Epithelial-mesenchymal transition-associated microRNAs in colorectal cancer and drug-targeted therapies (Review)

Oncology Reports

Volumn 33, Issue 2, 2015, Pages 515-525

  Jin, Dan Juan ^a   Fang, Yan Tian ^a   Li, Zhen Gyang ^a   Chen, Zongyou ^a   Xiang, Jian Bin ^a  

^a FUDAN UNIVERSITY   (China)

Author keywords

Colorectal cancer; Epithelial mesenchymal transition; microRNA

Indexed keywords

ANTAGOMIR; BETA CATENIN; EPIDERMAL GROWTH FACTOR RECEPTOR; FIBRONECTIN; LYMPHOID ENHANCER FACTOR 1; MICRORNA; MICRORNA 15A; MICRORNA 16 1; MICRORNA 200; MICRORNA 21; MICRORNA 31; MICRORNA 34; MOLECULAR MARKER; NERVE CELL ADHESION MOLECULE; NOTCH RECEPTOR; SMAD PROTEIN; SMALL UNTRANSLATED RNA; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; UVOMORULIN; VIMENTIN; WNT PROTEIN; ANTINEOPLASTIC AGENT;

BINDING AFFINITY; CANCER THERAPY; COLORECTAL CANCER; COMPLEX FORMATION; DISEASE ASSOCIATION; DRUG TARGETING; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; MOLECULAR PATHOLOGY; MOLECULARLY TARGETED THERAPY; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; COLORECTAL NEOPLASMS; DRUG EFFECTS; GENETICS; PATHOLOGY; PROCEDURES;

ANIMALS; ANTINEOPLASTIC AGENTS; COLORECTAL NEOPLASMS; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; MICRORNAS; MOLECULAR TARGETED THERAPY;

EID: 84919444114     PISSN: 1021335X     EISSN: 17912431     Source Type: Journal    
DOI: 10.3892/or.2014.3638     Document Type: Review

References (159)

1. Siegel R, Ma J, Zou Z and Jemal A: Cancer Statistics, 2014. CA Cancer J Clin 64: 9-29, 2014.
2. Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr opin Cell biol 15: 740-746, 2003.
3. Croce CM and Iorio MV: MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. EMBO Mol Med 4: 143-159, 2012.
4. Jeff JH and Yang J: Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 27: 2192-2206, 2013.
5. Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal-transitions. Nat Rev Mol Cell biol 7: 131-142, 2006.
6. Jang J and Weinberg RA: Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14: 818-829, 2008.
7. Pino MS, Kikuchi H, Zeng M, et al: Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 138: 1406-1417, 2010.
8. Savagner P: The epithelial-mesenchymal transition phenomenon. Ann oncol 21: 89-92, 2010.
9. Bonnomet A, Brysse A, Tachsidis A, et al: Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary gland biol Neoplasia 15: 261-273, 2010.
10. Lun H and Shourong S: EMT phenomenon and related microRNAs in the malignant progression of tumor. Chin oncol 21: 725-730, 2011.
11. Cavallaro U, Schaffhauser B, And Christofori G: Cadherins and the tumour progression: is it all in a switch? Cancer Lett 176: 123-128, 2002.
12. Saito Y, Takazawa H, Uzawa K, et al: Reduced expression of E-cadherin in oral squamous cell carcinoma: Relationship with DNA methylation of 5' Cpg island. Int J oncol 12: 293-298, 1998.
13. Lester RD, Jo M, Montel V, et al: uPAR induces epithelial-mesen-chymal transition in hypoxic breast cancer cells. J Cell biol 178: 425-436, 2007.
14. Berx G and Van Roy F: The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumoriGenesis and malignant progression. Breast Cancer Res 3: 289-293, 2001.
15. Canel M, Serrels A, Frame MC, et al: E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci 126: 393-401, 2013.
16. Derycke LD and Bracke ME: N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryoGenesis, invasion and signaling. Int J Dev biol 48: 463-476, 2004.
17. Hazan RB, Qiao R, Keren R, et al: Cadherin switch in tumor progression. Ann NY Acad Sci 1014: 155-163, 2004.
18. Rosivatz E, Becker I, Bamba M, et al: Neoexpression of N-cadherin in E-cadherin positive colon cancers. Int J Cancer 111: 711-719, 2004.
19. Colomiere M, Findlay J, Ackland L and Ahmed N: Epidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of alpha6betal integrin. Int J Biochem Cell Biol 41: 1034-1045, 2009.
20. Vora HH, Patel NA, Rajvik KN, et al: Cytokerain and vimentin expression in breast cancer. Int J biol Markers 24: 38-46, 2009.
21. Shirahata A, Sakata M, Sakuraba K, et al: Vimentin methylation as a marker or advanced colorectal carcinoma. Anticancer Res 29: 279-281, 2009.
22. Wei J, Xu G, Wu M, et al: overexpression of vimentin contributes to prostate cancer invasion and metastasis via src regulation. Anticancer Res 28: 327-334, 2008.
23. Pankov R and Yamada KM: Fibronectin at a glance. J Cell Science 115: 3861-3863, 2002.
24. Birchler MT, Milisavlijevic D, Pfaltz M, et al: Expression of the extra domain b of fbronectin, a marker of angioGenesis, in head and neck tumors. Laryngoscope 113: 1231-1237, 2003.
25. Cano A, Perez-Moreno MA, Rodrigo I, et al: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell biol 12: 76-83, 2000.
26. Hajra KM, Chen DY and Fearon ER: The SLug zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 62: 1613-1618, 2002.
27. Eger A, Aigner K, Sonderegger S, et al: DeltaEF1 is a transcrip-tional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24: 2375-2385, 2005.
28. Kim T, Veronese A, Pichiorri F, et al: p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEb1 and ZEb2. J Exp Med 208: 875-8832011.
29. Yang J, Mani SA, Donaher JL, et al: Twist, a master regulator of morphoGenesis, plays an essential role in tumor metastasis. Cell 117: 927-939, 2004.
30. Fang X, Cai Y, Liu J, et al: Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like cell self-renewal. Oncogene 30: 4707-4720, 2011.
31. Casas E, Kim J, Bendesky A, et al: Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res 71: 245-254, 2011.
32. Nusse R and Varmus HE: Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31: 99-109, 1982.
33. Kurayoshi M, Oue N, Yamamoto H, et al: Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res 66: 10439-10448, 2006.
34. Dissanayake SK, Wade M, Johnson CE, et al: The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem 282: 17259-17271, 2007.
35. Huelsken J and Behrens J: The Wnt signaling pathway. J Cell Sci 115: 3977-3978, 2002.
36. King TD, Zhang W, Suto MJ, et al: Frizzled7 as an emerging target for cancer therapy. Cell Signal 24: 846-851, 2012.
37. MacDonald BT, Tamai K and he X: Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17: 9-26, 2009.
38. Deka J, Wiedemann N, Anderle P, et al: Bcl9/Bcl9l are critical for Wnt-mediated regulation of stem cell traits in colon epithelium and adenocarcinomas. Cancer Res 70: 6619-6628, 2010.
39. Hlubek F, Spaderna S, Schmalhofer O, et al: Wnt/FZD signaling and colorectal cancer morphoGenesis. Front biosci 12: 458-470, 2007.
40. Beiter K, Hiendlmeyer E, Brabletz T, et al: Beta-catenin regulates the expression of tenascin-C in human colorectal tumors. Oncogene 24: 8200-8204, 2005.
41. Katsuno Y, Lamouille S and Derynck R: TgF-β signaling and epithelial-mesenchymal transition in cancer progression. Curr opin oncol 25: 76-84, 2013.
42. Watanabe Y, Itoh S, Goto T, et al: TMEPAI, A transmembrane TgF-beta-inducible protein, sequesters Smad proteins from active participation in TgF-beta signaling. Mol Cell 37: 123-134, 2010.
43. Shi Y and Massague J: Mechanisms of TgF-beta signaling from cell membrane to the nucleus. Cell 113: 685-700, 2003.
44. Tsukazaki T, Chiang TA, Davison AF, et al: SARA, A FYVE domain protein that recruits Smad2 to the TgFbeta receptor. Cell 95: 779-791, 1998.
45. Müller N, Reinacher-Schick A, Baldus S, et al: SMAD4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells. Oncogene 21: 6049-6058, 2002.
46. Mu Y, Gudey SK and Landström M: Non-SMAD signaling pathways. Cell Tissue Res 347: 11-20, 2012.
47. Hong M, Wilkes MC, Penheiter SG, et al: Non-Smad transforming growth factor-β signaling regulated by focal adhesion kinase binding the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem 286: 17841-17850, 2011.
48. Kang JS, Liu C and Derynck R: New regulatory mechanisms of TgF-beta receptor function. Trends Cell biol 19: 385-394, 2009.
49. Hartsough MT and Mulder KM: Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem 270: 7117-7124, 1995.
50. Park SS, Eom YW, Kim EH, et al: Involvement of c-Src kinase in the regulation of TgF-beta1-induced apoptosis. Oncogene 23: 6272-6281, 2004.
51. Yu L, Hebert MC and Zhang YE: TgF-beta receptor-activated p38 MAP kinase mediates Smad-independent TgF-beta responses. EMbo J 21: 3749-3759, 2002.
52. Timmerman LA, Grego bessa J, Raya A, et al: Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18: 99-115, 2004.
53. Leong KG, Niessen K, Kulic I, et al: Jagged l-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204: 2935-2948, 2007.
54. Sahlgren C, Gustafsson M V, Jin S, et al: Notch signaling mediates hypoxia induced tumor cell migration and invasion. Proc Natl Acad Sci uSA 105: 6392-6397, 2008.
55. Veenendaal LM, Kranenburg O, Smakman N, et al: Differential Notch and TgFbeta signaling in primary colorectal tumors and their corresponding metastases. Cell Oncol 30: 1-11, 2008.
56. Murone M, Rosenthal A and de Sauvage FJ: Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr biol 9: 76-84, 1999.
57. Chen JS, Huang XH, Wang Q, et al: Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer. CarcinoGenesis 34: 10-19, 2013.
58. Zhang H, Berezov A, Wang Q, et al: ErbB receptors: from Oncogenes to targeted cancer therapies. J Clin Invest 117: 2051-2058, 2007.
59. Oda K, Matsuoka Y, Funahashi A, et al: A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 1: 2005.0010, 2005.
60. Wu L, Fan J and Belasco JG: MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci uSA 103: 4034-4039, 2006.
61. Wienholds E, Koudijs MJ, Van Eeden FJ, et al: The microRNA-producing enzyme Dicer1 is essencial for zebrafsh development. Nat genet 35: 217-218, 2003.
62. Lee RC, Feinbaum RL and Ambros V: The C. elegans heter-ochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843-854, 1993.
63. Pasquinelli AE, Reinhart BJ, Slack F, et al: Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408: 86-89, 2000.
64. Fang Y, Shi C, Manduchi E, et al: MicroRNA-10a regulation of proinfammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci uSA 107: 13450-13455, 2010.
65. Tsai KW, Wu CW, Hu LY, et al: Epigenetic regulation of miR-34b and miR-129 expression in gastric cancer. Int J Cancer 129: 2600-2610, 2011
66. Yan W, Song g-X and Li Q: Advances in understanding the relationship between microRNAs and colorectal cancer. World Chin J Digestol 19: 3426-3431, 2011.
67. Ng EK, Chong W W, Jin H, et al: Differential expression of microRNAs in plasma of colorectal cancer patients: a potential marker for colorectal cancer screening. Gut 58: 1375-1381, 2009.
68. Lu J, Getz G, Miska EA, et al: MicroRNA expression profles classify human cancers. Nature 435: 834-838, 2005.
69. Calin GA, Sevignani C, Dumitru CD, et al: human microRNA Genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci uSA 101: 2999-3004, 2004.
70. Hurteau GJ, Carlson JA, Spivack SD, et al: overexpression of the microRNA has-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67: 7972-7976, 2007.
71. Gregory PA, Bert AG, Paterson EL, et al: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10: 593-601, 2008.
72. Park SM, Gaur AB, Lengyel E, et al: 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.
73. Burk U, Schubert J, Wellner U, et al: A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMbo Rep 9: 582-589, 2008.
74. Shell S, Park SM, Radjabi AR, et al: Let-7 expression defnes two differentiation stages of cancer. Proc Natl Acad Sci uSA 104: 11400-11405, 2007.
75. Liu X, Wang C, Chen Z, et al: MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma lines. Biochem J 440: 23-31, 2011.
76. Castilla MA, Moreno-bueno G, Romero-Perez L, et al: Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J Pathol 233: 72-80, 2011.
77. Li QQ, Chen ZQ, Cao XX, et al: Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells. Cell Death Differ 18: 16-25, 2011.
78. Meng Z, Fu X, Chen X, et al: miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology 52: 2148-2157, 2010.
79. Ma L, Teruya-Feldstein J and Weinberg RA: Tumor invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449: 682-688, 2007.
80. Kong W, Yang H, He L, et al: MicroRNA155 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.
81. Cottonham CL, Kaneko S and Xu L: miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem 285: 35293-35302, 2010.
82. Asangani IA, Rasheed SA, Nikolova DA, et al: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27: 2128-2136, 2008.
83. Wang P, Zho F, Zheng X, et al: microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res 69: 8157-8165, 2009.
84. Ma L, Young J, Prabhala H, et al: miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell biol 12: 247-256, 2010.
85. Vetter G, Saumet A, Moes M, et al: miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers. Oncogene 29: 4436-4448, 2010.
86. Castilla MA, Moreno-bueno G, Romero-Pérez L, et al: Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J Pathol 223: 72-80, 2011.
87. De Krijger I, Mekenkamp LJ, Punt CJ and Nagtegaal ID: MicroRNAs in colorectal cancer metastasis. J Pathol 224: 438-447, 2011.
88. Liu M and Chen H: The role of microRNAs in colorectal cancer. J genet genomics 37: 347-358, 2010.
89. Spaderna S, Schmalhofer O, Hlubek F, et al: A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 131: 830-840, 2006.
90. Spaderna S, Schmalhofer O, Wahlbuhl M, et al: The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 68: 537-544, 2008.
91. 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 repressors ZEB1 and ZEb2. J Biol Chem 283: 14910-14914, 2008.
92. Brabletz S and Brabletz T: The ZEb/miR-200 feedback loop-a motor of cellular plasticity in development and cancer? EMbo Rep 11: 670-677, 2010.
93. Fujita S, Ito T, Mizutani T, et al: miR-21 gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. J Mol Biol 378: 492-504, 2008.
94. Ferraro A, Kontos CK, Boni T, et al: Epigenetic regulation of miR-21 in colorectal cancer: ITgb4 as a novel miR-21 target and a three-gene network (miR-21-ITgΒ4-PDCD4) as predictor of metastatic tumor potential: Epigenetics 9: 129-141, 2014
95. Bommer GT, Gerin I, Feng Y, et al: p53-mediated activation of miRNA34 candidate tumor-suppressor Genes. Curr biol 17: 1298-1307, 2007
96. Chang TC, Wentzel EA, Kent OA, et al: Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26: 745-752, 2007
97. Yamakuchi M, Ferlito M and Lowenstein CJ: miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci uSA 105: 13421-13426, 2008.
98. Siemens H, Jackstadt R, Hünten S, et al: miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 10: 4256-4271, 2011.
99. Kim NH, Kim HS, Li XY, et al: A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell biol 195: 417-433, 2011.
100. Rokavec M, Oner MG, Li H, et al: IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 124: 1853-1867, 2014
101. Bandi N, Zbinden S, Gugger M, et al: miR-15a and miR16 are implicated in cell cycle regulation a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res 69: 5553-5559, 2009
102. Jackstadt R, Röh S, Neumann J, et al: AP4 is a mediator of epithelial-mesenchymal transition and metastasis in colorectal cancer. J Exp Med 210: 1331-1350, 2013.
103. Shi L, Jackstadt R, Siemens H, et al: p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. Cancer Res 74: 532-542, 2014
104. Dihlmann S, Siermann A and von Knebel Doeberitz M: The nonsteroidal anti-infammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene 20: 645-653, 2001.
105. Boon EM, Keller JJ, Wormhoudt TA, et al: Sulindac targets nuclear beta-catenin accumulation and Wnt signaling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br J Cancer 90: 224-229, 2004
106. Linna L and Shoujun Y Wnt/β-catenin signaling pathway and strategy of originating and treatment in colorectal cancer. World Chin J Digestol 14: 201-206, 2006.
107. Zhou L, An N, Haydon RC, et al: Tyrosine kinase inhibitor STI-571/gleevec down-regulatates the beta-catenin signaling activity. Cancer Lett 193: 161-170, 2003.
108. Green DW, Roh H, Pippin JA and Drebin JA: beta-catenin antisense treatment decreases beta-catenin expression and tumor growth rate in colon carcinoma xenografts. J Surg Res 101: 16-20, 2001.
109. Suzuki H, Watkins DN, Jair KW, et al: Epigenetic inactivation of SFRP Genes allows constitutive WNT signaling in colorectal cancer. Nat genet 36: 417-422, 2004.
110. Katz LH, Li Y, Chen JS, et al: Targeting TgF-β signaling in cancer. Expert opin Ther Targets 17: 743-760, 2013.
111. Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, et al: TgF-beta signaling in colon carcinoGenesis. Cancer Lett 314: 1-7, 2012.
112. Melisi D, Ishiyama S, Sclabas GM, et al: LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancteatic cancer metastasis. Mol Cancer Ther 7: 829-840, 2008.
113. Korpal M, Yan J, Lu X, et al: Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15: 960-966, 2009.
114. Zhang B, Halder SK, Zhang S and Datta PK: Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett 277: 114-120, 2009.
115. Connolly EC, Freimuth J and Akhurst RJ: Comlexities of TgF-β targeted cancer therapy. Int J biol Sci 8: 964-978, 2012.
116. Zhao BM and Hoffmann FM: Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Mol Biol Cell 17: 3819-3831, 2006.
117. Espinoza I, Pochampally R, Xing F, et al: Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther 6: 1249-1259, 2013.
118. Yan M and Plowman GD: Delta-like 4/Notch signaling and its therapeutic implications. Clin Cancer Res 13: 7243-7246, 2007.
119. Hayashi I, Takatori S, Urano Y, et al: Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin. Oncogene 31: 787-798, 2012.
120. Funahashi Y, Hernandez SL, Das I, et al: A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angioGenesis. Cancer Res 68: 4727-4735, 2008.
121. Tammam J, Ware C, Efferson C, et al: Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumor effects in mouse models of T-cell leukaemia. Br J Pharmacol 158: 1183-1195, 2009.
122. Fouladi M, Stewart CF, Olson J, et al: Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Clin oncol 29: 3529-3534, 2011.
123. Moellering RE, Cornejo M, Davis TN, et al: Direct inhibition of the NoTCh transcription factor complex. Nature 462: 182-188, 2009.
124. Zhou W, Kallifatidis G, Baumann B, et al: Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int J oncol 37: 551-561, 2010.
125. Kallifatidis G, Labsch S, Rausch V, et al: Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate. Mol Ther 19: 188-195, 2011.
126. Espinozal I and Miele L: Notch inhibitors for cancer treatment. Pharmacol Ther 139: 95-110, 2013.
127. Kelleher FC: hedgehog signaling and therapeutics in pancreatic cancer. CarcinoGenesis 32: 445-451, 2011.
128. Feldmann G, Dhara S, Fendrich V, et al: Blockade of Hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67: 2187-2196, 2007.
129. Agyeman A, Mazumdar T and houghton JA: Regulation of DNA damage following termination of hedgehog (hh) survival signaling at the level of the gLI Genes in human colon cancer. Oncotarget 3: 854-868, 2012.
130. Stecca B and Ruiz I Altaba A: Context-dependent regulation of the GLI code in cancer by Hedgehog and non-Hedgehog signals. J Mol Cell biol 2: 84-95, 2010.
131. Lauth M and Toftqard R: Non-canonical activation of gLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle 6: 2458-2463, 2007.
132. Hegan S, Orr MC and Doyle B: Targeted therapies in colorectal cancer-an integrative view by PPPM. EPMA J 4: 3, 2013.
133. Ebi H, Corcoran RB, Singh A, et al: Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest 121: 4311-4321, 2011.
134. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin oncol 25: 1658-1664, 2007.
135. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357: 2040-2048, 2007.
136. Van Cutsem E, Köhne CH, Lang I, et al: Cetuximab plus irinotecan, fuorouracil, and leucovorin as frst-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and bRAF mutation status. J Clin oncol 29: 2011-2019, 2011.
137. Heinemann V, Von Weikersthal LF, Decker T, et al: Randomized comparison of FoLFIRI plus cetuximab versus FoLFIRI plus bevacizumab as frst-line treatment of KRAS wild-type meta-static colorectal cancer: german AIo study KRK-0306 (FIRE-3). J Clin oncol 31: LbA3506 ASCo Annual Meeting, 2013.
138. Dassow H and Aigner A: MicroRNAs (miRNAs) in colorectal cancer: from aberrant expression towards therapy. Curr Pharm Des 19: 1242-1252, 2013.
139. Weiler J, Hunziker J and hall J: Anti-miRNA oligonucleotides (AMos): ammunition to target miRNAs implicated in human disease. Gene Ther 13: 496-502, 2006.
140. Garzon R, Marcucci G and Croce CM: Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9: 775-789, 2010.
141. Yang Z, Vilkaitis G, Yu B, et al: Approaches for studying MicroRNA and small interfering RNA methylation in vitro and in vivo. Methods Enzymol 427: 139-154, 2007.
142. Ørom UA, Kauppinen S and Lund AH: LNA-modifed oligo-nucleotides mediate specifc inhibition of microRNA function. Gene 10: 137-141, 2006.
143. Vester B and Wengel J: LNA (locked nucleic acid): high-affnity targeting of complementary RNA and DNA. Biochemistry 43: 13233-13241, 2004.
144. Krützfeldt J, Rajewsky N, Braich R, et al: Silencing of microRNAs in vivo with 'antagomirs'. Nature 438: 685-689, 2005.
145. Si ML, Zhu S, Wu H, et al: miR-21-mediated tumor growth. Oncogene 26: 2799-2803, 2007.
146. Corsten MF, Miranda R, Kasmieh R, et al: MicroRNA-21 knockdown disrupts glioma growth in vivo and displays syner-gistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res 67: 8994-9000, 2007.
147. Meng F, Henson R, Lang M, et al: Involvement of human microRNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 130: 2113-2129, 2006.
148. Ebert MS, Neilson JR and Sharp PA: MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4: 721-726, 2007.
149. Ebert MS and Sharp PA: MicroRNA sponges: progress and possibilities. RNA 16: 2043-2050, 2010.
150. Valastyan S, Reinhardt F, Benaich N, et al: A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137: 1032-1046, 2009.
151. Xiao J, Yang B, Lin H, et al: Novel approaches for gene-specifc interference via manipulating actions of microRNAs: examination on the pacemaker channel Genes hCN2 and hCN4. J Cell Physiol 212: 285-292, 2007.
152. Gumireddy K, Young DD, Xiong X, et al: Small-molecule inhibitors of microrna miR-21 function. Angew Chem Int Ed Engl 47: 7482-7484, 2008.
153. Lennox KA and Behlke MA: Chemical modifcation and design of anti-miRNA oligonucleotides. Gene Ther 18: 1111-1120, 2011.
154. Yang N, Kaur S, Volinia S, et al: MicroRNA microarray identifes Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer. Cancer Res 68: 10307-10314, 2008.
155. Kumar MS, Erkeland SJ, Pester RE, et al: Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci uSA 105: 3903-3908, 2008.
156. Bonci D, Coppola V, Musumeci M, et al: The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14: 1271-1277, 2008.
157. Wiggins JF, Ruffno L, Kelnar K, et al: Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 70: 5923-5930, 2010.
158. Chen Y, Zhu X, Zhang X, et al: Nanoparticles modifed with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol Ther 18: 1650-1656, 2010.
159. La Rocca G, Badin M, Shi B, et al: Mechanism of growth inhibition by MicroRNA 145: the role of the IgF-1 receptor signaling pathway. J Cell Physiol 220: 485-491, 2009.