Abstract
It has been recently shown that some microRNAs (miRNAs) are involved in oxidative stress-induced cellular responses. Our studies elucidated a new role for miR-200 family miRNAs and of its target ZEB1 in endothelial cells (EC) respon se to hydrogen peroxide (H2O2). Specifically, ZEB1 expression down-modulation was observed upon oxidative stress in human umbilical vein endothelial cells (HUVEC). ZEB1 and miR-200 family miRNAs were previously shown to be involved in the molecular mechanisms underpinning apoptosis and senescence, both in non-transformed cells and in tumor cells. Our study confirmed a prominent role of ZEB1 down-modulation in the induction of growth arrest, apoptosis and senescence in EC, consequently to the oxidative stress increase of miR-200 family expression.
In vivo experiments in a mouse model of acute hindlimb ischemia, an insult that induces an increase in oxidative stress, enhanced miR-200 family expression in wild-type mice skeletal muscle. In contrast in p66ShcA–/– mice, which display lower levels of oxidative stress after ischemia, up-regulation of miR-200 family members was markedly inhibited. Further studies are needed in order to comprehend whether ZEB1 down-modulation following oxidative stress inducing stimuli is also elicited by other miRNAs and which molecular pathways are involved in ZEB1 ability to modulate cell proliferation, apoptosis and senescence.
In conclusion, miRNAs may represent novel targets to prevent the deleterious consequences of diseases associated with enhanced oxidative stress.
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References
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Borras C, Gomez-Cabrera MC, Vina J (2011) The dual role of p53: DNA protection and antioxidant. Free Radic Res 45:643–652
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
Bui T, Sequeira J, Wen TC, Sola A, Higashi Y, Kondoh H, Genettea T (2009) ZEB1 links p63 and p73 in a novel neuronal survival pathway rapidly induced in response to cortical ischemia. PLoS One 4:e4373
Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–589
Campisi J (2011) Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev 21:107–112
Chang TC, Mendell JT (2007) MicroRNAs in vertebrate physiology and human disease. Annu Rev Genomics Hum Genet 8:215–239
Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, Liu M, Chen CT, Yu D, Hung MC et al (2011) p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13:317–323
Cicchillitti L, Fasanaro P, Biglioli P, Capogrossi MC, Martelli F (2003) Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. J Biol Chem 278:19509–19517
Cobrinik D (2005) Pocket proteins and cell cycle control. Oncogene 24:2796–2809
Eades G, Yao Y, Yang M, Zhang Y, Chumsri S, Zhou Q (2011) miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J Biol Chem 286:25992–26002
Finkel T (2003) Oxidant signals and oxidative stress. Curr Opin Cell Biol 15:247–254
Georges SA, Biery MC, Kim SY, Schelter JM, Guo J, Chang AN, Jackson AL, Carleton MO, Linsley PS, Cleary MA, Chau BN (2008) Coordinated regulation of cell cycle transcripts by p53-inducible microRNAs, miR-192 and miR-215. Cancer Res 68:10105–10112
Giorgio M, Trinei M, Migliaccio E, Pelicci PG (2007) Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol 8:722–728
Gorospe M, Wang X, Holbrook NJ (1999) Functional role of p21 during the cellular response to stress. Gene Express 7:377–385
Ito T, Yagi S, Yamakuchi M (2010) MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun 398:735–740
Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S, Pineau P, Marchio A, Palatini J, Suh SS, Alder H, Liu CG, Dejean A, Croce CM (2011) p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med 208:875–883
Li G, Luna C, Qiu J, Epstein DL, Gonzalez P (2009) Alterations in microRNA expression in stress-induced cellular senescence. Mech Ageing Dev 130:731–741
Lin Y, Liu X, Cheng Y, Yang J, Huo Y, Zhang C (2009) Involvement of microRNAs in hydrogen peroxide-mediated gene regulation and cellular injury response in vascular smooth muscle cells. J Biol Chem 284:7903–7913
Liu Y, Costantino ME, Montoya-Durango D, Higashi Y, Darling DS, Dean DC (2007) The zinc finger transcription factor ZFHX1A is linked to cell proliferation by Rb-E2F1. Biochem J 408:79–85
Liu Y, El-Naggar S, Darling DS, Higashi Y, Dean DC (2008) Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135:579–588
Magenta A, Fasanaro P, Romani S, Di Stefano V, Capogrossi MC, Martelli F (2008) Protein phosphatase 2A subunit PR70 interacts with pRb and mediates its dephosphorylation. Mol Cell Biol 28:873–882
Magenta A, Cencioni C, Fasanaro P, Zaccagnini G, Greco S, Sarra-Ferraris G, Antonini A, Martelli F, Capogrossi MC (2011) miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ 18:1628–1639
Mateescu B, Batista L, Cardon M, Gruosso T, de Feraudy Y, Mariani O, Nicolas A, Meyniel JP, Cottu P, Sastre-Garau X, Mechta-Grigoriou F (2011) miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med 17:1627–1635
Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309–313
Pei XH, Xiong Y (2005) Biochemical and cellular mechanisms of mammalian CDK inhibitors: a few unresolved issues. Oncogene 24:2787–2795
Postigo AA, Dean DC (1997) ZEB, a vertebrate homolog of drosophila Zfh-1, is a negative regulator of muscle differentiation. EMBO J 16:3935–3943
Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–990
Simone NL, Soule BP, Ly D, Saleh AD, Savage JE, Degraff W, Cook J, Harris CC, Gius D, Mitchell JB (2009) Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 4:e6377
Tan G, Shi Y, Wu ZH (2012) MicroRNA-22 promotes cell survival upon UV radiation by repressing PTEN. Biochem Biophys Res Commun 417:546–551
Vecchione A, Croce CM (2010) Apoptomirs: small molecules have gained the license to kill. Endocr Relat Cancer 17:F37–F50
Wang Z, Liu Y, Han N, Chen X, Yu W, Zhang W, Zou F (2010) Profiles of oxidative stress-related microRNA and mRNA expression in auditory cells. Brain Res 1346:14–25
Yamakuchi M, Lowenstein CJ (2009) MiR-34, SIRT1 and p53: the feedback loop. Cell Cycle 8:712–715
Yamakuchi M, Ferlito M, Lowenstein CJ (2008) miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A 105:13421–13426
Zaccagnini G, Martelli F, Fasanaro P, Magenta A, Gaetano C, Di Carlo A, Biglioli P, Giorgio M, Martin-Padura I, Pelicci PG, Capogrossi MC (2004) p66ShcA modulates tissue response to hindlimb ischemia. Circulation 109:2917–2923
Acknowledgements
This work has been partly supported by Ministero della Salute (R.C.07-1.13, RF07-56.1, RC4.01, RF07 85.1, RF07 onc 26.1, RFS07).
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Magenta, A., Capogrossi, M.C. (2013). Role of MicroRNAs and ZEB1 Downmodulation in Oxidative Stress-Induced Apoptosis and Senescence. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 1. Tumor Dormancy and Cellular Quiescence and Senescence, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5958-9_14
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