Skip to main content

Advertisement

SpringerLink
Log in

EMT signaling: potential contribution of CRISPR/Cas gene editing

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Epithelial to mesenchymal transition (EMT) is a complex plastic and reversible cellular process that has critical roles in diverse physiological and pathological phenomena. EMT is involved in embryonic development, organogenesis and tissue repair, as well as in fibrosis, cancer metastasis and drug resistance. In recent years, the ability to edit the genome using the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system has greatly contributed to identify or validate critical genes in pathway signaling. This review delineates the complex EMT networks and discusses recent studies that have used CRISPR/Cas technology to further advance our understanding of the EMT process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18:128–134

    CAS  PubMed  Google Scholar 

  2. Nieto MA, Huang RY, Jackson RA, Thiery JP (2016) Emt: 2016. Cell 166:21–45

    CAS  PubMed  Google Scholar 

  3. Lu W, Kang Y (2019) Epithelial–mesenchymal plasticity in cancer progression and metastasis. Dev Cell 49:361–374

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chu YS et al (2006) Prototypical type I E-cadherin and type II cadherin-7 mediate very distinct adhesiveness through their extracellular domains. J Biol Chem 281:2901–2910

    CAS  PubMed  Google Scholar 

  5. Pal M, Bhattacharya S, Kalyan G, Hazra S (2018) Cadherin profiling for therapeutic interventions in epithelial mesenchymal transition (EMT) and tumorigenesis. Exp Cell Res 368:137–146

    CAS  PubMed  Google Scholar 

  6. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    CAS  PubMed  Google Scholar 

  7. Puisieux A, Brabletz T, Caramel J (2014) Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol 16:488–494

    CAS  PubMed  Google Scholar 

  8. Kim DH, Xing T, Yang Z, Dudek R, Lu Q, Chen Y-H (2018) Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: a comprehensive overview. J Clin Med 7:1

    Google Scholar 

  9. Suhail Y, Cain MP, Vanaja K, Kurywchak PA, Levchenko A, Kalluri R (2019) Systems biology of cancer metastasis. Cell Syst 9:109–127

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629

    PubMed  PubMed Central  Google Scholar 

  11. Tsuji T, Ibaragi S, Hu GF (2009) Epithelial–mesenchymal transition and cell cooperativity in metastasis. Cancer Res 69:7135–7139

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis. Cancer Cell 20:576–590

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580–584

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Aceto N et al (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:1110–1122

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Szczerba BM et al (2019) Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 566:553–557

    CAS  PubMed  Google Scholar 

  16. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    CAS  PubMed  Google Scholar 

  17. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Huber V et al (2017) Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol 43:74–89

    CAS  PubMed  Google Scholar 

  19. Peppicelli S et al (2017) The acidic microenvironment as a possible niche of dormant tumor cells. Cell Mol Life Sci 74:2761–2771

    CAS  PubMed  Google Scholar 

  20. Samanta D, Semenza GL (2018) Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors. Biochim Biophys Acta Rev Cancer 1870:15–22

    CAS  PubMed  Google Scholar 

  21. Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2:758–770

    PubMed  Google Scholar 

  22. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10:295–305

    CAS  PubMed  Google Scholar 

  23. Mathieu J, Zhang Z, Nelson A, Lamba DA, Reh TA, Ware C, Ruohola-Baker H (2013) Hypoxia induces re-entry of committed cells into pluripotency. Stem Cells 31:1737–1748

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Azimi I, Petersen RM, Thompson EW, Roberts-Thomson SJ, Monteith GR (2017) Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells. Sci Rep 7:15140

    PubMed  PubMed Central  Google Scholar 

  25. Azimi I, Monteith GR (2016) Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells. Endocr Relat Cancer 23:R517–R525

    CAS  PubMed  Google Scholar 

  26. Azimi I (2018) The interplay between HIF-1 and calcium signalling in cancer. Int J Biochem Cell Biol 97:73–77

    CAS  PubMed  Google Scholar 

  27. Andreucci E et al (2017) Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. J Mol Med 95:1341–1353

    CAS  PubMed  Google Scholar 

  28. Lee SH et al (2018) Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. Br J Cancer 119:622–630

    CAS  PubMed  PubMed Central  Google Scholar 

  29. McDonald PC, Swayampakula M, Dedhar S (2018) Coordinated regulation of metabolic transporters and migration/invasion by carbonic anhydrase IX. Metabolites 8:1–11

    Google Scholar 

  30. Ward C, Meehan J, Gray M, Kunkler IH, Langdon SP, Argyle DJ (2018) Carbonic Anhydrase IX (CAIX), cancer, and radiation responsiveness. Metabolites 8:1–18

    CAS  Google Scholar 

  31. Sedlakova O, Svastova E, Takacova M, Kopacek J, Pastorek J, Pastorekova S (2014) Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Front Physiol 4:400

    PubMed  PubMed Central  Google Scholar 

  32. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    CAS  PubMed  Google Scholar 

  33. Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer–a double-edged sword. Trends Cell Biol 11:S44–51

    CAS  PubMed  Google Scholar 

  34. David CJ, Massague J (2018) Contextual determinants of TGFbeta action in development, immunity and cancer. Nat Rev Mol Cell Biol 19:419–435

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Derynck R, Budi EH (2019) Specificity, versatility, and control of TGF-β family signaling. Sci Signal 12:eaav5183

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Heldin C-H, Vanlandewijck M, Moustakas AJFI (2012) Regulation of EMT by TGFβ in cancer. FEBS Lett 586:1959–1970

    CAS  PubMed  Google Scholar 

  37. Laurenzana A et al (2015) Inhibition of uPAR-TGFbeta crosstalk blocks MSC-dependent EMT in melanoma cells. J Mol Med (Berl) 93:783–794

    CAS  Google Scholar 

  38. Guo Q (2017) Changes in mitochondrial function during EMT induced by TGFbeta-1 in pancreatic cancer. Oncol Lett 13:1575–1580

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Moreno-Bueno G et al (2009) The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat Protoc 4:1591–1613

    CAS  PubMed  Google Scholar 

  40. Huang RY et al (2013) An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis 4:e915

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Li G, Liu Y, Yin H, Zhang X, Mo X, Tang J, Chen W (2014) E-cadherin gene promoter hypermethylation may contribute to the risk of bladder cancer among Asian populations. Gene 534:48–53

    CAS  PubMed  Google Scholar 

  42. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428

    CAS  PubMed  Google Scholar 

  43. Song Y et al (2014) MicroRNA-9 promotes tumor metastasis via repressing E-cadherin in esophageal squamous cell carcinoma. Oncotarget 5:11669–11680

    PubMed  PubMed Central  Google Scholar 

  44. Antony J et al (2016) The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer. Sci Signal 9:ra97

    PubMed  Google Scholar 

  45. Aref AR et al (2013) Screening therapeutic EMT blocking agents in a three-dimensional microenvironment. Integr Biol (Camb) 5:381–389

    CAS  Google Scholar 

  46. Chua KN, Sim WJ, Racine V, Lee SY, Goh BC, Thiery JP (2012) A cell-based small molecule screening method for identifying inhibitors of epithelial–mesenchymal transition in carcinoma. PLoS One 7:e33183

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Chung VY et al (2016) GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification. Sci Rep 6:19943

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Jia D, Park JH, Jung KH, Levine H, Kaipparettu BA (2018) Elucidating the metabolic plasticity of cancer: mitochondrial reprogramming and hybrid metabolic states. Cells 7:21

    PubMed Central  Google Scholar 

  49. LeBleu VS et al (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16(992–1003):1–15

    Google Scholar 

  50. Jolly MK, Boareto M, Huang B, Jia D, Lu M, Ben-Jacob E, Onuchic JN, Levine H (2015) Implications of the hybrid epithelial/mesenchymal phenotype in metastasis. Front Oncol 5:155

    PubMed  PubMed Central  Google Scholar 

  51. Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284

    CAS  PubMed  Google Scholar 

  52. Khoo BL et al (2015) Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget 6:15578–15593

    PubMed  PubMed Central  Google Scholar 

  53. Plaks V, Koopman CD, Werb Z (2013) Circulating tumor cells. Science 341:1186–1188

    CAS  PubMed  Google Scholar 

  54. Tan TZ, Miow QH, Miki Y, Noda T, Mori S, Huang RY, Thiery JP (2014) Epithelial–mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med 6:1279–1293

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Yadavalli S et al (2017) Data-driven discovery of extravasation pathway in circulating tumor cells. Sci Rep 7:43710

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fischer KR et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zheng X et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Aiello NM, Brabletz T, Kang Y, Nieto MA, Weinberg RA, Stanger BZ (2017) Upholding a role for EMT in pancreatic cancer metastasis. Nature 547:E7–E8

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ye X, Brabletz T, Kang Y, Longmore GD, Nieto MA, Stanger BZ, Yang J, Weinberg RA (2017) Upholding a role for EMT in breast cancer metastasis. Nature 547:E1–E3

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Krebs AM et al (2017) The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 19:518–529

    CAS  PubMed  Google Scholar 

  61. Aiello NM, Kang Y (2019) Context-dependent EMT programs in cancer metastasis. J Exp Med 216:1016–1026

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu X, Fan D (2015) The epithelial–mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des 21:1279–1291

    CAS  PubMed  Google Scholar 

  63. Nel I, David P, Gerken GG, Schlaak JF, Hoffmann AC (2014) Role of circulating tumor cells and cancer stem cells in hepatocellular carcinoma. Hepatol Int 8:321–329

    PubMed  Google Scholar 

  64. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Investig 119:1420–1428

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Stemmler MP, Eccles RL, Brabletz S, Brabletz T (2019) Non-redundant functions of EMT transcription factors. Nat Cell Biol 21:102–112

    CAS  PubMed  Google Scholar 

  66. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang J, Weinberg RA (2008) Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829

    CAS  PubMed  Google Scholar 

  68. Pei D, Shu X, Gassama-Diagne A, Thiery JP (2019) Mesenchymal–epithelial transition in development and reprogramming. Nat Cell Biol 21:44

    CAS  PubMed  Google Scholar 

  69. Dongre A, Weinberg RA (2018) New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20:69–84

    Google Scholar 

  70. Zhang Y, Weinberg RA (2018) Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med 12:361–373

    PubMed  PubMed Central  Google Scholar 

  71. Hay ED (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233:706–720

    CAS  PubMed  Google Scholar 

  72. Timmerman LA et al (2004) Notch promotes epithelial–mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 18:99–115

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18:816–827

    CAS  PubMed  Google Scholar 

  74. Kaimori A, Potter J, Kaimori JY, Wang C, Mezey E, Koteish A (2007) Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 282:22089–22101

    CAS  PubMed  Google Scholar 

  75. Saika S et al (2009) TGF beta in fibroproliferative diseases in the eye. Front Biosci (Schol Ed) 1:376–390

    Google Scholar 

  76. Kriz W, Kaissling B, Le Hir M (2011) Epithelial–mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J Clin Investig 121:468–474

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lovisa S et al (2015) Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med 21:998–1009

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Grande MT et al (2015) Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med 21:989–997

    CAS  PubMed  Google Scholar 

  79. Bi WR, Yang CQ, Shi Q (2012) Transforming growth factor-beta1 induced epithelial–mesenchymal transition in hepatic fibrosis. Hepatogastroenterology 59:1960–1963

    CAS  PubMed  Google Scholar 

  80. Pourgholamhossein F et al (2018) Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression. Food Chem Toxicol 112:39–46

    CAS  PubMed  Google Scholar 

  81. Mamuya FA, Wang Y, Roop VH, Scheiblin DA, Zajac JC, Duncan MK (2014) The roles of alphaV integrins in lens EMT and posterior capsular opacification. J Cell Mol Med 18:656–670

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chang KC, Petrash JM (2015) Aldose reductase mediates transforming growth factor beta2 (TGF-beta2)-induced migration and epithelial-to-mesenchymal transition of lens-derived epithelial cells. Investig Ophthalmol Vis Sci 56:4198–4210

    CAS  Google Scholar 

  83. Chang KC, Shieh B, Petrash JM (2017) Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells. Chem Biol Interact 276:149–154

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Nahomi RB, Pantcheva MB, Nagaraj RH (2016) alphaB-crystallin is essential for the TGF-beta2-mediated epithelial to mesenchymal transition of lens epithelial cells. Biochem J 473:1455–1469

    CAS  PubMed  Google Scholar 

  85. Teven CM, Farina EM, Rivas J, Reid RR (2014) Fibroblast growth factor (FGF) signaling in development and skeletal diseases. Genes Dis 1:199–213

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Correia AC, Moonen JR, Brinker MG, Krenning G (2016) FGF2 inhibits endothelial-mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-beta signaling. J Cell Sci 129:569–579

    CAS  PubMed  Google Scholar 

  87. Ciruna B, Rossant J (2001) FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell 1:37–49

    CAS  PubMed  Google Scholar 

  88. Pera EM, Ikeda A, Eivers E, De Robertis EM (2003) Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev 17:3023–3028

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wu C et al (2016) Interaction between Wnt/beta-catenin pathway and microRNAs regulates epithelial–mesenchymal transition in gastric cancer (Review). Int J Oncol 48:2236–2246

    CAS  PubMed  Google Scholar 

  90. Du B, Shim JS (2016) Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules 21:1–15

    Google Scholar 

  91. Roy M, Pear WS, Aster JC (2007) The multifaceted role of Notch in cancer. Curr Opin Genet Dev 17:52–59

    CAS  PubMed  Google Scholar 

  92. Wels C, Joshi S, Koefinger P, Bergler H, Schaider H (2011) Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial–mesenchymal transition-like phenotype in melanoma. J Investig Dermatol 131:1877–1885

    CAS  PubMed  Google Scholar 

  93. Sinh ND, Endo K, Miyazawa K, Saitoh M (2017) Ets1 and ESE1 reciprocally regulate expression of ZEB1/ZEB2, dependent on ERK1/2 activity, in breast cancer cells. Cancer Sci 108:952–960

    PubMed  PubMed Central  Google Scholar 

  94. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23:1155–1165

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Chang K-C et al (2019) Opposing effects of growth and differentiation factors in cell-fate specification. Curr Biol 29:1963–1975

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yuan X et al (2014) Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol 7:87

    PubMed  PubMed Central  Google Scholar 

  97. Tan C, Hu W, He Y, Zhang Y, Zhang G, Xu Y, Tang J (2018) Cytokine-mediated therapeutic resistance in breast cancer. Cytokine 108:151–159

    CAS  PubMed  Google Scholar 

  98. Wang J, Knaut H (2014) Chemokine signaling in development and disease. Development 141:4199–4205

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Maritzen T, Schachtner H, Legler DF (2015) On the move: endocytic trafficking in cell migration. Cell Mol Life Sci 72:2119–2134

    CAS  PubMed  Google Scholar 

  100. Rokavec M et al (2014) IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Investig 124:1853–1867

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Antoon JW et al (2012) Altered death receptor signaling promotes epithelial-to-mesenchymal transition and acquired chemoresistance. Sci Rep 2:539

    PubMed  PubMed Central  Google Scholar 

  102. Sonego M et al (2019) USP1 links platinum resistance to cancer cell dissemination by regulating Snail stability. Sci Adv 5:eaav3235

    PubMed  PubMed Central  Google Scholar 

  103. van Staalduinen J, Baker D, ten Dijke P, van Dam H (2018) Epithelial–mesenchymal-transition-inducing transcription factors: new targets for tackling chemoresistance in cancer? Oncogene 37:6195–6211

    PubMed  Google Scholar 

  104. Peebles CL, Perlman P, Mecklenburg K, Petrillo M, Tabor J, Jarrell K, Cheng H-L (1986) A self-splicing RNA excises an intron lariat. Cell 44:213–223

    CAS  PubMed  Google Scholar 

  105. Carninci P et al (2005) The transcriptional landscape of the mammalian genome. Science 309:1559–1563

    CAS  PubMed  Google Scholar 

  106. Park S-M, Gaur AB, Lengyel E, Peter ME (2008) 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

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Moreno-Bueno G, Portillo F, Cano A (2008) Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27:6958–6969

    CAS  PubMed  Google Scholar 

  108. Arun K, Arunkumar G, Bennet D, Chandramohan SM, Murugan AK, Munirajan AK (2018) Comprehensive analysis of aberrantly expressed lncRNAs and construction of ceRNA network in gastric cancer. Oncotarget 9:18386

    PubMed  PubMed Central  Google Scholar 

  109. Tamagawa S, Beder LB, Hotomi M, Gunduz M, Yata K, Grenman R, Yamanaka N (2014) Role of miR-200c/miR-141 in the regulation of epithelial–mesenchymal transition and migration in head and neck squamous cell carcinoma. Int J Mol Med 33:879–886

    CAS  PubMed  Google Scholar 

  110. Chen H-Y et al (2012) miR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4. Can Res 72:3631–3641

    CAS  Google Scholar 

  111. Martello G et al (2010) A MicroRNA targeting dicer for metastasis control. Cell 141:1195–1207

    CAS  PubMed  Google Scholar 

  112. Zhang Y et al (2015) miR-103/107 modulates multidrug resistance in human gastric carcinoma by downregulating Cav-1. Tumor Biol 36:2277–2285

    CAS  Google Scholar 

  113. Bornachea O et al (2012) EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours. Sci Rep 2:434

    PubMed  PubMed Central  Google Scholar 

  114. Chang C-J et al (2011) Let-7d functions as novel regulator of epithelial–mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep 26:1003–1010

    CAS  PubMed  Google Scholar 

  115. Manikandan M, Rao AKDM, Arunkumar G, Manickavasagam M, Rajkumar KS, Rajaraman R, Munirajan AK (2016) Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism. Mol Cancer 15:28

    PubMed  PubMed Central  Google Scholar 

  116. Manikandan M, Rao DM, Arunagiri K, Rajkumar KS, Rajaraman R, Munirajan AK (2015) Altered levels of miR-21, miR-125b-2*, miR-138, miR-155, miR-184, and miR-205 in oral squamous cell carcinoma and association with clinicopathological characteristics. J Oral Pathol Med 44:792–800

    CAS  PubMed  Google Scholar 

  117. Lin C-H, Chiang M-C, Chen Y-J (2018) Microrna-328 inhibits migration and epithelial–mesenchymal transition by targeting cD44 in nasopharyngeal carcinoma cells. Oncotargets Ther 11:2375

    Google Scholar 

  118. Luo H, Liang C (2018) MicroRNA-148b inhibits proliferation and the epithelial–mesenchymal transition and increases radiosensitivity in non-small cell lung carcinomas by regulating ROCK1. Exp Ther Med 15:3609–3616

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang J, Wang X, Liu F, Fu Y (2017) microRNA-335 inhibits colorectal cancer HCT116 cells growth and epithelial–mesenchymal transition (EMT) process by targeting Twist1. Die Pharmazie Int J Pharm Sci 72:475–481

    CAS  Google Scholar 

  120. Liu H, Pan Y, Han X, Liu J, Li R (2017) Microrna-216a promotes the metastasis and epithelial–mesenchymal transition of ovarian cancer by suppressing the PTen/aKT pathway. Oncotargets Ther 10:2701

    Google Scholar 

  121. Lu C, Shan Z, Hong J, Yang L (2017) MicroRNA-92a promotes epithelial–mesenchymal transition through activation of PTEN/PI3K/AKT signaling pathway in non-small cell lung cancer metastasis. Int J Oncol 51:235–244

    CAS  PubMed  Google Scholar 

  122. Zhang N, Tian L, Miao Z, Guo N (2018) MicroRNA-197 induces epithelial–mesenchymal transition and invasion through the downregulation of HIPK2 in lung adenocarcinoma. J Genet 97:47–53

    CAS  Google Scholar 

  123. Song X-F, Wang Q-H, Huo R (2017) Effects of microRNA-708 on epithelial–mesenchymal transition, cell proliferation and apoptosis in melanoma cells by targeting LEF1 through the Wnt signaling pathway. Pathol Oncol Res 25:377–389

    PubMed  Google Scholar 

  124. Kung JT, Colognori D, Lee JT (2013) Long noncoding RNAs: past, present, and future. Genetics 193:651–669

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Arunkumar G, Murugan AK, Rao PSH, Subbiah S, Rajaraman R, Munirajan AK (2017) Long non-coding RNA CCAT1 is overexpressed in oral squamous cell carcinomas and predicts poor prognosis. Biomed Rep 6:455–462

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Xu Y, Yao Y, Qin W, Zhong X, Jiang X, Cui Y (2018) Long non-coding RNA CCAT2 promotes cholangiocarcinoma cells migration and invasion by induction of epithelial-to-mesenchymal transition. Biomed Pharmacother 99:121–127

    CAS  PubMed  Google Scholar 

  127. Kawasaki N, Miwa T, Hokari S, Sakurai T, Ohmori K, Miyauchi K, Miyazono K, Koinuma D (2018) Long noncoding RNA NORAD regulates transforming growth factor-β signaling and epithelial-to-mesenchymal transition-like phenotype. Cancer Sci 109:2211–2220

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Du D, Lian D, Amin B, Yan W (2017) Long non-coding RNA CRNDE is a novel tumor promoter by modulating PI3K/AKT signal pathways in human gastric cancer. Eur Rev Med Pharmacol Sci 21:5392–5398

    PubMed  Google Scholar 

  129. Lv W-Q, Wang H-C, Peng J, Wang Y-X, Jiang J-H, Li C-Y (2017) Gene editing of the extra domain A positive fibronectin in various tumors, amplified the effects of CRISPR/Cas system on the inhibition of tumor progression. Oncotarget 8:105020

    PubMed  PubMed Central  Google Scholar 

  130. Zarringhalam K, Tay Y, Kulkarni P, Bester AC, Pandolfi PP, Kulkarni RV (2017) Identification of competing endogenous RNAs of the tumor suppressor gene PTEN: a probabilistic approach. Sci Rep 7:7755

    PubMed  PubMed Central  Google Scholar 

  131. Li C et al (2018) Long non-coding RNA XIST promotes TGF-β-induced epithelial–mesenchymal transition by regulating miR-367/141-ZEB2 axis in non-small-cell lung cancer. Cancer Lett 418:185–195

    CAS  PubMed  Google Scholar 

  132. Dasgupta P et al (2018) MicroRNA-203 inhibits long noncoding RNA HOTAIR and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma. Mol Cancer Ther 17:1061–1069

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Ge Y et al (2015) fMiRNA-192 and miRNA-204 directly suppress lncRNA HOTTIP and interrupt GLS1-mediated glutaminolysis in hepatocellular carcinoma. PLoS Genet 11:e1005726

    PubMed  PubMed Central  Google Scholar 

  134. Shapiro RS, Chavez A, Collins JJ (2018) CRISPR-based genomic tools for the manipulation of genetically intractable microorganisms. Nat Rev Microbiol 16:333–339

    CAS  PubMed  Google Scholar 

  135. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–821

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Sander JD, Joung JK (2014) CRISPR–Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32:347

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Cho SW, Kim S, Kim JM, Kim J-S (2013) Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol 31:230

    CAS  PubMed  Google Scholar 

  138. Cong L et al (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J (2013) RNA-programmed genome editing in human cells. eLife 2:1–9

    Google Scholar 

  140. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826

    CAS  PubMed  PubMed Central  Google Scholar 

  141. La Russa MF, Qi LS (2015) The new state of the art: Cas9 for gene activation and repression. Mol Cell Biol 35:3800–3809

    PubMed  PubMed Central  Google Scholar 

  142. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–1183

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Gilbert LA et al (2014) Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159:647–661

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Hilton IB, D'ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, Gersbach CA (2015) Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol 33:510

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Klann TS et al (2017) CRISPR–Cas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome. Nat Biotechnol 35:561

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Liu XS et al (2016) Editing DNA methylation in the mammalian genome. Cell 167(233–247):e17

    Google Scholar 

  147. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR (2017) Programmable base editing of A• T to G• C in genomic DNA without DNA cleavage. Nature 551:464

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Cox DB, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F (2017) RNA editing with CRISPR-Cas13. Science 358:1019–1027

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Adli M (2018) The CRISPR tool kit for genome editing and beyond. Nat Commun 9:1911

    PubMed  PubMed Central  Google Scholar 

  150. Sánchez-Rivera FJ, Jacks T (2015) Applications of the CRISPR–Cas9 system in cancer biology. Nat Rev Cancer 15:387

    PubMed  PubMed Central  Google Scholar 

  151. Zhang L et al (2020) FRK plays an oncogenic role in non-small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming. Int J Cancer 146:208–222

    CAS  PubMed  Google Scholar 

  152. Xu X et al (2017) CRISPR-ON-Mediated KLF4 overexpression inhibits the proliferation, migration and invasion of urothelial bladder cancer in vitro and in vivo. Oncotarget 8:102078–102087

    PubMed  PubMed Central  Google Scholar 

  153. Shibata T, Shibata S, Ishigaki Y, Kiyokawa E, Ikawa M, Singh DP, Sasaki H, Kubo E (2018) Tropomyosin 2 heterozygous knockout in mice using CRISPR-Cas9 system displays the inhibition of injury-induced epithelial–mesenchymal transition, and lens opacity. Mech Ageing Dev 171:24–30

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Haraguchi M, Sato M, Ozawa M (2015) CRISPR/Cas9n-mediated deletion of the Snail 1Gene (SNAI1) reveals its role in regulating cell morphology, cell–cell interactions, and gene expression in ovarian cancer (RMG-1) cells. PLoS One 10:e0132260

    PubMed  PubMed Central  Google Scholar 

  155. Wang HC, Yang Y, Xu SY, Peng J, Jiang JH, Li CY (2015) The CRISPR/Cas system inhibited the pro-oncogenic effects of alternatively spliced fibronectin extra domain A via editing the genome in salivary adenoid cystic carcinoma cells. Oral Dis 21:608–618

    PubMed  Google Scholar 

  156. Zhao G et al (2017) Lentiviral CRISPR/Cas9 nickase vector mediated BIRC5 editing inhibits epithelial to mesenchymal transition in ovarian cancer cells. Oncotarget 8:94666

    PubMed  PubMed Central  Google Scholar 

  157. McFaline-Figueroa JL, Hill AJ, Qiu X, Jackson D, Shendure J, Trapnell C (2019) A pooled single-cell genetic screen identifies regulatory checkpoints in the continuum of the epithelial-to-mesenchymal transition. Nat Genet 51:1389–1398

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Qu X et al (2019) c-Myb promotes growth and metastasis of colorectal cancer through c-fos-induced epithelial–mesenchymal transition. Cancer Sci 110:3183–3196

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Freihen V et al (2019) SNAIL1 employs β-Catenin-LEF1 complexes to control colorectal cancer cell invasion and proliferation. Int J Cancer. https://doi.org/10.1002/ijc.32644

    Article  PubMed  Google Scholar 

  160. Zeng K et al (2018) LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation. Oncogene 37:5534–5551

    CAS  PubMed  Google Scholar 

  161. Liu Z et al (2019) Tn antigen promotes human colorectal cancer metastasis via H-Ras mediated epithelial–mesenchymal transition activation. J Cell Mol Med 23:2083–2092

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Jubair L, Fallaha S, McMillan NA (2019) Systemic delivery of CRISPR/Cas9 targeting HPV oncogenes is effective at eliminating established tumors. Mol Ther 27:2091–2099

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Wilbie D, Walther J, Mastrobattista E (2019) Delivery aspects of CRISPR/Cas for in vivo genome editing. Acc Chem Res 52:1555–1564

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Tong S, Moyo B, Lee CM, Leong K, Bao G (2019) Engineered materials for in vivo delivery of genome-editing machinery. Nat Rev Mater 4:726–737

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Liu Q et al (2019) Multistage delivery nanoparticle facilitates efficient CRISPR/dCas9 activation and tumor growth suppression in vivo. Adv Sci 6:1–12

    Google Scholar 

  166. Luther D, Lee Y, Nagaraj H, Scaletti F, Rotello V (2018) Delivery approaches for CRISPR/Cas9 therapeutics in vivo: advances and challenges. Expert Opin Drug Deliv 15:905–913

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Biagioni A, Laurenzana A, Margheri F, Chillà A, Fibbi G (2018) Delivery systems of CRISPR/Cas9-based cancer gene therapy. J Biol Eng 12:33

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Lu Y, Liang M, Zhang Q, Liu Z, Song Y, Lai L, Li Z (2019) Mutations of GADD45G in rabbits cause cleft lip by the disorder of proliferation, apoptosis and epithelial–mesenchymal transition (EMT). Biochimica et Biophysica Acta (BBA) Mol Basis Dis 1865:2356–2367

    CAS  Google Scholar 

  169. Seok H, Lee H, Jang E-S, Chi SW (2018) Evaluation and control of miRNA-like off-target repression for RNA interference. Cell Mol Life Sci 75:797–814

    CAS  PubMed  Google Scholar 

  170. Spagnou S, Miller AD, Keller M (2004) Lipidic carriers of siRNA: differences in the formulation, cellular uptake, and delivery with plasmid DNA. Biochemistry 43:13348–13356

    CAS  PubMed  Google Scholar 

  171. Zhou J, Shum K-T, Burnett JC, Rossi JJ (2013) Nanoparticle-based delivery of RNAi therapeutics: progress and challenges. Pharmaceuticals 6:85–107

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Fedorov Y, King A, Anderson E, Karpilow J, Ilsley D, Marshall W, Khvorova A (2005) Different delivery methods—different expression profiles. Nat Methods 2:241

    CAS  PubMed  Google Scholar 

  173. Luo J (2016) CRISPR/Cas9: from genome engineering to cancer drug discovery. Trends Cancer 2:313–324

    PubMed  PubMed Central  Google Scholar 

  174. Goyal A, Myacheva K, Groß M, Klingenberg M, Duran Arqué B, Diederichs SJN (2017) Challenges of CRISPR/Cas9 applications for long non-coding RNA genes. Nucleic Acids Res 45:e12–e12

    PubMed  Google Scholar 

  175. Chen F, Ji J, Shen J, Lu XJ (2017) When long noncoding RNAs meet genome editing in pluripotent stem cells. Stem Cells Int 2017:1–13

    Google Scholar 

  176. Szafranski P, Karolak JA, Lanza D, Gajęcka M, Heaney J, Stankiewicz P (2017) CRISPR/Cas9-mediated deletion of lncRNA Gm26878 in the distant Foxf1 enhancer region. Mamm Genome 28:275–282

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Koike-Yusa H, Li Y, Tan E-P, Velasco-Herrera MDC, Yusa K (2014) Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library. Nat Biotechnol 32:267–273

    CAS  PubMed  Google Scholar 

  178. Zare K, Shademan M, Seno MMG, Dehghani H (2018) CRISPR/Cas9 knockout strategies to ablate CCAT1 lncRNA gene in cancer cells. Biol Proced Online 20:21

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Jiang Q, Meng X, Meng L, Chang N, Xiong J, Cao H, Liang Z (2014) Small indels induced by CRISPR/Cas9 in the 5′ region of microRNA lead to its depletion and Drosha processing retardance. RNA Biol 11:1243–1249

    PubMed  Google Scholar 

  180. Zhao Y, Dai Z, Liang Y, Yin M, Ma K, He M, Ouyang H, Teng C-B (2014) Sequence-specific inhibition of microRNA via CRISPR/CRISPRi system. Sci Rep 4:3943

    PubMed  PubMed Central  Google Scholar 

  181. Chang H, Yi B, Ma R, Zhang X, Zhao H, Xi Y (2016) CRISPR/cas9, a novel genomic tool to knock down microRNA in vitro and in vivo. Sci Rep 6:22312

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM (2009) Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res 37:2584–2595

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658

    CAS  PubMed  Google Scholar 

  184. Sabatel C et al (2011) MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells. PLoS One 6:e16979

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Kim YJ, Hwang SJ, Bae YC, Jung JS (2009) MiR-21 regulates adipogenic differentiation through the modulation of TGF-β signaling in mesenchymal stem cells derived from human adipose tissue. Stem cells 27:3093–3102

    CAS  PubMed  Google Scholar 

  186. Papagiannakopoulos T, Shapiro A, Kosik KS (2008) MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Can Res 68:8164–8172

    CAS  Google Scholar 

  187. Huo W et al (2017) Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells. J Cancer 8:57

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Yoshino H, Yonemori M, Miyamoto K, Tatarano S, Kofuji S, Nohata N, Nakagawa M, Enokida H (2017) microRNA-210-3p depletion by CRISPR/Cas9 promoted tumorigenesis through revival of TWIST1 in renal cell carcinoma. Oncotarget 8:20881

    PubMed  PubMed Central  Google Scholar 

  189. Hoffmann MD et al (2019) Cell-specific CRISPR–Cas9 activation by microRNA-dependent expression of anti-CRISPR proteins. Nucleic Acids Res 47:e75–e75

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Voets O et al (2017) Highly efficient gene inactivation by adenoviral CRISPR/Cas9 in human primary cells. PLoS One 12:e0182974

    PubMed  PubMed Central  Google Scholar 

  191. Fang S et al (2018) circHECTD1 promotes the silica-induced pulmonary endothelial–mesenchymal transition via HECTD1. Cell Death Dis 9:396

    PubMed  PubMed Central  Google Scholar 

  192. Jiang R et al (2019) The emerging roles of a novel CCCH-type zinc finger protein, ZC3H4, in silica-induced epithelial to mesenchymal transition. Toxicol Lett 307:26–40

    CAS  PubMed  Google Scholar 

  193. Tedja R et al (2019) Protein kinase Cα–mediated phosphorylation of Twist1 at Ser-144 prevents Twist1 ubiquitination and stabilizes it. J Biol Chem 294:5082–5093

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Isaji T, Im S, Kameyama A, Wang Y, Fukuda T, Gu J (2019) A complex between phosphatidylinositol 4-kinase IIα and integrin α3β1 is required for N-glycan sialylation in cancer cells. J Biol Chem 294:4425–4436

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Wang X, Zhang W, Ding Y, Guo X, Yuan Y, Li D (2017) CRISPR/Cas9-mediated genome engineering of CXCR4 decreases the malignancy of hepatocellular carcinoma cells in vitro and in vivo. Oncol Rep 37:3565–3571

    CAS  PubMed  Google Scholar 

  196. He J, Zhang W, Li A, Chen F, Luo RJB (2018) Knockout of NCOA5 impairs proliferation and migration of hepatocellular carcinoma cells by suppressing epithelial-to-mesenchymal transition. Biochem Biophys Res Commun 500:177–183

    CAS  PubMed  Google Scholar 

  197. Qi X-K et al (2018) OVOL2 links stemness and metastasis via fine-tuning epithelial–mesenchymal transition in nasopharyngeal carcinoma. Theranostics 8:2202–2216

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Jägle S, Dertmann A, Schrempp M, Hecht A (2017) ZEB1 is neither sufficient nor required for epithelial–mesenchymal transition in LS174T colorectal cancer cells. Biochem Biophys Res Commun 482:1226–1232

    PubMed  Google Scholar 

  199. Dong X, Jiang Y, Liu J, Liu Z, Gao T, An G, Wen T (2018) T-Synthase deficiency enhances oncogenic features in human colorectal cancer cells via activation of epithelial–mesenchymal transition. Biomed Res Int 2018:1–7

    Google Scholar 

  200. Franke FC et al (2019) The tumor suppressor SASH1 interacts with the signal adaptor CRKL to inhibit epithelial–mesenchymal transition and metastasis in colorectal cancer. Cell Mol Gastroenterol Hepatol 7:33–53

    PubMed  Google Scholar 

  201. Wang X et al (2018) The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68. Mol Cancer 17:110

    PubMed  PubMed Central  Google Scholar 

  202. Zhou M, Liu X, Li Z, Huang Q, Li F, Li CY (2018) Caspase-3 regulates the migration, invasion and metastasis of colon cancer cells. Int J Cancer 143:921–930

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Hosain SB et al (2016) Inhibition of glucosylceramide synthase eliminates the oncogenic function of p53 R273H mutant in the epithelial–mesenchymal transition and induced pluripotency of colon cancer cells. Oncotarget 7:60575

    PubMed  PubMed Central  Google Scholar 

  204. Schokrpur S et al (2016) CRISPR-mediated VHL knockout generates an improved model for metastatic renal cell carcinoma. Sci Rep 6:29032

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Lin Y et al (2015) PIK3R1 negatively regulates the epithelial–mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3β/CTNNB1 signaling pathway. Sci Rep 5:8997

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Belvedere R et al (2018) miR-196a is able to restore the aggressive phenotype of annexin A1 knock-out in pancreatic cancer cells by CRISPR/Cas9 genome editing. Int J Mol Sci 19:1–15

    Google Scholar 

  207. Pessolano E et al (2018) Annexin A1 may induce pancreatic cancer progression as a key player of extracellular vesicles effects as evidenced in the in vitro MIA PaCa-2 model system. Int J Mol Sci 19:3878

    PubMed Central  Google Scholar 

  208. Santoro R, Zanotto M, Carbone C, Piro G, Tortora G, Melisi D (2018) MEKK3 sustains EMT and stemness in pancreatic cancer by regulating YAP and TAZ transcriptional activity. Anticancer Res 38:1937–1946

    CAS  PubMed  Google Scholar 

  209. Zhang P et al (2018) Knockdown of survivin results in inhibition of epithelial to mesenchymal transition in retinal pigment epithelial cells by attenuating the TGFβ pathway. Biochem Biophys Res Commun 498:573–578

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Liu B et al (2019) Blockade of MDM2 with inactive Cas9 prevents epithelial to mesenchymal transition in retinal pigment epithelial cells. Lab Investig 99:1874–1886

    CAS  PubMed  Google Scholar 

  211. Tordjman J, Majumder M, Amiri M, Hasan A, Hess D, Lala PK (2019) Tumor suppressor role of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in human mammary epithelial cells. BMC Cancer 19:561

    PubMed  PubMed Central  Google Scholar 

  212. Fröse J, Chen MB, Hebron KE, Reinhardt F, Hajal C, Zijlstra A, Kamm RD, Weinberg RA (2018) Epithelial–mesenchymal transition induces podocalyxin to promote extravasation via ezrin signaling. Cell Rep 24:962–972

    PubMed  PubMed Central  Google Scholar 

  213. Wu C-L et al (2018) BECN1-knockout impairs tumor growth, migration and invasion by suppressing the cell cycle and partially suppressing the epithelial–mesenchymal transition of human triple-negative breast cancer cells. Int J Oncol 53:1301–1312

    CAS  PubMed  Google Scholar 

  214. Hodge DQ, Cui J, Gamble MJ, Guo WJ (2018) Histone variant macroH2A1 plays an isoform-specific role in suppressing epithelial–mesenchymal transition. Sci Rep 8:841

    PubMed  PubMed Central  Google Scholar 

  215. Røsland GV et al (2019) Epithelial to mesenchymal transition (EMT) is associated with attenuation of succinate dehydrogenase (SDH) in breast cancer through reduced expression of SDHC. Cancer Metab 7:6

    PubMed  PubMed Central  Google Scholar 

  216. Riaz SK, Ke Y, Wang F, Kayani MA, Malik MFA (2019) Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells. Sci Rep 9:6620

    PubMed  PubMed Central  Google Scholar 

  217. Sun Y, Gao X, Wu P, Wink M, Li J, Dian L, Liang Z (2019) Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial–mesenchymal transition (EMT). Phytomedicine 63:153015

    CAS  PubMed  Google Scholar 

  218. Ramachandran A et al (2018) TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition. eLife 7:e31756

    PubMed  PubMed Central  Google Scholar 

  219. Sossey-Alaoui K, Pluskota E, Szpak D, Schiemann WP, Plow EF (2018) The Kindlin-2 regulation of epithelial-to-mesenchymal transition in breast cancer metastasis is mediated through miR-200b. Sci Rep 8:7360

    PubMed  PubMed Central  Google Scholar 

  220. Maturi V, Enroth S, Heldin CH, Moustakas A (2018) Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells. J Cell Physiol 233:7113–7127

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Maturi V, Morén A, Enroth S, Heldin CH, Moustakas A (2018) Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells. Mol Oncol 12:1153–1174

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Kumar S, Davra V, Obr AE, Geng K, Wood TL, De Lorenzo MS, Birge RB (2018) Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer. Oncoimmunology 7:e1376155

    Google Scholar 

  223. Beck C et al (2019) PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers. Cell Death Differ 26:1615–1630

    CAS  PubMed  Google Scholar 

  224. Kobayashi W, Ozawa M (2018) The epithelial–mesenchymal transition induced by transcription factor LEF-1 is independent of β-catenin. Biochem Biophys Rep 15:13–18

    PubMed  PubMed Central  Google Scholar 

  225. Ma Y et al (2018) CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial–mesenchymal transition. Cancer Lett 430:201–214

    CAS  PubMed  Google Scholar 

  226. Jacob F et al (2018) Transition of mesenchymal and epithelial cancer cells depends on α1-4 galactosyltransferase-mediated glycosphingolipids. Cancer Res 2223:2017

    Google Scholar 

  227. Haraguchi M, Fukushige T, Kanekura T, Ozawa MJB (2019) E-cadherin loss in RMG-1 cells inhibits cell migration and its regulation by Rho GTPases. Biochem Biophys Rep 18:100650

    PubMed  PubMed Central  Google Scholar 

  228. Ji L et al (2018) Knockout of MTF1 inhibits the epithelial to mesenchymal transition in ovarian cancer cells. J Cancer 9:4578–4585

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Jiang X et al (2018) Metastatic prostate cancer-associated P62 inhibits autophagy flux and promotes epithelial to mesenchymal transition by sustaining the level of HDAC6. Prostate 78:426–434

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Huang G et al (2016) TGF-β signal rewiring sustains epithelial–mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts. Oncotarget 7:77124

    PubMed  PubMed Central  Google Scholar 

  231. Katikireddy KR et al (2018) NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy. Free Radic Biol Med 116:19–30

    CAS  PubMed  Google Scholar 

  232. Sommerova L, Ondrouskova E, Vojtesek B, Hrstka R (2017) Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial–mesenchymal transition. BMC Cancer 17:546

    PubMed  PubMed Central  Google Scholar 

  233. Chockley PJ, Chen J, Chen G, Beer DG, Standiford TJ, Keshamouni VG (2018) Epithelial–mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer. J Clin Investig 128:1384–1396

    PubMed  PubMed Central  Google Scholar 

  234. Liu Y et al (2019) Competitive endogenous RNA is an intrinsic component of EMT regulatory circuits and modulates EMT. Nat Commun 10:1637

    PubMed  PubMed Central  Google Scholar 

  235. Vad-Nielsen J, Gammelgaard KR, Daugaard TF, Nielsen AL (2019) Cause-and-effect relationship between FGFR1 expression and epithelial–mesenchymal transition in EGFR-mutated non-small cell lung cancer cells. Lung Cancer 132:132–140

    PubMed  Google Scholar 

  236. Perumal E, Youn KS, Sun S, Seung-Hyun J, Suji M, Jieying L, Yeun-Jun C (2019) PTEN inactivation induces epithelial–mesenchymal transition and metastasis by intranuclear translocation of β-catenin and snail/slug in non-small cell lung carcinoma cells. Lung Cancer 130:25–34

    PubMed  Google Scholar 

  237. Raoof S et al (2019) Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer. Oncogene 38:6399–6413

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Zhang Y-Q, Pei J-H, Shi S-S, Guo X-S, Cui G-Y, Li Y-F, Zhang H-P, Hu W-Q (2019) CRISPR/Cas9-mediated knockout of the PDEF gene inhibits migration and invasion of human gastric cancer AGS cells. Biomed Pharmacother 111:76–85

    CAS  PubMed  Google Scholar 

  239. Paulitschke V et al (2019) Proteomic identification of a marker signature for MAPKi resistance in melanoma. EMBO J 38:e95874

    PubMed  PubMed Central  Google Scholar 

  240. Deiana M et al (2018) New insights into the runt domain of RUNX2 in melanoma cell proliferation and migration. Cells 7:220

    CAS  PubMed Central  Google Scholar 

  241. Cecconi D et al (2019) Runx2 stimulates neoangiogenesis through the Runt domain in melanoma. Sci Rep 9:8052

    PubMed  PubMed Central  Google Scholar 

  242. Kim HS et al (2017) Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels. Oncotarget 8:100339–100352

    PubMed  PubMed Central  Google Scholar 

  243. Sui A, Xu Y, Yang J, Pan B, Wu J, Guo T, Shen Y, Guo X (2019) The histone H3 Lys 27 demethylase KDM6B promotes migration and invasion of glioma cells partly by regulating the expression of SNAI1. Neurochem Int 124:123–129

    CAS  PubMed  Google Scholar 

  244. Tome-Garcia J et al (2018) Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma. Nat Commun 9:4020

    PubMed  PubMed Central  Google Scholar 

  245. Zhang Q et al (2019) Acidic bile salts induce epithelial to mesenchymal transition via VEGF signaling in non-neoplastic Barrett’s cells. Gastroenterology 156(130–144):e10

    Google Scholar 

  246. Abudureheman A et al (2018) High MLL2 expression predicts poor prognosis and promotes tumor progression by inducing EMT in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 144:1025–1035

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Frausto RF et al (2019) ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. PLoS One 14:e0218279

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Liu Y, Dakou E, Meng Y, Leyns L (2019) Loss of Emp2 compromises cardiogenic differentiation in mouse embryonic stem cells. Biochem Biophys Res Commun 511:173–178

    CAS  PubMed  Google Scholar 

  249. Eskildsen TV et al (2019) MESP1 knock-down in human iPSC attenuates early vascular progenitor cell differentiation after completed primitive streak specification. Dev Biol 445:1–7

    CAS  PubMed  Google Scholar 

  250. Soderquist RS et al (2018) Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity. Nat Commun 9:3513

    PubMed  PubMed Central  Google Scholar 

  251. Hu Q et al (2019) LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition. Cell Res 29:286–304

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Santamaria PG, Moreno-Bueno G, Portillo F, Cano A (2017) EMT: present and future in clinical oncology. Mol Oncol 11:718–738

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Yamini Dalal (National Cancer Institute) for constructive criticism of the manuscript.

Author information

Authors and Affiliations

  1. Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Reza Mohammadinejad

  2. Section of Experimental Pathology and Oncology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy

    Alessio Biagioni

  3. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Ganesan Arunkumar

  4. Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada

    Rebecca Shapiro

  5. Department of Ophthalmology, School of Medicine, Byers Eye Institute, Stanford University, Palo Alto, CA, 94303, USA

    Kun-Che Chang

  6. Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia

    Mohammed Sedeeq & Iman Azimi

  7. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada

    Aftab Taiyab

  8. Department of Biology, Faculty of Sciences, Shahid Bahonar University, Kerman, Iran

    Mohammad Hashemabadi

  9. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

    Mohammad Hashemabadi

  10. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Abbas Pardakhty

  11. Physiology Research Center, Institute of Neuropharmacology and Department of Toxicology & Pharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Ali Mandegary

  12. Guangzhou Regenerative Medicine and Health, Guangdong Laboratory, Guangzhou, China

    Jean-Paul Thiery

  13. Department of Medical Oncology, Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

    Amir Reza Aref

Authors
  1. Reza Mohammadinejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessio Biagioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ganesan Arunkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rebecca Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kun-Che Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammed Sedeeq
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aftab Taiyab
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohammad Hashemabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Abbas Pardakhty
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ali Mandegary
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean-Paul Thiery
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Amir Reza Aref
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Iman Azimi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Amir Reza Aref or Iman Azimi.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohammadinejad, R., Biagioni, A., Arunkumar, G. et al. EMT signaling: potential contribution of CRISPR/Cas gene editing. Cell. Mol. Life Sci. 77, 2701–2722 (2020). https://doi.org/10.1007/s00018-020-03449-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-020-03449-3

Keywords

Search

Navigation