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Stem Cells International
Volume 2016, Article ID 5285892, 10 pages
http://dx.doi.org/10.1155/2016/5285892
Review Article

Tackling Cancer Stem Cells via Inhibition of EMT Transcription Factors

1Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11790, USA
2Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA
3Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA

Received 30 June 2016; Accepted 3 October 2016

Academic Editor: Robert Gourdie

Copyright © 2016 Megan Mladinich et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. V. J. Findlay, C. Wang, D. K. Watson, and E. R. Camp, “Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer,” Cancer Gene Therapy, vol. 21, no. 5, pp. 181–187, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. L. Vermeulen, M. Todaro, F. De Sousa Mello et al., “Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 36, pp. 13427–13432, 2008. View at Publisher · View at Google Scholar · View at Scopus
  3. S. A. Mani, W. Guo, M.-J. Liao et al., “The epithelial-mesenchymal transition generates cells with properties of stem cells,” Cell, vol. 133, no. 4, pp. 704–715, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. S. H. Sahlberg, D. Spiegelberg, B. Glimelius, B. Stenerlöw, and M. Nestor, “Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells,” PLoS ONE, vol. 9, no. 4, article e94621, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. T. Woo, K. Okudela, H. Mitsui et al., “Prognostic value of CD133 expression in stage I lung adenocarcinomas,” International Journal of Clinical and Experimental Pathology, vol. 4, no. 1, pp. 32–42, 2010. View at Google Scholar · View at Scopus
  6. R. Pallini, L. Ricci-Vitiani, G. L. Banna et al., “Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme,” Clinical Cancer Research, vol. 14, no. 24, pp. 8205–8212, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Shipitsin, L. L. Campbell, P. Argani et al., “Molecular definition of breast tumor heterogeneity,” Cancer Cell, vol. 11, no. 3, pp. 259–273, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. L. V. Nguyen, R. Vanner, P. Dirks, and C. J. Eaves, “Cancer stem cells: an evolving concept,” Nature Reviews Cancer, vol. 12, no. 2, pp. 133–143, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. K. Rycaj and D. G. Tang, “Cell-of-origin of cancer versus cancer stem cells: assays and interpretations,” Cancer Research, vol. 75, no. 19, pp. 4003–4011, 2015. View at Publisher · View at Google Scholar · View at Scopus
  10. D. A. Lawson, N. R. Bhakta, K. Kessenbrock et al., “Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells,” Nature, vol. 526, no. 7571, pp. 131–135, 2015. View at Publisher · View at Google Scholar · View at Scopus
  11. A. Kreso and J. E. Dick, “Evolution of the cancer stem cell model,” Cell Stem Cell, vol. 14, no. 3, pp. 275–291, 2014. View at Publisher · View at Google Scholar · View at Scopus
  12. P. Dalerba, T. Kalisky, D. Sahoo et al., “Single-cell dissection of transcriptional heterogeneity in human colon tumors,” Nature Biotechnology, vol. 29, no. 12, pp. 1120–1127, 2011. View at Publisher · View at Google Scholar · View at Scopus
  13. K. Ito, A. Carracedo, D. Weiss et al., “A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance,” Nature Medicine, vol. 18, no. 9, pp. 1350–1358, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. T. Suda, K. Takubo, and G. L. Semenza, “Metabolic regulation of hematopoietic stem cells in the hypoxic niche,” Cell Stem Cell, vol. 9, no. 4, pp. 298–310, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. N. A. Dallas, L. Xia, F. Fan et al., “Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition,” Cancer Research, vol. 69, no. 5, pp. 1951–1957, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. C. A. O'Brien, A. Pollett, S. Gallinger, and J. E. Dick, “A human colon cancer cell capable of initiating tumour growth in immunodeficient mice,” Nature, vol. 445, no. 7123, pp. 106–110, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. A. Kreso, C. A. O'Brien, P. Van Galen et al., “Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer,” Science, vol. 339, no. 6119, pp. 543–548, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. M. P. Ponnusamy and S. K. Batra, “Ovarian cancer: emerging concept on cancer stem cells,” Journal of Ovarian Research, vol. 1, article 4, 2008. View at Publisher · View at Google Scholar
  19. M. Al-Hajj, M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F. Clarke, “Prospective identification of tumorigenic breast cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 3983–3988, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. W. Matsui, C. A. Huff, Q. Wang et al., “Characterization of clonogenic multiple myeloma cells,” Blood, vol. 103, no. 6, pp. 2332–2336, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. T. Lapidot, C. Sirard, J. Vormoor et al., “A cell initiating human acute myeloid leukaemia after transplantation into SCID mice,” Nature, vol. 367, no. 6464, pp. 645–648, 1994. View at Publisher · View at Google Scholar · View at Scopus
  22. D. Bonnet and J. E. Dick, “Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell,” Nature Medicine, vol. 3, no. 7, pp. 730–737, 1997. View at Publisher · View at Google Scholar · View at Scopus
  23. V. Plaks, N. Kong, and Z. Werb, “The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?” Cell Stem Cell, vol. 16, no. 3, pp. 225–238, 2015. View at Publisher · View at Google Scholar · View at Scopus
  24. H. F. Dvorak, “Tumors: wounds that do not heal: similarities between tumor stroma generation and wound healing,” New England Journal of Medicine, vol. 315, no. 26, pp. 1650–1659, 1986. View at Publisher · View at Google Scholar · View at Scopus
  25. M. J. Bissell, H. G. Hall, and G. Parry, “How does the extracellular matrix direct gene expression?” Journal of Theoretical Biology, vol. 99, no. 1, pp. 31–68, 1982. View at Publisher · View at Google Scholar · View at Scopus
  26. X. Zheng, J. L. Carstens, J. Kim et al., “Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer,” Nature, vol. 527, no. 7579, pp. 525–530, 2015. View at Publisher · View at Google Scholar · View at Scopus
  27. R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. J. P. Thiery and J. P. Sleeman, “Complex networks orchestrate epithelial-mesenchymal transitions,” Nature Reviews Molecular Cell Biology, vol. 7, no. 2, pp. 131–142, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. B. Toh, X. Wang, J. Keeble et al., “Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor,” PLoS Biology, vol. 9, no. 9, Article ID e1001162, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Cano, M. A. Pérez-Moreno, I. Rodrigo et al., “The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression,” Nature Cell Biology, vol. 2, no. 2, pp. 76–83, 2000. View at Publisher · View at Google Scholar · View at Scopus
  31. J. A. Efstathiou, D. Liu, J. M. D. Wheeler et al., “Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 5, pp. 2316–2321, 1999. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Woischke, C. Blaj, E. M. Schmidt et al., “CYB5R1 links epithelial-mesenchymal transition and poor prognosis in colorectal cancer,” Oncotarget, vol. 7, no. 21, pp. 31350–31360, 2016. View at Google Scholar
  33. M. H. Jang, H. J. Kim, E. J. Kim, Y. R. Chung, and S. Y. Park, “Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome,” Human Pathology, vol. 46, no. 9, pp. 1267–1274, 2015. View at Publisher · View at Google Scholar · View at Scopus
  34. M. M. Javle, J. F. Gibbs, K. K. Iwata et al., “Epithelial-Mesenchymal Transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer,” Annals of Surgical Oncology, vol. 14, no. 12, pp. 3527–3533, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Dima, V. Pecce, M. Biffoni et al., “Molecular profiles of cancer stem-like cell populations in aggressive thyroid cancers,” Endocrine, vol. 53, no. 1, pp. 145–156, 2016. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Alonso-Alconada, L. Muinelo-Romay, K. Madissoo et al., “Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer,” Molecular Cancer, vol. 13, no. 1, article 223, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. F. Tomao, A. Papa, S. Martina et al., “Investigating molecular profiles of ovarian cancer: an update on cancer stem cells,” Journal of Cancer, vol. 5, no. 5, pp. 301–310, 2014. View at Publisher · View at Google Scholar · View at Scopus
  38. T. A. DiMeo, K. Anderson, P. Phadke et al., “A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer,” Cancer Research, vol. 69, no. 13, pp. 5364–5373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. B. C. Fuchs, T. Fujii, J. D. Dorfman et al., “Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells,” Cancer Research, vol. 68, no. 7, pp. 2391–2399, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. K. Polyak and R. A. Weinberg, “Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits,” Nature Reviews Cancer, vol. 9, no. 4, pp. 265–273, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. I. Fabregat, A. Malfettone, and J. Soukupova, “New insights into the crossroads between EMT and stemness in the context of cancer,” Journal of Clinical Medicine, vol. 5, no. 3, article 37, 2016. View at Publisher · View at Google Scholar
  42. N. McCormack and S. O'Dea, “Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins,” Cellular Signalling, vol. 25, no. 12, pp. 2856–2862, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. J.-Y. Yang, C. S. Zong, W. Xia et al., “MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation,” Molecular and Cellular Biology, vol. 26, no. 19, pp. 7269–7282, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Puisieux, T. Brabletz, and J. Caramel, “Oncogenic roles of EMT-inducing transcription factors,” Nature Cell Biology, vol. 16, no. 6, pp. 488–494, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. H. Zheng and Y. Kang, “Multilayer control of the EMT master regulators,” Oncogene, vol. 33, no. 14, pp. 1755–1763, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Garg, “Epithelial-mesenchymal transition-activating transcription factors-multifunctional regulators in cancer,” World Journal of Stem Cells, vol. 5, no. 4, pp. 188–195, 2013. View at Publisher · View at Google Scholar
  47. S. A. Mani, J. Yang, M. Brooks et al., “Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 24, pp. 10069–10074, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. G. Z. Cheng, J. Chan, Q. Wang, W. Zhang, C. D. Sun, and L.-H. Wang, “Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel,” Cancer Research, vol. 67, no. 5, pp. 1979–1987, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. K. A. Hartwell, B. Muir, F. Reinhardt, A. E. Carpenter, D. C. Sgroi, and R. A. Weinberg, “The Spemann organizer gene, Goosecoid, promotes tumor metastasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 50, pp. 18969–18974, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Lamouille, J. Xu, and R. Derynck, “Molecular mechanisms of epithelial-mesenchymal transition,” Nature Reviews Molecular Cell Biology, vol. 15, no. 3, pp. 178–196, 2014. View at Publisher · View at Google Scholar · View at Scopus
  51. W. Guo, Z. Keckesova, J. L. Donaher et al., “Slug and Sox9 cooperatively determine the mammary stem cell state,” Cell, vol. 148, no. 5, pp. 1015–1028, 2012. View at Publisher · View at Google Scholar · View at Scopus
  52. J. Fu, L. Qin, T. He et al., “The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis,” Cell Research, vol. 21, no. 2, pp. 275–289, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. E. Batlle, E. Sancho, C. Franci et al., “The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells,” Nature Cell Biology, vol. 2, no. 2, pp. 84–89, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Peinado, E. Ballestar, M. Esteller, and A. Cano, “Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex,” Molecular and Cellular Biology, vol. 24, no. 1, pp. 306–319, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. V. Bolós, H. Peinado, M. A. Pérez-Moreno, M. F. Fraga, M. Esteller, and A. Cano, “The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors,” Journal of Cell Science, vol. 116, no. 3, pp. 499–511, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. W. Zhou, R. Lv, W. Qi et al., “Snail contributes to the maintenance of stem cell-like phenotype cells in human pancreatic cancer,” PLoS ONE, vol. 9, no. 1, article e87409, 2014. View at Publisher · View at Google Scholar · View at Scopus
  57. Y.-N. Liu, J. J. Yin, W. Abou-Kheir et al., “MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms,” Oncogene, vol. 32, no. 3, pp. 296–306, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. T. A. Proia, P. J. Keller, P. B. Gupta et al., “Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate,” Cell Stem Cell, vol. 8, no. 2, pp. 149–163, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. N. K. Kurrey, S. P. Jalgaonkar, A. V. Joglekar et al., “Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells,” Stem Cells, vol. 27, no. 9, pp. 2059–2068, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. J. Yang, S. A. Mani, J. L. Donaher et al., “Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis,” Cell, vol. 117, no. 7, pp. 927–939, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. E. Casas, J. Kim, A. Bendesky, L. Ohno-Machado, C. J. Wolfe, and J. Yang, “Snail2 is an essential mediator of twist1-induced epithelial mesenchymal transition and metastasis,” Cancer Research, vol. 71, no. 1, pp. 245–254, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. F. Yang, L. Sun, Q. Li et al., “SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities,” EMBO Journal, vol. 31, no. 1, pp. 110–123, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. M.-H. Yang, D. S.-S. Hsu, H.-W. Wang et al., “Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition,” Nature Cell Biology, vol. 12, no. 10, pp. 982–992, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. N. Dave, S. Guaita-Esteruelas, S. Gutarra et al., “Functional cooperation between snail1 and twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition,” Journal of Biological Chemistry, vol. 286, no. 14, pp. 12024–12032, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. U. Wellner, J. Schubert, U. C. Burk et al., “The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs,” Nature Cell Biology, vol. 11, no. 12, pp. 1487–1495, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. B.-T. Preca, K. Bajdak, K. Mock et al., “A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells,” International Journal of Cancer, vol. 137, no. 11, pp. 2566–2577, 2015. View at Publisher · View at Google Scholar · View at Scopus
  67. P. Zhang, Y. Sun, and L. Ma, “ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance,” Cell Cycle, vol. 14, no. 4, pp. 481–487, 2015. View at Publisher · View at Google Scholar · View at Scopus
  68. T. Imai, A. Horiuchi, C. Wang et al., “Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells,” American Journal of Pathology, vol. 163, no. 4, pp. 1437–1447, 2003. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Sahlgren, M. V. Gustafsson, S. Jin, L. Poellinger, and U. Lendahl, “Notch signaling mediates hypoxia-induced tumor cell migration and invasion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 17, pp. 6392–6397, 2008. View at Publisher · View at Google Scholar · View at Scopus
  70. O. M. Martínez-Estrada, L. A. Lettice, A. Essafi et al., “Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin,” Nature Genetics, vol. 42, no. 1, pp. 89–93, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. V. B. Sampson, J. M. David, I. Puig et al., “Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma,” PLoS ONE, vol. 9, no. 7, article e102041, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. J. Hu, H. Guo, H. Li et al., “MiR-145 regulates epithelial to mesenchymal transition of breast cancer cells by targeting Oct4,” PLoS ONE, vol. 7, no. 9, Article ID e45965, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. R. Li, J. Liang, S. Ni et al., “A mesenchymal-to-Epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts,” Cell Stem Cell, vol. 7, no. 1, pp. 51–63, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Pérez-Losada, M. Sánchez-Martín, M. Pérez-Caro, P. A. Pérez-Mancera, and I. Sánchez-García, “The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug,” Oncogene, vol. 22, no. 27, pp. 4205–4211, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. B. Tanno, F. Sesti, V. Cesi et al., “Expression of slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin,” Journal of Biological Chemistry, vol. 285, no. 38, pp. 29434–29445, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. Y.-N. Liu, W. Abou-Kheir, J. J. Yin et al., “Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition,” Molecular and Cellular Biology, vol. 32, no. 5, pp. 941–953, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. C.-W. Li, W. Xia, L. Huo et al., “Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1,” Cancer Research, vol. 72, no. 5, pp. 1290–1300, 2012. View at Publisher · View at Google Scholar · View at Scopus
  78. K.-W. Hsu, R.-H. Hsieh, K.-H. Huang et al., “Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression,” Carcinogenesis, vol. 33, no. 8, pp. 1459–1467, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. Z.-F. Chen and R. R. Behringer, “Twist is required in head mesenchyme for cranial neural tube morphogenesis,” Genes and Development, vol. 9, no. 6, pp. 686–699, 1995. View at Publisher · View at Google Scholar · View at Scopus
  80. M.-H. Yang, M.-Z. Wu, S.-H. Chiou et al., “Direct regulation of TWIST by HIF-1α promotes metastasis,” Nature Cell Biology, vol. 10, no. 3, pp. 295–305, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. E. L. Spaeth, A. M. Labaff, B. P. Toole, A. Klopp, M. Andreeff, and F. C. Marini, “Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment,” Cancer Research, vol. 73, no. 17, pp. 5347–5359, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. S. M. Elbashir, J. Martinez, A. Patkaniowska, W. Lendeckel, and T. Tuschl, “Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate,” EMBO Journal, vol. 20, no. 23, pp. 6877–6888, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. S. M. Elbashir, W. Lendeckel, and T. Tuschl, “RNA interference is mediated by 21- and 22-nucleotide RNAs,” Genes and Development, vol. 15, no. 2, pp. 188–200, 2001. View at Publisher · View at Google Scholar · View at Scopus
  84. G. Grelier, N. Voirin, A.-S. Ay et al., “Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype,” British Journal of Cancer, vol. 101, no. 4, pp. 673–683, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. N. H. Kim, H. S. Kim, X.-Y. Li et al., “A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition,” Journal of Cell Biology, vol. 195, no. 3, pp. 417–433, 2011. View at Publisher · View at Google Scholar · View at Scopus
  86. H. Siemens, R. Jackstadt, S. Hünten et al., “miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions,” Cell Cycle, vol. 10, no. 24, pp. 4256–4271, 2011. View at Publisher · View at Google Scholar · View at Scopus
  87. P. Bu, K.-Y. Chen, J. H. Chen et al., “A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells,” Cell Stem Cell, vol. 12, no. 5, pp. 602–615, 2013. View at Publisher · View at Google Scholar · View at Scopus
  88. C. Moyret-Lalle, E. Ruiz, and A. Puisieux, “Epithelial-mesenchymal transition transcription factors and miRNAs: ‘Plastic surgeons’ of breast cancer,” World Journal of Clinical Oncology, vol. 5, no. 3, pp. 311–322, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. R. Kumarswamy, G. Mudduluru, P. Ceppi et al., “MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer,” International Journal of Cancer, vol. 130, no. 9, pp. 2044–2053, 2012. View at Publisher · View at Google Scholar · View at Scopus
  90. S. Liu, S. M. Kumar, H. Lu et al., “MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1-Snail1 pathway in melanoma,” Journal of Pathology, vol. 226, no. 1, pp. 61–72, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. C. Jin, B. Yan, Q. Lu, Y. Lin, and L. Ma, “The role of MALAT1/miR-1/slug axis on radioresistance in nasopharyngeal carcinoma,” Tumor Biology, vol. 37, no. 3, pp. 4025–4033, 2016. View at Publisher · View at Google Scholar · View at Scopus
  92. H. Xia, W. K. C. Cheung, S. S. Ng et al., “Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells,” Journal of Biological Chemistry, vol. 287, no. 13, pp. 9962–9971, 2012. View at Publisher · View at Google Scholar · View at Scopus
  93. Z. Zhang, B. Zhang, W. Li et al., “Epigenetic silencing of miR-203 upregulates SNAI2 and Contributes to the invasiveness of malignant breast cancer cells,” Genes and Cancer, vol. 2, no. 8, pp. 782–791, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. F. E. Wang, C. Zhang, A. Maminishkis et al., “MicroRNA-204/211 alters epithelial physiology,” FASEB Journal, vol. 24, no. 5, pp. 1552–1571, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. M. R. Lee, J. S. Kim, and K.-S. Kim, “MiR-124a is important for migratory cell fate transition during gastrulation of human embryonic stem cells,” Stem Cells, vol. 28, no. 9, pp. 1550–1559, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. B. Li, Q. Han, Y. Zhu, Y. Yu, J. Wang, and X. Jiang, “Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist,” FEBS Journal, vol. 279, no. 13, pp. 2393–2398, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. M.-L. Nairismägi, A. Vislovukh, Q. Meng et al., “Translational control of TWIST1 expression in MCF-10A cell lines recapitulating breast cancer progression,” Oncogene, vol. 31, no. 47, pp. 4960–4966, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. C.-J. Chang, C.-C. Hsu, C.-H. Chang et al., “Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer,” Oncology Reports, vol. 26, no. 4, pp. 1003–1010, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. E. Sánchez-Tilló, Y. Liu, O. De Barrios et al., “EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness,” Cellular and Molecular Life Sciences, vol. 69, no. 20, pp. 3429–3456, 2012. View at Publisher · View at Google Scholar · View at Scopus
  100. C. Liu, K. Kelnar, B. Liu et al., “The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44,” Nature Medicine, vol. 17, no. 2, pp. 211–216, 2011. View at Publisher · View at Google Scholar · View at Scopus
  101. P. Trang, J. F. Wiggins, C. L. Daige et al., “Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice,” Molecular Therapy, vol. 19, no. 6, pp. 1116–1122, 2011. View at Publisher · View at Google Scholar · View at Scopus
  102. Z. Yang, S. Rayala, D. Nguyen, R. K. Vadlamudi, S. Chen, and R. Kumar, “Pak1 phosphorylation of Snail, a master regulator of epithelial-to- mesenchyme transition, modulates Snail's subcellular localization and functions,” Cancer Research, vol. 65, no. 8, pp. 3179–3184, 2005. View at Google Scholar · View at Scopus
  103. K. Zhang, E. Rodriguez-Aznar, N. Yabuta et al., “Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation,” EMBO Journal, vol. 31, no. 1, pp. 29–43, 2012. View at Publisher · View at Google Scholar · View at Scopus
  104. C. Du, C. Zhang, S. Hassan, M. H. U. Biswas, and K. C. Balaji, “Protein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail,” Cancer Research, vol. 70, no. 20, pp. 7810–7819, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. B. N. Smith, L. J. Burton, V. Henderson et al., “Snail promotes epithelial mesenchymal transition in breast cancer cells in part via activation of nuclear ERK2,” PLoS ONE, vol. 9, no. 8, Article ID e104987, 2014. View at Publisher · View at Google Scholar · View at Scopus
  106. J. I. Yook, X.-Y. Li, I. Ota et al., “A Wnt-Axin2-GSK3β cascade regulates Snail1 activity in breast cancer cells,” Nature Cell Biology, vol. 8, no. 12, pp. 1398–1406, 2006. View at Publisher · View at Google Scholar · View at Scopus
  107. C. W. Li, W. Xia, S. O. Lim et al., “AKT1 inhibits epithelial-to-mesenchymal transition in breast cancer through phosphorylation-dependent twist1 degradation,” Cancer Research, vol. 76, no. 6, pp. 1451–1462, 2016. View at Publisher · View at Google Scholar
  108. J. Zhong, K. Ogura, Z. Wang, and H. Inuzuka, “Degradation of the transcription factor twist, an oncoprotein that promotes cancer metastasis,” Discovery Medicine, vol. 15, no. 80, pp. 7–15, 2013. View at Google Scholar · View at Scopus
  109. R. Lander, T. Nasr, S. D. Ochoa, K. Nordin, M. S. Prasad, and C. Labonne, “Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation,” Nature Communications, vol. 4, article 1542, 2013. View at Publisher · View at Google Scholar · View at Scopus
  110. J. Hong, J. Zhou, J. Fu et al., “Phosphorylation of serine 68 of twist1 by MAPKs stabilizes twist1 protein and promotes breast cancer cell invasiveness,” Cancer Research, vol. 71, no. 11, pp. 3980–3990, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. R. Lander, K. Nordin, and C. LaBonne, “The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1,” Journal of Cell Biology, vol. 194, no. 1, pp. 17–25, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. J. Shi, Y. Wang, L. Zeng et al., “Disrupting the interaction of BRD4 with diacetylated twist suppresses tumorigenesis in basal-like breast cancer,” Cancer Cell, vol. 25, no. 2, pp. 210–225, 2014. View at Publisher · View at Google Scholar · View at Scopus
  113. S.-P. Wang, W.-L. Wang, Y.-L. Chang et al., “p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug,” Nature Cell Biology, vol. 11, no. 6, pp. 694–704, 2009. View at Publisher · View at Google Scholar · View at Scopus
  114. H. Zheng, M. Shen, Y.-L. Zha et al., “PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis,” Cancer Cell, vol. 26, no. 3, pp. 358–373, 2014. View at Publisher · View at Google Scholar · View at Scopus
  115. M. Y. Shah and G. A. Calin, “MicroRNAs as therapeutic targets in human cancers,” Wiley Interdisciplinary Reviews: RNA, vol. 5, no. 4, pp. 537–548, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. X. Zhao, F. Pan, C. M. Holt, A. L. Lewis, and J. R. Lu, “Controlled delivery of antisense oligonucleotides: a brief review of current strategies,” Expert Opinion on Drug Delivery, vol. 6, no. 7, pp. 673–686, 2009. View at Publisher · View at Google Scholar · View at Scopus
  117. R. Garzon, G. Marcucci, and C. M. Croce, “Targeting microRNAs in cancer: rationale, strategies and challenges,” Nature Reviews Drug Discovery, vol. 9, no. 10, pp. 775–789, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. N. M. Weathington and R. K. Mallampalli, “Emerging therapies targeting the ubiquitin proteasome system in cancer,” Journal of Clinical Investigation, vol. 124, no. 1, pp. 6–12, 2014. View at Publisher · View at Google Scholar · View at Scopus
  119. Z. J. Chen, “Ubiquitination in signaling to and activation of IKK,” Immunological Reviews, vol. 246, no. 1, pp. 95–106, 2012. View at Google Scholar · View at Scopus
  120. C. H. Chan, U. Jo, A. Kohrman et al., “Posttranslational regulation of Akt in human cancer,” Cell & Bioscience, vol. 4, no. 1, article 59, 2014. View at Publisher · View at Google Scholar
  121. H. Lee, C. Li, D. Ruan et al., “The DNA damage transducer RNF8 facilitates cancer chemoresistance and progression through twist activation,” Molecular Cell, vol. 63, no. 6, pp. 1021–1033, 2016. View at Publisher · View at Google Scholar
  122. B. Beck, G. Lapouge, S. Rorive et al., “Different levels of Twist1 regulate skin tumor initiation, stemness, and progression,” Cell Stem Cell, vol. 16, no. 1, pp. 67–79, 2015. View at Publisher · View at Google Scholar · View at Scopus
  123. J. M. Schmidt, E. Panzilius, H. S. Bartsch et al., “Stem-cell-like properties and epithelial plasticity arise as stable traits after transient twist1 activation,” Cell Reports, vol. 10, no. 2, pp. 131–139, 2015. View at Publisher · View at Google Scholar · View at Scopus