider M, Hansen JL, and Sheikh SP. S100A4: A common mediator of epithelial-mesenchymal transition, fibro-sis and regeneration in diseases? J Mol Med 86: 507-522, 2008.
230. Schreck R and Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of NFkB transcription factor and HIV-1. Trends Cell Biol 1: 39-42, 1991.
231. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721-732, 2003.
232. Shirakihara T, Saitoh M, and Miyazono K. Differential regulation of epithelial and mesenchymal markers by del-taEF1 proteins in epithelial mesenchymal transition induced by TGF-beta. Mol Biol Cell 18: 3533-3544, 2007.
233. Shock F and Perrimon N. Molecular mechanisms of epithelial morphogenesis. Annu Rev Cell Dev Biol 18: 463-493, 2002.
234. Simon MC and Keith B. The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9: 285-296, 2008.
235. Slater TF. Free Radical Mechanisms in Tissue Injury. Pion Ltd, London, UK; 1972.
236. Slater TF. Necrogenic action of carbon tetrachloride in the rat: A speculative mechanism based on activation. Nature 209: 36-40,1966.
237. Soberman RJ. The expanding network of redox signaling: new observations, complexities, and perspectives. J Clin Invest 111: 571-574, 2003.
238. Sobrado VR, Moreno-Bueno G, Cubillo E, Holt LJ, Nieto MA, Portillo F, and Cano A. The class I bHLH factors E2-2A and E2-2B regulate EMT. J Cell Sci 122: 1014-1024, 2009.
239. Somasiri A, Howarth A, Goswami D, Dedhar S, and Ros-kelley CD. Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells. J Cell Sci 114: 1125-1136, 2001.
240. Strutz F, Mü ller GA, and Neilson EG. Transdifferentiat-ion: A new angle on renal fibrosis. Exp Nephrol 4: 267-270, 1996.
241. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, and Neilson EG. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130: 393-405, 1995.
242. Strutz FM. EMT and proteinuria as progression factors. Kidney Int 75: 475-481, 2009.
243. Takai Y, Sasaki T, and Matozaki T. Small GTP-binding proteins. Physiol Rev 81: 153-208, 2001.
244. Tarabykina S, Griffiths TR, Tulchinsky E, Mellon JK, Bronstein IB, and Kriajevska M. Metastasis-associated protein S100A4: Spotlight on its role in cell migration. Curr Cancer Drug Targets 7: 217-228, 2007
245. Tarabykina S, Kriajevska M, Scott DJ, Hill TJ, Lafitte D, Derrick PJ, Dodson GG, Lukanidin E, and Bronstein I. Heterocomplex formation between metastasis-related protein S100A4 (Mts1) and S100A1 as revealed by the yeast two-hybrid system. FEBS Lett 475: 187-191, 2000.
246. Tarin D, Thompson EW, and Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65: 5996-6000, 2005.
247. Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, and Massagué J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451: 147-152, 2008.
248. Temkin V and Karin M. From death receptor to reactive oxygen species and c-Jun N-terminal protein kinase: The receptor-interacting protein 1 odyssey. Immunol Rev 220: 8-21, 2007.
249. Thannickal VJ and Farnburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279: L1005-L1028, 2000.
250. Thiery JP and Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nature Rev Mol Cell Biol 7: 131-142, 2006.
251. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nature Rev Cancer 2: 442-454, 2002.
252. Thorgeirsson SS and Grisham JW. Hematopoietic cells as hepatocyte stem cells: A critical review of the evidence. Hepatology 43: 2-8, 2006.
253. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, and Moustakas A. Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol 174: 175-183, 2006.
254. Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, D?́ez J, Aranda S, Palomo S, McCormick F, Izpisúa-Belmonte JC, and de la Pompa JL. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18: 99-115, 2004.
255. Tonks KN. Redox redux: Revisiting PTPs and the control of cell signaling. Cell 121: 667-670, 2005.
256. Tonks NK. Protein tyrosine phosphatases: From genes, to function, to disease. Mol Cell Biol 7: 833-845, 2006.
257. Trelstad RL, Hay ED, and Revel JP. Cell contact during early morphogenesis in the chick embryo. Dev Biol 16: 78-106, 1967.
258. Trelstad RL, Revel JP, and Hay ED. Tight junctions between cells in the early chick embryo as visualized with the electron microscopy. J Cell Biol 31: C6-C10, 1966.
259. Tucker GC, Duband JL, Dufour S, and Thiery JP. Cell-adhesion and substrate-adhesion molecules: Their instructive roles in neural crest cell migration. Development Suppl 103: 81-94, 1988.
260. Tucker GC, Boyer B, Gavrilovic J, Emonard H, and Thiery JP. Role of collagen as an EMT inducer: Collagen-mediated dispersion of NBT-II rat bladder carcinoma cells. Cancer Res 50: 129-137, 1990.
261. Uchida K. 4-Hydroxy-2-nonenal: A product and mediator of oxidative stress. Prog Lipid Res 42: 318-343, 2003.
262. Valfrè di Bonzo L, Ferrero I, Cravanzola C, Mareschi K, Rustichelli D, Novo E, Sanavio F, Cannito S, Zamara E, Bertero M, Davit A, Francica S, Novelli F, Colombatto S, Fagioli F, and Parola M. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: Engraftment and hepatocyte differentiation versus profi-brogenic potential. Gut 57: 223-231, 2008.
263. Vallés AM, Beuvin M, and Boyer B. Activation of Rac1 by paxillin-Crk-DOCK180 signaling complex is antagonized by Rap1 in migrating NBT-II cells. J Biol Chem 279: 44490-44496, 2004.
264. Vaupel P and Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev 26: 225-239, 2007.
265. Venkov CD, Link AJ, Jennings JL, Plieth D, Inoue T, Nagai K, Xu C, Dimitrova YN, Rauscher FJ, and Neilson EG. A proximal activator of transcription in epithelial-mesenchymal transition. J Clin Invest 117: 482-491, 2007.
266. Viebahn C. Epithelio-mesenchymal transformation during formation of the mesoderm in the mammalian embryo. Acta Anat 154: 79-97, 1995.
267. Vongwiwatana A, Tasanarong A, Rayner DC, Melk A, and Halloran PF. Epithelial to mesenchymal transition during late deterioration of human kidney transplants: The role of tubular cells in fibrogenesis. Am J Transplant 5: 1367-1374, 2005.
268. Weiss FU, Daub H, and Ullrich A. Novel mechanisms of RTK signal generation. Curr Opin Genet Dev 7: 80-86, 1997.
269. White AA, Crawford KM, Patt CS, and Lad PJ. Activation of soluble guanylate cyclase from rat lung by incubation or by hydrogen peroxide. J Biol Chem 251: 7304-7312, 1976.
270. Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E, Horvitz HR, Kauppinen S, and Plasterk RH. MicroRNA expression in zebrafish embryonic development. Science 309: 310-311, 2005.
271. Willis BC and Borok Z. TGFb-induced EMT: Mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 293: L525-534, 2007.
272. Willis BC, duBois RM, and Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 3: 377-382, 2006.
273. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, and Borok Z. Induction of epi-thelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: Potential role in idi-opathic pulmonary fibrosis. Am J Pathol 166: 1321-1332, 2005.
274. Wilson MS and Wynn TA. Pulmonary fibrosis: Pathogen-esis, etiology and regulation. Mucosal Immunol 2: 103-121, 2009.
275. Witztum JL and Steinberg D: The oxidative modification hypothesis of atherosclerosis: Does it hold for humans? Trends Cardiovasc Med 11: 93-102, 2001.
276. Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev 25: 695-705, 2006.
277. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, and Zhou BP. Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15: 416-428, 2009.
278. Wu Z, Yang L, Cai L, Zhang M, Cheng X, Yang X, and Xu J. Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse. Respir Res 8: 1, 2007.
279. Wynn TA. Common and unique mechanisms regulate fi-brosis in various fibroproliferative diseases. J Clin Invest 117: 524-529, 2007.
280. Xia JL, Dai C, Michalopoulos GK, and Liu Y. Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. Am J Pathol 168: 1500-1512, 2006.
281. Xue C, Plieth D, Venkov C, Xu C, and Neilson EG. The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 63: 3386-3394, 2003.
282. Yamada M, Kuwano K, Maeyama T, Hamada N, Yoshimi M, Nakanishi Y, and Kasper M. Dual-immunohistochem-istry provides little evidence for epithelial-mesenchymal transition in pulmonary fibrosis. Histochem Cell Biol 129: 453-462, 2008.
283. Yang J and Weinberg RA. Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell 14: 818-829, 2008.
284. Yang J, Dai C, and Liu Y. Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am J Pathol 163: 621-632, 2003.
285. Yang L, Lin C and Liu Z-R. P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing axin from b-catenin. Cell 127: 139-155, 2006.
286. Yi R, O'Carroll D, Pasolli HA, Zhang Z, Dietrich FS, Tarakhovsky A, and Fuchs E. Morphogenesis in skin is governed by discrete sets of differentially expressed mi-croRNAs. Nat Genet 38: 356-362, 2006.
287. Yi R, Qin Y, Macara IG, and Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17: 3011-3016, 2003.
288. Young IS and Woodside JV. Antioxidant in health and disease. J Clin Pathol 54: 176-186, 2001.
289. Zamara E, Novo E, and Parola M. Oxidative stress and liver fibrosis: From liver injury to the modulation of cell signaling and response. In: Liver Diseases: Biochemical Mechanisms and New Therapeutic Insights Volume, edited by Ali S, Mann DA, and Friedman SL. New York: M=s Sc. Pub 2004, pp. 93-114.
290. Zavadil J, Cermak L, Soto-Nieves N, and Böttinger EP. Integration of TGF-beta=Smad and Jagged1=Notch signaling in epithelial-to-mesenchymal transition. EMBO J 23: 1155-1165, 2004.
291. Zavadil J, Narasimhan M, Blumenberg M, and Schneider RJ. Transforming growth factor-beta and micro-RNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 185: 157-161, 2007.
292. Zavadil J and Böttinger EP. TGF-b and epithelial-to-mesenchymal transition. Oncogene 24: 5764-5774, 2005.
293. Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, and Kalluri R. Fibroblasts in kidney fibrosis emerge via endo-thelial-to-mesenchymal transition. J Am Soc Nephrol 19: 2282-2287; 2008.
294. Zeisberg EM, Potenta SE, Xie L, Zeisberg M, and Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67: 10123-10128, 2007.
295. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan C, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, and Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13: 952-961, 2006.
296. Zeisberg M and Kalluri R. Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. Pediatr Nephrol 23: 1395-1398, 2008.
297. Zeisberg M and Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med 82: 175-181, 2004.
298. Zeisberg M and Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119: 1429-1437, 2009.
299. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, and Kalluri R. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9: 964-968, 2003.
300. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, and Kalluri R. Fibroblasts derive from hepato-cytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282: 23337-23347, 2007.
301. Zhang A, Dong Z, and Yang T. Prostaglandin D2 inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in MDCK cells. Am J Physiol Renal Physiol 291: F1332-1342, 2006.
302. Zhang A, Jia Z, Guo X, and Yang T. Aldosterone induces epithelial-mesenchymal transition via ROS of mito-chondrial origin. Am J Physiol Renal Physiol 293: F723-731, 2007.
303. Zhang G, Kernan KA, Collins SJ, Cai X, López-Guisa JM, Degen JL, Shvil Y, and Eddy AA. Plasmin(ogen) promotes renal interstitial fibrosis by promoting epithelial-to-mesenchymal transition: role of plasmin-activated signals. J Am Soc Nephrol 18: 846-859, 2007.
304. Zhang KH, Tian HY, Gao X, Lei WW, Hu Y, Wang DM, Pan XC, Yu ML, Xu GJ, Zhao FK, and Song JG. Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. Cancer Res 69: 5340-5348, 2009.
305. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, and Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6: 931-940, 2004.
306. Zhu X, Su B, Wang X, Smith MA, and Perry G. Causes of oxidative stress in Alzheimer diseases. Cell Mol Life Sci 64: 2202-2210, 2007. (Pubitemid 47347959)
307. Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, and Collard JG. Oncogenic Ras down-regulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol 149: 775-782, 2000.