Abstract
Epithelial-Mesenchymal Transition (EMT) is a major cellular process involved at the very first steps of the development. Recent work strongly implicates EMT in cancer progression as well as initiation. The role of EMT during metastatic process has long been controversial since pathologists failed to detect mesenchymal cells in carcinomas. Now, data clearly show the presence of mesenchymal and dedifferentiated cells at the invasive front of some solid tumors. The extra and intracellular signals that lead to EMT are only starting to be understood. Ultimately, every EMT-inducing pathway will activate any of the E-cadherin transcriptional repressors (Zeb1, Zeb2, Twist, Snail or Slug). Some of these repressors were found over-expressed in cancer and their expression correlates with the presence of metastases. Recently, studies have implicated the siRNA/miRNA biogenesis enzyme Dicer in EMT and metastatic progression. Dicer inhibition promotes metastasis while restoring its expression suppresses metastasis. Decreased Dicer expression leads to Zeb1/Zeb2 proteins increased expression and EMT induction. Due to its central role in neuronal regulation cell fate and the importance of miRNA biogenesis in neuronal differentiation, an important direction for future research may involve determining whether Dicer has metastasis-suppressive role in Central Nervous System cancers.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, Caron de Fromentel C, Puisieux A (2008) Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14:79–89
Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52:1399–1405
Bernstein E, Kim SY, Carmell MA, Murchison EP, Alcorn H, Li MZ, Mills AA, Elledge SJ, Anderson KV, Hannon GJ (2003) Dicer is essential for mouse development. Nat Genet 35:215–217, Erratum in: Nat Genet 35:287
Brabletz S, Brabletz T (2010) The ZEB/miR-200 feedback loop-a motor of cellular plasticity in development and cancer? EMBO Rep 11:670–677
Bremer J, O’Connor T, Tiberi C, Rehrauer H, Weis J, Aguzzi A (2010) Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination. PLoS One 5:12450–12460
Bui T, Sequeira J, Wen TC, Sola A, Higashi Y, Kondoh H, Genetta T (2009) ZEB1 links p63 and p73 in a novel neuronal survival pathway rapidly induced in response to cortical ischemia. PLoS One 4:4373–4390
Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83
Carver EA, Jiang R, Lan Y, Oram KF, Gridley T (2001) The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 21:8184–8188
Ciruna B, Rossant J (2001) FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell 1:37–49
Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, Ullian EM (2008) Conditional loss of dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 28:4322–4330
Grelier G, Voirin N, Ay AS, Cox DG, Chabaud S, Treilleux I, Leon-Goddard S, Rimokh R, Mikaelian I, Venoux C, Puisieux A, Lasset C, Moyret-Lalle C (2009) Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. Br J Cancer 101:673–683
Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012
Hebert SS, Papadopoulou AS, Pascal Smith P, Galas MC, Planel E, Silahtaroglu AN, Sergeant N, Bue L, De Strooper B (2010) Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum Mol Genet 19:3959–3969
Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ (2009) DICER1 mutations in familial pleuropulmonary blastoma. Science 325:965
Hinkal GW, Grelier G, Puisieux A, Moyret-Lalle C (2011) Complexity in the regulation of Dicer expression: Dicer variant proteins are differentially expressed in epithelial and mesenchymal breast cancer cells and decreased during EMT. Br J Cancer 104:387–388
Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, Kleinman ME, Ponicsan SL, Hauswirth WW, Chiodo VA, Karikó K, Yoo JW, Lee DK, Hadziahmetovic M, Song Y, Misra S, Chaudhuri G, Buaas FW, Braun RE, Hinton DR, Zhang Q, Grossniklaus HE, Provis JM, Madigan MC, Milam AH, Justice NL, Albuquerque RJ, Blandford AD, Bogdanovich S, Hirano Y, Witta J, Fuchs E, Littman DR, Ambati BK, Rudin CM, Chong MM, Provost P, Kugel JF, Goodrich JA, Dunaief JL, Baffi JZ, Ambati J (2011) DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471:325–330
Kawahara Y, Megraw M, Kreider E, Iizasa H, Valente L, Hatzigeorgiou AG, Nishikura K (2008) Frequency and fate of microRNA editing inhuman brain. Nucleic Acids Res 36:5270–5280
Kawase-Koga Y, Low R, Otaegi G, Pollock A, Deng H, Eisenhaber F, Maurer-Stroh S, Sun T (2010) RNAase-III enzyme Dicer maintains signaling pathways for differentiation and survival in mouse cortical neural stem cells. J Cell Sci 123:586–594
Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139
Klein CA (2008) Cancer. The metastasis cascade. Science 321:1785–1787
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39:673–677
Martello G, Rosat A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T, Parenti AR, Daidone MG, Bicciato S, Piccolo S (2010) A MicroRNA targeting dicer for metastasis control. Cell 141:1195–1207
Merritt WM, Lin YG, Han LY, Kamat AA, Spannuth WA, Schmandt R, Urbauer D, Pennacchio LA, Cheng JF, Nick AM, Deavers MT, Mourad-Zeidan A, Wang H, Mueller P, Lenburg ME, Gray JW, Mok S, Birrer MJ, Lopez-Berestein G, Coleman RL, Bar-Eli M, Sood AK (2008) Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med 359:2641–2650
Morel AP, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3:2888–2894
Moser JJ, Fritzler MJ (2010) The microRNA and messengerRNA profile of the RNA induced silencing complex in human primary astrocyte and astrocytoma cells. PLoS One 5:13445–13463
Obernosterer G, Leuschner PJF, Alenius M, Martinez J (2006) Post-transcriptional regulation of microRNA expression. RNA 12:1161–1167
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
Potenza N, Papa U, Scaruffi P, Mosca N, Tonini GP, Aniello Russo A (2010) A novel splice variant of the human dicer gene is expressed in neuroblastoma cells. FEBS Lett 584:3452–3457
Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn M, Liu H, Panula SP, Chiao E, Dirbas FM, Somlo G, Pera RA, Lao K, Clarke MF (2009) Down-regulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2138:592–603
Sleeman JP, Thiery JP (2011) SnapShot: the epithelial-mesenchymal transition. Cell 145:162
Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, Hlubek F, Jung A, Strand D, Eger A, Kirchner T, Behrens J, Brabletz T (2008) The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 68:537–544
Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, Flores ER (2010) TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467:986–990
Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, Creasap N, Rosol TJ, Robinson ML, Eng C, Ostrowski MC, Leone G (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68:937–945
Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101:816–829
Ueda R, Kohanbash G, Sasaki K, Fujita M, Zhu X, Kastenhuber ER, McDonald HA, Potter DM, Hamilton RL, Lotze MT, Khan SA, Sobol RW, Okada H (2009) Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Proc Natl Acad Sci USA 106:10746–10751
Wienholds E, Plasterk RH (2005) MicroRNA function in animal development. FEBS Lett 579:5911–5922
Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Courtois-Cox, S., Moyret-Lalle, C. (2012). Epithelial-Mesenchymal Transition and Metastasis: Role of Dicer Expression. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 6. Stem Cells and Cancer Stem Cells, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2993-3_19
Download citation
DOI: https://doi.org/10.1007/978-94-007-2993-3_19
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-2992-6
Online ISBN: 978-94-007-2993-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)