Reactivation of epithelial-mesenchymal transition in invasive and metastatic cancer

Signaling Pathways and Molecular Mediators in Metastasis

Volumn 9789400725584, Issue , 2012, Pages 13-69

  Amatangelo, Michael D ^a   Stearns, Mark E ^a  

^a DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84924756121     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-94-007-2558-4_2     Document Type: Chapter

References (490)

1. Viebahn C (1995) Epithelio-mesenchymal transformation during formation of the mesoderm in the mammalian embryo. Acta Anat (Basel) 154(1):79-97
2. Duband JL et al (1995) Epithelium-mesenchyme transition during neural crest development. Acta Anat (Basel) 154(1):63-78
3. Krug EL, Runyan RB, Markwald RR (1985) Protein extracts from early embryonic hearts initiate cardiac endothelial cytodifferentiation. Dev Biol 112(2):414-426
4. Yan C et al (2010) Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol 176(5):2247-2258
5. Greenburg G, Hay ED (1982) Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 95(1):333-339
6. Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154(1):8-20
7. Xue C et al (2003) The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 63(12):3386-3394
8. Davies JA (1996) Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat (Basel) 156(3):187-201
9. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420-1428
10. Micalizzi DS, Farabaugh SM, Ford HL (2010) Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15(2):117-134
11. Tarin D, Thompson EW, Newgreen DF (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65(14):5996-6000; discussion 6000-1
12. Trimboli AJ et al (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68(3):937-945
13. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10(7):445-457
14. Giampieri S et al (2009) Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 11(11):1287-1296
15. Braun S et al (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342(8):525-533
16. Friedl P, Wolf K (2008) Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res 68(18):7247-7249
17. Gaggioli C et al (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9(12):1392-1400
18. Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704-715
19. Kong D et al (2010) Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 5(8):e12445
20. Shimoyama Y et al (1989) Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res 49(8):2128-2133
21. McNeill H et al (1990) Novel function of the cell adhesion molecule uvomorulin as an inducer of cell surface polarity. Cell 62(2):309-316
22. Marrs JA et al (1995) Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules. J Cell Biol 129(2):507-519
23. Hay ED, Zuk A (1995) Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 26(4):678-690
24. Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198(1): 11-26
25. Byers SW et al (1995) Role of E-cadherin in the response of tumor cell aggregates to lymphatic, venous and arterial flow: measurement of cell-cell adhesion strength. J Cell Sci 108(Pt 5):2053-2064
26. Thiery JP et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871-890
27. Onder TT et al (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68(10):3645-3654
28. Vleminckx K et al (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66(1):107-119
29. Frixen UH et al (1991) E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113(1):173-185
30. Perl AK et al (1998) A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392(6672):190-193
31. Gottardi CJ, Wong E, Gumbiner BM (2001) E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol 153(5): 1049-1060
32. Berx G, Van Roy F (2001) The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res 3(5):289-293
33. Christofori G, Semb H (1999) The role of the cell-adhesion molecule E-cadherin as a tumoursuppressor gene. Trends Biochem Sci 24(2):73-76
34. Liebner S et al (2004) Beta-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 166(3):359-367
35. Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112(12):1776-1784
36. Brabletz T et al (1998) Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 194(10):701-704
37. Brabletz T et al (2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 98(18):10356-10361
38. Prasad CP et al (2009) Expression analysis of E-cadherin, Slug and GSK3beta in invasive ductal carcinoma of breast. BMC Cancer 9:325
39. Logullo AF et al (2010) Concomitant expression of epithelial-mesenchymal transition biomarkers in breast ductal carcinoma: association with progression. Oncol Rep 23(2):313-320
40. Christofori G (2003) Changing neighbours, changing behaviour: cell adhesion moleculemediated signalling during tumour progression. EMBO J 22(10):2318-2323
41. Ong LL et al (1998) Trabecular myocytes of the embryonic heart require N-cadherin for migratory unit identity. Dev Biol 193(1):1-9
42. Hatta K, Takeichi M (1986) Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development. Nature 320(6061):447-449
43. Tomita K et al (2000) Cadherin switching in human prostate cancer progression. Cancer Res 60(13):3650-3654
44. Hazan RB et al (1997) N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes Commun 4(6):399-411
45. Li G, Herlyn M (2000) Dynamics of intercellular communication during melanoma development. Mol Med Today 6(4):163-169
46. Hazan RB et al (2000) Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 148(4):779-790
47. Gravdal K et al (2007) A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res 13(23):7003-7011
48. Simonneau L et al (1995) Cadherin 11 expression marks the mesenchymal phenotype: towards new functions for cadherins? Cell Adhes Commun 3(2):115-130
49. Matsuyoshi N et al (1997) Identification of novel cadherins expressed in human melanoma cells. J Invest Dermatol 108(6):908-913
50. Pishvaian MJ et al (1999) Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res 59(4):947-952
51. Nieman MT et al (1999) N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 147(3):631-644
52. Pekny M, Lane EB (2007) Intermediate filaments and stress. Exp Cell Res 313(10): 2244-2254
53. Eckes B et al (2000) Impaired wound healing in embryonic and adult mice lacking vimentin. J Cell Sci 113(Pt 13):2455-2462
54. Franke WW et al (1982) Formation of cytoskeletal elements during mouse embryogenesis. III. Primary mesenchymal cells and the first appearance of vimentin filaments. Differentiation 23(1):43-59
55. Duprey P, Paulin D (1995) What can be learned from intermediate filament gene regulation in the mouse embryo. Int J Dev Biol 39(3):443-457
56. Page M (1989) Changing patterns of cytokeratins and vimentin in the early chick embryo. Development 105(1):97-107
57. Thomas PA et al (1999) Association between keratin and vimentin expression, malignant phenotype, and survival in postmenopausal breast cancer patients. Clin Cancer Res 5(10):2698-2703
58. Gilles C et al (1996) Vimentin expression in cervical carcinomas: association with invasive and migratory potential. J Pathol 180(2):175-180
59. Hu L et al (2004) Association of Vimentin overexpression and hepatocellular carcinoma metastasis. Oncogene 23(1):298-302
60. Lang SH et al (2002) Enhanced expression of vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate 52(4):253-263
61. Otsuki S et al (2011) Vimentin expression is associated with decreased survival in gastric cancer. Oncol Rep 25(5):1235-1242
62. McInroy L, Maatta A (2007) Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun 360(1):109-114
63. Zhao Y et al (2008) Vimentin affects the mobility and invasiveness of prostate cancer cells. Cell Biochem Funct 26(5):571-577
64. Heatley M et al (1995) Vimentin and cytokeratin expression in nodular hyperplasia and carcinoma of the prostate. J Clin Pathol 48(11):1031-1034
65. Raimondi C et al (2011) Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat 130:449-455
66. Hofman V et al (2010) Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small cell lung carcinoma: comparison of the efficacy of the CellSearch Assay and the isolation by size of epithelial tumor cell method. Int J Cancer 129(7):1651-1660
67. Thompson EW, Newgreen DF, Tarin D (2005) Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 65(14):5991-5995; discussion 5995
68. Barraclough R (1998) Calcium-binding protein S100A4 in health and disease. Biochim Biophys Acta 1448(2):190-199
69. Strutz F et al (1995) Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130(2):393-405
70. Takenaga K, Nakamura Y, Sakiyama S (1994) Cellular localization of pEL98 protein, an S100-related calcium binding protein, in fibroblasts and its tissue distribution analyzed by monoclonal antibodies. Cell Struct Funct 19(3):133-141
71. Cabezon T et al (2007) Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer. Int J Cancer 121(7):1433-1444
72. Kim EJ, Helfman DM (2003) Characterization of the metastasis-associated protein, S100A4. Roles of calcium binding and dimerization in cellular localization and interaction with myosin. J Biol Chem 278(32):30063-30073
73. Okada H et al (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273(4 Pt 2):F563-F574
74. Iwano M et al (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110(3):341-350
75. Stein U et al (2006) The metastasis-associated gene S100A4 is a novel target of beta-catenin/ T-cell factor signaling in colon cancer. Gastroenterology 131(5):1486-1500
76. Grigorian M et al (1996) Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. Int J Cancer 67(6):831-841
77. Levett D et al (2002) Transfection of S100A4 produces metastatic variants of an orthotopic model of bladder cancer. Am J Pathol 160(2):693-700
78. Takenaga K, Nakamura Y, Sakiyama S (1997) Expression of antisense RNA to S100A4 gene encoding an S100-related calcium-binding protein suppresses metastatic potential of highmetastatic Lewis lung carcinoma cells. Oncogene 14(3):331-337
79. Ambartsumian NS et al (1996) Metastasis of mammary carcinomas in GRS/A hybrid mice transgenic for the mts1 gene. Oncogene 13(8):1621-1630
80. Rudland PS et al (2000) Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer. Cancer Res 60(6):1595-1603
81. Helfman DM et al (2005) The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 92(11):1955-1958
82. Hay ED (1999) Biogenesis and organization of extracellular matrix. FASEB J 13(Suppl 2): S281-S283
83. Lee GY et al (2007) Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods 4(4):359-365
84. Barsky SH et al (1983) Loss of basement membrane components by invasive tumors but not by their benign counterparts. Lab Invest 49(2):140-147
85. Duband JL, Thiery JP (1982) Appearance and distribution of fibronectin during chick embryo gastrulation and neurulation. Dev Biol 94(2):337-350
86. Poelmann RE et al (1990) The extracellular matrix during neural crest formation and migration in rat embryos. Anat Embryol (Berl) 182(1):29-39
87. Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119(6):1429-1437
88. Gaggioli C et al (2007) Tumor-derived fibronectin is involved in melanoma cell invasion and regulated by V600E B-Raf signaling pathway. J Invest Dermatol 127:400-410
89. Gehlsen KR et al (1988) Inhibition of in vitro tumor cell invasion by Arg-Gly-Asp-containing synthetic peptides. J Cell Biol 106:925-930
90. Zeng ZZ et al (2006) Role of focal adhesion kinase and phosphatidylinositol 3 ¢ -kinase in integrin fibronectin receptor-mediated, matrix metalloproteinase-1-dependent invasion by metastatic prostate cancer cells. Cancer Res 66(16):8091-8099
91. Jia Y et al (2004) Integrin fibronectin receptors in matrix metalloproteinase-1-dependent invasion by breast cancer and mammary epithelial cells. Cancer Res 64(23):8674-8681
92. Yang Z et al (2007) Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun 358(3):925-930
93. Allen M, Louise Jones J (2011) Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol 223(2):162-176
94. Gorczyca W, Holm R, Nesland JM (1993) Laminin production and fibronectin immunoreactivity in breast carcinomas. Anticancer Res 13(4):851-858
95. Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241-254
96. Boyd NF et al (2005) Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 6(10):798-808
97. Davidson LA et al (2006) Integrin alpha5beta1 and fibronectin regulate polarized cell protrusions required for Xenopus convergence and extension. Curr Biol 16(9):833-844
98. Maschler S et al (2005) Tumor cell invasiveness correlates with changes in integrin expression and localization. Oncogene 24(12):2032-2041
99. Qian F et al (2005) Interaction between integrin alpha(5) and fibronectin is required for metastasis of B16F10 melanoma cells. Biochem Biophys Res Commun 333(4):1269-1275
100. Fridman R et al (1995) Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res 55(12):2548-2555
101. Ramos-DeSimone N et al (1999) Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem 274(19): 13066-13076
102. Sato H et al (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370(6484):61-65
103. Dufour A et al (2008) Role of the hemopexin domain of matrix metalloproteinases in cell migration. J Cell Physiol 217(3):643-651
104. Olson MW et al (2000) Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9. Differential rates for activation by stromelysin 1. J Biol Chem 275(4):2661-2668
105. Duong TD, Erickson CA (2004) MMP-2 plays an essential role in producing epithelialmesenchymal transformations in the avian embryo. Dev Dyn 229(1):42-53
106. Cai DH, Brauer PR (2002) Synthetic matrix metalloproteinase inhibitor decreases early cardiac neural crest migration in chicken embryos. Dev Dyn 224(4):441-449
107. Giambernardi TA et al (2001) Neutrophil collagenase (MMP-8) is expressed during early development in neural crest cells as well as in adult melanoma cells. Matrix Biol 20(8):577-587
108. Alexander SM et al (1997) Spatial and temporal expression of the 72-kDa type IV collagenase (MMP-2) correlates with development and differentiation of valves in the embryonic avian heart. Dev Dyn 209(3):261-268
109. Song W, Jackson K, McGuire PG (2000) Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions. Dev Biol 227(2):606-617
110. Buisson AC et al (1996) Gelatinase B is involved in the in vitro wound repair of human respiratory epithelium. J Cell Physiol 166(2):413-426
111. Legrand C et al (1999) Airway epithelial cell migration dynamics. MMP-9 role in cellextracellular matrix remodeling. J Cell Biol 146(2):517-529
112. Buisson AC et al (1996) Wound repair-induced expression of a stromelysins is associated with the acquisition of a mesenchymal phenotype in human respiratory epithelial cells. Lab Invest 74(3):658-669
113. Schmalfeldt B et al (2001) Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer. Clin Cancer Res 7(8):2396-2404
114. Sier CF et al (1996) Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer 74(3): 413-417
115. Liabakk NB et al (1996) Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 56(1):190-196
116. Morgia G et al (2005) Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res 33(1):44-50
117. Jones JL, Glynn P, Walker RA (1999) Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol 189(2):161-168
118. Hotary K et al (2000) Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J Cell Biol 149(6):1309-1323
119. Bonfil RD et al (2007) Prostate cancer-associated membrane type 1-matrix metalloproteinase: a pivotal role in bone response and intraosseous tumor growth. Am J Pathol 170(6):2100-2111
120. Gavrilovic J et al (1990) Expression of transfected transforming growth factor alpha induces a motile fibroblast-like phenotype with extracellular matrix-degrading potential in a rat bladder carcinoma cell line. Cell Regul 1(13):1003-1014
121. Pulyaeva H et al (1997) MT1-MMP correlates with MMP-2 activation potential seen after epithelial to mesenchymal transition in human breast carcinoma cells. Clin Exp Metastasis 15(2):111-120
122. Daja MM et al (2003) Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines. Prostate Cancer Prostatic Dis 6(1):15-26
123. Zajchowski DA et al (2001) Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61(13):5168-5178
124. Bhowmick NA et al (2001) Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J Biol Chem 276(50): 46707-46713
125. Galliher AJ, Schiemann WP (2006) Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res 8(4):R42
126. Sternlicht MD et al (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98(2):137-146
127. Lochter A et al (1997) 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(7):1861-1872
128. Cowden Dahl KD et al (2008) Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res 68(12): 4606-4613
129. Cao J et al (2008) Membrane type 1 matrix metalloproteinase induces epithelial-tomesenchymal transition in prostate cancer. J Biol Chem 283(10):6232-6240
130. Trudel D et al (2003) Significance of MMP-2 expression in prostate cancer: an immunohistochemical study. Cancer Res 63(23):8511-8515
131. Millan FA et al (1991) Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development 111(1):131-143
132. Hayashi H et al (1997) The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89(7):1165-1173
133. Kavsak P et al (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6(6):1365-1375
134. Gingery A et al (2008) TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival. Exp Cell Res 314(15):2725-2738
135. Kato M et al (2009) TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat Cell Biol 11(7):881-889
136. Lee MK et al (2007) TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 26(17):3957-3967
137. Perlman R et al (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3(8):708-714
138. Conlon FL et al (1994) A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120(7):1919-1928
139. Shah SB et al (1997) Misexpression of chick Vg1 in the marginal zone induces primitive streak formation. Development 124(24):5127-5138
140. Goldstein AM et al (2005) BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system. Mech Dev 122(6):821-833
141. Boyer AS et al (1999) TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol 208(2):530-545
142. Sato M et al (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 112(10): 1486-1494
143. Khalil N et al (1996) TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol 14(2):131-138
144. Piek E et al (1999) TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112 (Pt 24):4557-4568
145. Kowanetz M et al (2004) Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein. Mol Cell Biol 24(10):4241-4254
146. Do TV et al (2008) Transforming growth factor-beta1, transforming growth factor-beta2, and transforming growth factor-beta3 enhance ovarian cancer metastatic potential by inducing a Smad3-dependent epithelial-to-mesenchymal transition. Mol Cancer Res 6(5):695-705
147. Eastham JA et al (1995) Transforming growth factor-beta 1: comparative immunohistochemical localization in human primary and metastatic prostate cancer. Lab Invest 73(5): 628-635
148. Krasagakis K et al (1998) Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma. Br J Cancer 77(9):1492-1494
149. Cardillo MR, Yap E, Castagna G (1997) Molecular genetic analysis of TGF beta1 in breast cancer. J Exp Clin Cancer Res 16(1):57-63
150. Langenskiold M et al (2008) Increased TGF-beta 1 protein expression in patients with advanced colorectal cancer. J Surg Oncol 97(5):409-415
151. Pardali K, Moustakas A (2007) Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775(1):21-62
152. Janda E et al (2006) Raf plus TGFbeta-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin. Oncogene 25(54):7117-7130
153. Vogelmann R et al (2005) TGFbeta-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN. J Cell Sci 118(Pt 20):4901-4912
154. Ozdamar B et al (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307(5715):1603-1609
155. Oft M, Heider KH, Beug H (1998) TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8(23):1243-1252
156. Hocevar BA, Brown TL, Howe PH (1999) TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J 18(5):1345-1356
157. Zapatka M et al (2007) Basement membrane component laminin-5 is a target of the tumor suppressor Smad4. Oncogene 26(10):1417-1427
158. Ignotz RA, Massague J (1986) Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261(9):4337-4345
159. Giannelli G et al (2005) Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129(5):1375-1383
160. Pyke C et al (1995) Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res 55(18):4132-4139
161. Pyke C et al (1994) The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers. Am J Pathol 145(4):782-791
162. Koshikawa N et al (1999) Overexpression of laminin gamma2 chain monomer in invading gastric carcinoma cells. Cancer Res 59(21):5596-5601
163. Katayama M et al (2003) Laminin gamma2-chain fragment in the circulation: a prognostic indicator of epithelial tumor invasion. Cancer Res 63(1):222-229
164. Koshikawa N et al (2000) Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148(3):615-624
165. Giannelli G et al (1997) Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277(5323):225-228
166. Kim ES, Kim MS, Moon A (2004) TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 25(5):1375-1382
167. Padua D et al (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133(1):66-77
168. Bardeesy N et al (2006) Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 20(22):3130-3146
169. Takano S et al (2007) Smad4 is essential for down-regulation of E-cadherin induced by TGFbeta in pancreatic cancer cell line PANC-1. J Biochem 141(3):345-351
170. Deckers M et al (2006) The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res 66(4):2202-2209
171. Brown KA, Pietenpol JA, Moses HL (2007) A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 101(1):9-33
172. Hoot KE et al (2008) Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest 118(8):2722-2732
173. Ju W et al (2006) Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol 26(2):654-667
174. Saika S et al (2004) Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol 164(2):651-663
175. Dunn NR et al (2004) Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo. Development 131(8):1717-1728
176. Brown KA et al (2004) Induction by transforming growth factor-beta1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res 6(3):R215-R231
177. Salomon DS et al (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19(3):183-232
178. Normanno N et al (2005) The ErbB receptors and their ligands in cancer: an overview. Curr Drug Targets 6(3):243-257
179. Price JT, Wilson HM, Haites NE (1996) Epidermal growth factor (EGF) increases the in vitro invasion, motility and adhesion interactions of the primary renal carcinoma cell line, A704. Eur J Cancer 32A(11):1977-1982
180. Ignatoski KM et al (2000) ERBB-2 overexpression confers PI 3 ¢ kinase-dependent invasion capacity on human mammary epithelial cells. Br J Cancer 82(3):666-674
181. Spano JP et al (2005) Impact of EGFR expression on colorectal cancer patient prognosis and survival. Ann Oncol 16(1):102-108
182. Normanno N et al (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366(1):2-16
183. Graus-Porta D et al (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16(7):1647-1655
184. Goishi K et al (2003) Inhibition of zebrafish epidermal growth factor receptor activity results in cardiovascular defects. Mech Dev 120(7):811-822
185. Iwamoto R, Mekada E (2006) ErbB and HB-EGF signaling in heart development and function. Cell Struct Funct 31(1):1-14
186. Santoro MM, Gaudino G (2005) Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp Cell Res 304(1):274-286
187. Lu Z et al (2003) Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4(6):499-515
188. Ackland ML et al (2003) Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest 83(3):435-448
189. Yates CC et al (2007) Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. Br J Cancer 96(8):1246-1252
190. Aranda V et al (2006) Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 8(11):1235-1245
191. Kheradmand F, Rishi K, Werb Z (2002) Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J Cell Sci 115(Pt 4):839-848
192. Reddy KB et al (1999) Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. Int J Cancer 82(2):268-273
193. Watabe T et al (1998) The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Int J Cancer 77(1):128-137
194. Kim IY et al (2009) Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9. Cancer Lett 275(2):227-233
195. DesMarais V et al (2004) Synergistic interaction between the Arp2/3 complex and cofilin drives stimulated lamellipod extension. J Cell Sci 117(Pt 16):3499-3510
196. Turner T et al (1996) EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells. Clin Exp Metastasis 14(4):409-418
197. Hill K et al (2000) Specific requirement for the p85-p110alpha phosphatidylinositol 3-kinase during epidermal growth factor-stimulated actin nucleation in breast cancer cells. J Biol Chem 275(6):3741-3744
198. Kedrin D et al (2007) Cell motility and cytoskeletal regulation in invasion and metastasis. J Mammary Gland Biol Neoplasia 12(2-3):143-152
199. Mouneimne G et al (2004) Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation. J Cell Biol 166(5):697-708
200. Price JT et al (1999) Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3 ¢ -kinase and phospholipase C-dependent mechanism. Cancer Res 59(21):5475-5478
201. Marshall CJ (1996) Ras effectors. Curr Opin Cell Biol 8(2):197-204
202. Oft M, Akhurst RJ, Balmain A (2002) Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 4(7):487-494
203. Xie L et al (2004) Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia 6(5):603-610
204. Kim ES, Kim MS, Moon A (2005) Transforming growth factor (TGF)-beta in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine 29(2):84-91
205. Horiguchi K et al (2009) Role of Ras signaling in the induction of snail by transforming growth factor-beta. J Biol Chem 284(1):245-253
206. Jechlinger M et al (2003) Expression profiling of epithelial plasticity in tumor progression. Oncogene 22(46):7155-7169
207. Seton-Rogers SE et al (2004) Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 101(5):1257-1262
208. Zhau HE et al (2008) Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. Clin Exp Metastasis 25(6):601-610
209. Shin S et al (2010) ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol Cell 38(1):114-127
210. Chuang CF, Ng SY (1994) Functional divergence of the MAP kinase pathway. ERK1 and ERK2 activate specific transcription factors. FEBS Lett 346(2-3):229-234
211. Skarpen E et al (2008) MEK1 and MEK2 regulate distinct functions by sorting ERK2 to different intracellular compartments. FASEB J 22(2):466-476
212. Janda E et al (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156(2):299-313
213. Wyckoff J et al (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022-7029
214. Klein CA (2008) Cancer. The metastasis cascade. Science 321(5897):1785-1787
215. Maroun CR et al (1999) The Gab1 PH domain is required for localization of Gab1 at sites of cell-cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol Cell Biol 19(3):1784-1799
216. Stoker M et al (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327(6119):239-242
217. Uehara Y, Kitamura N (1992) Expression of a human hepatocyte growth factor/scatter factor cDNA in MDCK epithelial cells influences cell morphology, motility, and anchorageindependent growth. J Cell Biol 117(4):889-894
218. Humphrey PA et al (1995) Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147(2):386-396
219. Takeuchi H et al (2003) c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9(4):1480-1488
220. Ueki T et al (1997) Expression of hepatocyte growth factor and its receptor c-met protooncogene in hepatocellular carcinoma. Hepatology 25(4):862-866
221. Di Renzo MF et al (1994) Overexpression of the Met/HGF receptor in ovarian cancer. Int J Cancer 58(5):658-662
222. Beviglia L et al (1997) Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 74(3):301-309
223. Kankuri E et al (2005) Induction of hepatocyte growth factor/scatter factor by fibroblast clustering directly promotes tumor cell invasiveness. Cancer Res 65(21):9914-9922
224. Royal I, Fournier TM, Park M (1997) Differential requirement of Grb2 and PI3-kinase in HGF/SF-induced cell motility and tubulogenesis. J Cell Physiol 173(2):196-201
225. Giordano S et al (1997) A point mutation in the MET oncogene abrogates metastasis without affecting transformation. Proc Natl Acad Sci USA 94(25):13868-13872
226. Pon YL et al (2008) p70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells. Cancer Res 68(16):6524-6532
227. Zhou HY, Wong AS (2006) Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells. Endocrinology 147(5):2557-2566
228. Grille SJ et al (2003) The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 63(9):2172-2178
229. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116-129
230. Colvin JS et al (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12(4):390-397
231. Ciruna B, Rossant J (2001) FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell 1(1):37-49
232. Darby IA, Hewitson T.D 2007 Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol 257:143-179
233. Ornitz DM, Itoh N (2001) Fibroblast growth factors. Genome Biol 2(3):REVIEWS3005
234. Billottet C et al (2008) Modulation of several waves of gene expression during FGF-1 induced epithelial-mesenchymal transition of carcinoma cells. J Cell Biochem 104(3):826-839
235. Boyer B et al (1989) Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells. J Cell Biol 109(4 Pt 1):1495-1509
236. Acevedo VD et al (2007) Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 12(6):559-571
237. Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15(6):740-746
238. Kemler R et al (2004) Stabilization of beta-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast. Development 131(23):5817-5824
239. Gilles C et al (2003) Transactivation of vimentin by beta-catenin in human breast cancer cells. Cancer Res 63(10):2658-2664
240. Kim K, Lu Z, Hay ED (2002) Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int 26(5):463-476
241. Crawford HC et al (1999) The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 18(18):2883-2891
242. Takahashi M et al (2002) Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers. Oncogene 21(38):5861-5867
243. Marchenko GN et al (2002) Promoter characterization of the novel human matrix metalloproteinase- 26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin. Biochem J 363(Pt 2):253-262
244. Jass JR et al (2003) APC mutation and tumour budding in colorectal cancer. J Clin Pathol 56(1):69-73
245. Weeraratna AT et al (2002) Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 1(3):279-288
246. Danilkovitch-Miagkova A et al (2001) Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway. Mol Cell Biol 21(17):5857-5868
247. Labbe E, Letamendia A, Attisano L (2000) 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(15):8358-8363
248. Timmerman LA et al (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18(1):99-115
249. Endo Y, Osumi N, Wakamatsu Y (2002) Bimodal functions of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development 129(4):863-873
250. Shou J et al (2001) Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res 61(19):7291-7297
251. Reedijk M et al (2005) High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65(18):8530-8537
252. Miyamoto Y et al (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3(6):565-576
253. Peinado H, Cano A (2008) A hypoxic twist in metastasis. Nat Cell Biol 10(3):253-254
254. Yan W et al (2009) PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells. Biochem Biophys Res Commun 382(3):631-636
255. Sahlgren C et al (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105(17):6392-6397
256. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216-233
257. Zavadil J et al (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23(5):1155-1165
258. Wicking C, Smyth I, Bale A (1999) The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18(55):7844-7851
259. Lai K et al (2003) Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6(1):21-27
260. Burglin T (2008) The Hedgehog protein family. Genome Biol 9(11):241
261. Jenkins D (2009) Hedgehog signalling: emerging evidence for non-canonical pathways. Cell Signal 21(7):1023-1034
262. Zhang XM, Ramalho-Santos M, McMahon AP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 105(6):781-792
263. Mullor JL et al (2001) Wnt signals are targets and mediators of Gli function. Curr Biol 11(10):769-773
264. Omenetti A et al (2008) Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118(10):3331-3342
265. Louro ID et al (2002) Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 62(20):5867-5873
266. Karhadkar SS et al (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431(7009):707-712
267. Feldmann G et al (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67(5):2187-2196
268. Wu WS (2006) The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev 25(4):695-705
269. Fischer AN et al (2007) PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26(23):3395-3405
270. Barrallo-Gimeno A, Nieto MA (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132(14):3151-3161
271. Bolos V et al (2003) The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 116(Pt 3):499-511
272. Cano A et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2(2):76-83
273. Conacci-Sorrell M et al (2003) Autoregulation of E-cadherin expression by cadherin- cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 163(4):847-857
274. Grotegut S et al (2006) Hepatocyte growth factor induces cell scattering through MAPK/ Egr-1-mediated upregulation of Snail. EMBO J 25(15):3534-3545
275. Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278(23):21113-21123
276. Li X et al (2007) Gli1 acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin. Oncogene 26(31):4489-4498
277. Kurrey NK, Amit K, Bapat SA (2005) Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Oncol 97(1):155-165
278. Sakai D et al (2005) Regulation of Slug transcription in embryonic ectoderm by beta-catenin- Lef/Tcf and BMP-Smad signaling. Dev Growth Differ 47(7):471-482
279. Barbera MJ et al (2004) Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23(44):7345-7354
280. Peiro S et al (2006) Snail1 transcriptional repressor binds to its own promoter and controls its expression. Nucleic Acids Res 34(7):2077-2084
281. Yang Z et al (2005) Pak1 phosphorylation of snail, a master regulator of epithelial-tomesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res 65(8):3179-3184
282. Zhou BP et al (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6(10):931-940
283. Vernon AE, LaBonne C (2006) Slug stability is dynamically regulated during neural crest development by the F-box protein Ppa. Development 133(17):3359-3370
284. Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3(3):155-166
285. Peinado H et al (2004) Snail mediates E-cadherin repression by the recruitment of the Sin3A/ histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol 24(1):306-319
286. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415-428
287. Vincent T et al (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol 11(8):943-950
288. Shook D, Keller R (2003) Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev 120(11):1351-1383
289. Vuoriluoto K et al (2011) Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 30(12):1436-1448
290. Blanco MJ et al (2002) Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21(20):3241-3246
291. Batlle E et al (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2(2):84-89
292. Come C et al (2006) Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 12(18):5395-5402
293. Elloul S et al (2005) Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103(8):1631-1643
294. Roy HK et al (2005) The transcriptional repressor SNAIL is overexpressed in human colon cancer. Dig Dis Sci 50(1):42-46
295. Shioiri M et al (2006) Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer 94(12):1816-1822
296. Yokoyama K et al (2003) Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol 22(4): 891-898
297. Jorda M et al (2005) Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci 118(Pt 15):3371-3385
298. Miyoshi A et al (2005) Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer 92(2): 252-258
299. Ota I et al (2009) Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci USA 106(48): 20318-20323
300. Sugimachi K et al (2003) Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin Cancer Res 9:2657-2664
301. Takeno S et al (2004) E-cadherin expression in patients with esophageal squamous cell carcinoma: promoter hypermethylation, Snail overexpression, and clinicopathologic implications. Am J Clin Pathol 122:78-84
302. Emadi Baygi M et al (2010) Slug/SNAI2 regulates cell proliferation and invasiveness of metastatic prostate cancer cell lines. Tumour Biol 31(4):297-307
303. Gupta PB et al (2005) The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat Genet 37(10):1047-1054
304. Comijn J et al (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7(6):1267-1278
305. Eger A et al (2005) DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24(14):2375-2385
306. Verschueren K et al (1999) SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5 ¢ -CACCT sequences in candidate target genes. J Biol Chem 274(29):20489-20498
307. Postigo AA (2003) Opposing functions of ZEB proteins in the regulation of the TGFbeta/ BMP signaling pathway. EMBO J 22(10):2443-2452
308. Costantino ME et al (2002) Cell-specific phosphorylation of Zfhep transcription factor. Biochem Biophys Res Commun 296(2):368-373
309. Long J, Zuo D, Park M (2005) Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. J Biol Chem 280(42):35477-35489
310. Krishnamachary B et al (2006) Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 66(5):2725-2731
311. Chua HL et al (2007) 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(5):711-724
312. Shirakihara T, Saitoh M, Miyazono K (2007) Differential regulation of epithelial and mesenchymal markers by deltaEF1 proteins in epithelial mesenchymal transition induced by TGFbeta. Mol Biol Cell 18(9):3533-3544
313. Huber MA et al (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114(4):569-581
314. Katoh M (2009) Integrative genomic analyses of ZEB2: transcriptional regulation of ZEB2 based on SMADs, ETS1, HIF1alpha, POU/OCT, and NF-kappaB. Int J Oncol 34(6): 1737-1742
315. Remacle JE et al (1999) New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO J 18(18):5073-5084
316. Shi Y et al (2003) Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422(6933):735-738
317. Zhang Q et al (2006) Redox sensor CtBP mediates hypoxia-induced tumor cell migration. Proc Natl Acad Sci USA 103(24):9029-9033
318. Grooteclaes ML, Frisch SM (2000) Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 19(33):3823-3828
319. Sanchez-Tillo E et al (2010) ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 29(24):3490-3500
320. Vandewalle C et al (2005) SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res 33(20):6566-6578
321. Pena C et al (2006) The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas. Int J Cancer 119(9):2098-2104
322. Vandewalle C, Van Roy F, Berx G (2009) The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 66(5):773-787
323. Van de Putte T et al (2003) Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome. Am J Hum Genet 72(2):465-470
324. Imamichi Y et al (2007) Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer. Oncogene 26(16):2381-2385
325. Haddad Y, Choi W, McConkey DJ (2009) Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines. Clin Cancer Res 15(2):532-542
326. Taki M et al (2006) Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase- 2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Int J Oncol 28(2):487-496
327. Guaita S et al (2002) Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 277(42):39209-39216
328. Howe LR et al (2003) Twist is up-regulated in response to Wnt1 and inhibits mouse mammary cell differentiation. Cancer Res 63(8):1906-1913
329. Hornik C et al (2004) Twist is an integrator of SHH, FGF, and BMP signaling. Anat Embryol (Berl) 209(1):31-39
330. Sosic D et al (2003) Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell 112(2):169-180
331. Yang MH et al (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295-305
332. Benezra R et al (1990) The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61(1):49-59
333. Firulli BA et al (2005) Altered Twist1 and Hand2 dimerization is associated with Saethre- Chotzen syndrome and limb abnormalities. Nat Genet 37(4):373-381
334. Connerney J et al (2006) Twist1 dimer selection regulates cranial suture patterning and fusion. Dev Dyn 235(5):1345-1357
335. Ansieau S et al (2008) Induction of EMT by twist proteins as a collateral effect of tumorpromoting inactivation of premature senescence. Cancer Cell 14(1):79-89
336. Puisieux A, Valsesia-Wittmann S, Ansieau S (2006) A twist for survival and cancer progression. Br J Cancer 94(1):13-17
337. Lluis F et al (2005) E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription. EMBO J 24(5):974-984
338. Nie L et al (2003) Notch-induced E2A ubiquitination and degradation are controlled by MAP kinase activities. EMBO J 22(21):5780-5792
339. Firulli BA et al (2007) Mutations within helix I of Twist1 result in distinct limb defects and variation of DNA binding affinities. J Biol Chem 282(37):27536-27546
340. Firulli BA et al (2003) PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation. Mol Cell 12(5): 1225-1237
341. Vichalkovski A et al (2010) PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage. Oncogene 29(24):3554-3565
342. Massari ME et al (1999) A conserved motif present in a class of helix-loop-helix proteins activates transcription by direct recruitment of the SAGA complex. Mol Cell 4(1):63-73
343. Hamamori Y et al (1999) Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A. Cell 96(3):405-413
344. Koh HS et al (2009) Twist2 regulates CD7 expression and galectin-1-induced apoptosis in mature T-cells. Mol Cells 28(6):553-558
345. Hayashi M et al (2007) Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling. J Cell Sci 120(Pt 8):1350-1357
346. Bechtel W, Zeisberg M (2009) Twist: a new link from hypoxia to fibrosis. Kidney Int 75(12):1255-1256
347. Thuault S et al (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelialmesenchymal transition. J Cell Biol 174(2):175-183
348. Yu W, Kamara H, Svoboda KK (2008) The role of twist during palate development. Dev Dyn 237(10):2716-2725
349. Lee YH et al (2008) Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis 29(12):2243-2251
350. Pozharskaya V et al (2009) Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis. PLoS One 4(10):e7559
351. Mironchik Y et al (2005) Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65(23):10801-10809
352. Kwok WK et al (2005) Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res 65(12):5153-5162
353. Yuen HF et al (2007) Upregulation of Twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis. J Clin Pathol 60(5):510-514
354. Lee TK et al (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12(18):5369-5376
355. Yang J et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927-939
356. Whitehead J et al (2008) Mechanical factors activate beta-catenin-dependent oncogene expression in APC mouse colon. HFSP J 2(5):286-294
357. Alexander NR et al (2006) N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res 66(7):3365-3369
358. Mikheeva SA et al (2010) TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer 9:194
359. Reichenberger KJ et al (2005) Gene amplification is a mechanism of Six1 overexpression in breast cancer. Cancer Res 65(7):2668-2675
360. Young AP, Nagarajan R, Longmore GD (2003) Mechanisms of transcriptional regulation by Rb-E2F segregate by biological pathway. Oncogene 22(46):7209-7217
361. Ford HL et al (1998) Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis. Proc Natl Acad Sci USA 95(21):12608-12613
362. Christensen KL et al (2007) Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1). Oncogene 26(23):3406-3414
363. Brodbeck S, Besenbeck B, Englert C (2004) The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter. Mech Dev 121(10):1211-1222
364. Ando Z et al (2005) Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. FEBS J 272(12):3026-3041
365. Spitz F et al (1998) Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site. Proc Natl Acad Sci USA 95(24):14220-14225
366. Xu PX et al (2003) Six1 is required for the early organogenesis of mammalian kidney. Development 130(14):3085-3094
367. Grifone R et al (2005) Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development 132(9):2235-2249
368. Self M et al (2006) Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J 25(21):5214-5228
369. Micalizzi DS et al (2009) The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest 119(9):2678-2690
370. McCoy EL et al (2009) Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. J Clin Invest 119(9):2663-2677
371. Gross MK et al (2000) Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127(2):413-424
372. Yu M et al (2009) A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev 23(15):1737-1742
373. Satoh K, Ginsburg E, Vonderhaar BK (2004) Msx-1 and Msx-2 in mammary gland development. J Mammary Gland Biol Neoplasia 9(2):195-205
374. Ramos C, Robert B (2005) msh/Msx gene family in neural development. Trends Genet 21(11):624-632
375. di Bari MG et al (2009) Msx2 induces epithelial-mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto-1. J Cell Physiol 219(3):659-666
376. Satoh K et al (2008) Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells. Am J Pathol 172(4):926-939
377. Wechselberger C et al (2001) Cripto-1 enhances migration and branching morphogenesis of mouse mammary epithelial cells. Exp Cell Res 266(1):95-105
378. Strizzi L et al (2004) Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J Cell Physiol 201(2):266-276
379. Blum M et al (1992) Gastrulation in the mouse: the role of the homeobox gene goosecoid. Cell 69(7):1097-1106
380. Niehrs C et al (1993) The homeobox gene goosecoid controls cell migration in Xenopus embryos. Cell 72(4):491-503
381. Niehrs C, Steinbeisser H, De Robertis EM (1994) Mesodermal patterning by a gradient of the vertebrate homeobox gene goosecoid. Science 263(5148):817-820
382. Hartwell KA et al (2006) The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci USA 103(50):18969-18974
383. Taube JH et al (2010) Core epithelial-to-mesenchymal transition interactome gene- expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA 107(35):15449-15454
384. Rogalla P et al (1996) HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors. Am J Pathol 149(3):775-779
385. Hirning-Folz U et al (1998) The expression pattern of the Hmgic gene during development. Genes Chromosomes Cancer 23(4):350-357
386. Monzen K et al (2008) A crucial role of a high mobility group protein HMGA2 in cardiogenesis. Nat Cell Biol 10(5):567-574
387. Rogalla P et al (1997) Expression of HMGI-C, a member of the high mobility group protein family, in a subset of breast cancers: relationship to histologic grade. Mol Carcinog 19(3):153-156
388. Abe N et al (2003) An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue. Br J Cancer 89(11):2104-2109
389. Meyer B et al (2007) HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog 46(7):503-511
390. Miyazawa J et al (2004) Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res 64(6):2024-2029
391. Thuault S et al (2008) HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 283(48):33437-33446
392. Reeves R, Nissen MS (1990) The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure. J Biol Chem 265(15):8573-8582
393. Thanos D, Maniatis T (1992) The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell 71(5):777-789
394. Fedele M et al (2006) HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell 9(6):459-471
395. Mantovani F et al (1998) NF-kappaB mediated transcriptional activation is enhanced by the architectural factor HMGI-C. Nucleic Acids Res 26(6):1433-1439
396. Cleynen I et al (2007) HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-kappaB. Mol Cancer Res 5(4):363-372
397. Hommura F et al (2004) HMG-I/Y is a c-Jun/activator protein-1 target gene and is necessary for c-Jun-induced anchorage-independent growth in Rat1a cells. Mol Cancer Res 2(5):305-314
398. Wood LJ et al (2000) HMG-I/Y, a new c-Myc target gene and potential oncogene. Mol Cell Biol 20(15):5490-5502
399. Cao R et al (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298(5595):1039-1043
400. Wang H et al (2004) Role of histone H2A ubiquitination in Polycomb silencing. Nature 431(7010):873-878
401. Sparmann A, van Lohuizen M (2006) Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6(11):846-856
402. Boyer LA et al (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441(7091):349-353
403. Ezhkova E et al (2009) Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136(6):1122-1135
404. van Lohuizen M et al (1991) Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65(5):737-752
405. Kim JH et al (2004) Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast 13(5):383-388
406. Yonemitsu Y et al (2009) Distinct expression of polycomb group proteins EZH2 and BMI1 in hepatocellular carcinoma. Hum Pathol 40(9):1304-1311
407. van Leenders GJ et al (2007) Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 52(2):455-463
408. He XT et al (2009) Association between Bmi1 and clinicopathological status of esophageal squamous cell carcinoma. World J Gastroenterol 15(19):2389-2394
409. Shafaroudi AM et al (2008) Overexpression of BMI1, a polycomb group repressor protein, in bladder tumors: a preliminary report. Urol J 5(2):99-105
410. Mihic-Probst D et al (2007) Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 121(8):1764-1770
411. Hoenerhoff MJ et al (2009) BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 28(34):3022-3032
412. Datta S et al (2007) Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth-regulatory pathways. Cancer Res 67(21):10286-10295
413. Yang MH et al (2010) Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 12(10):982-992
414. Song LB et al (2009) The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest 119(12):3626-3636
415. Su IH et al (2005) Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell 121(3):425-436
416. Cao Q et al (2008) Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27(58):7274-7284
417. Min J et al (2010) An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med 16(3):286-294
418. Peinado H et al (2004) Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117(Pt 13):2827-2839
419. Hugo HJ et al (2011) Defining the E-cadherin repressor interactome in epithelial- mesenchymal transition: the PMC42 model as a case study. Cells Tissues Organs 193(1-2):23-40
420. Weinberg RA (2008) Leaving home early: reexamination of the canonical models of tumor progression. Cancer Cell 14(4):283-284
421. Siomi H, Siomi MC (2010) Posttranscriptional regulation of microRNA biogenesis in animals. Mol Cell 38(3):323-332
422. Yanaihara N et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189-198
423. Iorio MV et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065-7070
424. Lee EJ et al (2007) Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 120(5):1046-1054
425. Ambs S et al (2008) Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 68(15):6162-6170
426. Lotterman CD, Kent OA, Mendell JT (2008) Functional integration of microRNAs into oncogenic and tumor suppressor pathways. Cell Cycle 7(16):2493-2499
427. Lu J et al (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043): 834-838
428. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2): 215-233
429. Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10(2):126-139
430. Gregory RI et al (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235-240
431. Yi R et al (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17(24):3011-3016
432. Hammond SM et al (2001) Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293(5532):1146-1150
433. Calin GA et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101(9):2999-3004
434. Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11(9):597-610
435. Kumar MS et al (2009) Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev 23(23):2700-2704
436. Lambertz I et al (2010) Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo. Cell Death Differ 17(4):633-641
437. Kumar MS et al (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39(5):673-677
438. Paroo Z et al (2009) Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling. Cell 139(1):112-122
439. Davis BN et al (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454(7200):56-61
440. Viswanathan SR, Daley GQ, Gregory RI (2008) Selective blockade of microRNA processing by Lin28. Science 320(5872):97-100
441. Newman MA, Thomson JM, Hammond SM (2008) Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14(8):1539-1549
442. Wang M et al (2011) Role of ribosomal protein RPS2 in controlling let-7a expression in human prostate cancer. Mol Cancer Res 9(1):36-50
443. Heo I et al (2009) TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell 138(4):696-708
444. Heo I et al (2008) Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell 32(2):276-284
445. Wang YC et al (2010) Lin-28B expression promotes transformation and invasion in human hepatocellular carcinoma. Carcinogenesis 31(9):1516-1522
446. Chang TC et al (2008) Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40(1):43-50
447. Mu P et al (2009) Genetic dissection of the miR-17 92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev 23(24):2806-2811
448. Sampson VB et al (2007) MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67(20):9762-9770
449. Park SM et al (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22(7):894-907
450. Korpal M et al (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283(22):14910-14914
451. Gregory PA et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593-601
452. Bracken CP et al (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68(19): 7846-7854
453. Xia H et al (2010) miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem Biophys Res Commun 391(1):535-541
454. Burk U et al (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9(6):582-589
455. Shimono Y et al (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138(3):592-603
456. Cochrane DR et al (2009) MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. Mol Cancer Ther 8(5):1055-1066
457. Olson P et al (2009) MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev 23(18):2152-2165
458. Gibbons DL et al (2009) Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev 23(18):2140-2151
459. Sossey-Alaoui K, Bialkowska K, Plow EF (2009) The miR200 family of microRNAs regulates WAVE3-dependent cancer cell invasion. J Biol Chem 284(48):33019-33029
460. Dykxhoorn DM et al (2009) miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One 4(9):e7181
461. Pasquinelli AE et al (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408(6808):86-89
462. Sempere LF et al (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5(3):R13
463. Lagos-Quintana M et al (2001) Identification of novel genes coding for small expressed RNAs. Science 294(5543):853-858
464. Grosshans H et al (2005) The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans. Dev Cell 8(3):321-330
465. Nam EJ et al (2008) MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 14(9):2690-2695
466. Motoyama K et al (2008) Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res 14(8):2334-2340
467. Schultz J et al (2008) MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res 18(5):549-557
468. Ozen M et al (2008) Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 27(12):1788-1793
469. Kumar MS et al (2008) Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 105(10):3903-3908
470. Johnson SM et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120(5):635-647
471. Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21(9):1025-1030
472. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315(5818):1576-1579
473. Shell S et al (2007) Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci USA 104(27):11400-11405
474. Watanabe S et al (2009) HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells. Am J Pathol 174(3):854-868
475. Dangi-Garimella S et al (2009) Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 28(4):347-358
476. Zhu J, Blenis J, Yuan J (2008) Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci USA 105(18):6584-6589
477. Nakagawa M et al (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101-106
478. Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861-872
479. Morel AP et al (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3(8):e2888
480. Yu F et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131(6):1109-1123
481. Kong W et al (2008) 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(22):6773-6784
482. Gebeshuber CA, Zatloukal K, Martinez J (2009) miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep 10(4):400-405
483. Asangani IA et al (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27(15):2128-2136
484. Lu Z et al (2008) MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27(31):4373-4379
485. Zhu S et al (2008) MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 18(3):350-359
486. Du J et al (2009) BMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1. Cell Res 19(4):487-496
487. Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449(7163):682-688
488. Ma L et al (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12(3):247-256
489. Baffa R et al (2009) MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol 219(2):214-221
490. Gee HE et al (2008) MicroRNA-10b and breast cancer metastasis. Nature 455(7216):E8-E9; author reply E9