The miR-302-Mediated Induction of Pluripotent Stem Cells (iPSC): Multiple Synergistic Reprogramming Mechanisms

Part of the Methods in Molecular Biology book series (MIMB, volume 1733)


Pluripotency represents a unique feature of embryonic stem cells (ESCs). To generate ESC-like-induced pluripotent stem cells (iPSCs) derived from somatic cells, the cell genome needs to be reset and reprogrammed to express the ESC-specific transcriptome. Numerous studies have shown that genomic DNA demethylation is required for epigenetic reprogramming of somatic cell nuclei to form iPSCs; yet, the mechanism remains largely unclear. In ESCs, the reprogramming process goes through two critical stages: germline and zygotic demethylation, both of which erase genomic DNA methylation sites and hence allow for different gene expression patterns to be reset into a pluripotent state. Recently, miR-302, an ESC-specific microRNA (miRNA), was found to play an essential role in four aspects of this reprogramming mechanism—(1) initiating global genomic DNA demethylation, (2) activating ESC-specific gene expression, (3) inhibiting developmental signaling, and (4) preventing stem cell tumorigenicity. In this review, we will summarize miR-302 functions in all four reprogramming aspects and further discuss how these findings may improve the efficiency and safety of the current iPSC technology.

Key words

miR-302 MicroRNA Induced pluripotent stem cell Epigenetic reprogramming DNA demethylation Pluripotency 



The 3′-untranslated regions



Ago 1–4

Argonaute proteins 1–4


Activation-induced cytidine deaminase

AOF1/2 (LSD1/2 or KMD1/1B)

Flavin-containing amine oxidase domain-containing protein ½


A base excision DNA repair


B Lymphoma mouse Moloney leukemia virus insertion region


Bone morphogenetic protein


c-Myelocytomatosis oncogene


C-X-C Chemokine receptor type 4


DAZ-associated protein 2


DNA (Cytosine-5-)-methyltransferase 1


Eukaryotic translation initiation factor 2C


Embryonic stem cells


Germ cell nuclear factor


Methylation of histone 3 on lysine 4


Histone deacetylase 2 and 4


E3 ubiquitin ligase for p53


Induced pluripotent stem cells


Kruppel-like factor 4


La ribonucleoprotein domain family member 7 gene


RNA-binding protein LIN-28


P53 E3 ubiquitin protein ligase


Methyl-CpG binding 1 and 2







mirPS cells

miR-302-mediated pluripotent stem cells


A transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells


Noncoding RNAs


Nuclear receptor subfamily 2, group F, member 2


Octamer-binding transcription factor 4; a protein that is critically involved in the self-renewal of undifferentiated embryonic stem cells


p300-CBP-associated factor


Primordial germ cells


Hairpin-like miRNA precursors


Primary miRNA precursors


Ras-mitogen-activated protein kinase


RNA-induced silencing complexes

RNA pol II

Type-II RNA polymerases


Somatic cell nuclear transfer


Somatic cell reprogramming


SLAIN motif family, member 1


SRY (sex determining region Y)-box 2


3-Mercaptopyruvate sulfurtransferase-3 or 4


Transcription factor 3


Tet methylcytosine dioxygenase 1 or 2


Transforming growth factorβ-mothers against DPP homolog family members


Protein Tob2; transducer of erbB-2 2


Undifferentiated embryonic cell transcription factor 1


  1. 1.
    Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23CrossRefPubMedGoogle Scholar
  2. 2.
    Szabó PE, Mann JR (1999) Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting. Genes Dev 9:1857–1868CrossRefGoogle Scholar
  3. 3.
    Mayer W, Niveleau A, Walter J, Fundele R, Haaf T (2000) Demethylation of the zygotic paternal genome. Nature 403:501–502CrossRefPubMedGoogle Scholar
  4. 4.
    Santos F, Hendrich B, Reik W, Dean W (2002) Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 241:172–182CrossRefPubMedGoogle Scholar
  5. 5.
    Stöger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H, Barlow DP (1993) Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 73:61–71CrossRefPubMedGoogle Scholar
  6. 6.
    Tremblay KD, Saam JR, Ingram RS, Tilghman SM, Bartolomei MS (1995) A paternal-specific methylation imprint marks the alleles of the mouse H19 gene. Nat Genet 9:407–413CrossRefPubMedGoogle Scholar
  7. 7.
    Lin SL, Chang D, Chang-Lin S, Lin CH, Wu DTS, Chen DT, Ying SY (2008) Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 14:2115–2124.PMID: 18755840. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lin SL, Ying SY (2008) Role of mir-302 microRNA family in stem cell pluripotency and renewal. In: Ying SY (ed) Current perspectives in microRNAs. Springer, New York, pp 167–185CrossRefGoogle Scholar
  9. 9.
    Lin SL, Chang D, Lin CH, Ying SY, Leu D, Wu DTS (2011) Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res 39:1054–1065CrossRefPubMedGoogle Scholar
  10. 10.
    Lin SL (2011) Deciphering the mechanism behind induced pluripotent stem cell generation. Stem Cells 29:1645–1649CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285–290CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhao T, Zhang ZN, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215CrossRefPubMedGoogle Scholar
  13. 13.
    Ohi Y, Qin H, Hong C, Blouin L, Polo JM, Guo T, Qi Z, Downey SL, Manos PD, Rossi DJ (2011) Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 2011(13):541–549Google Scholar
  14. 14.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676CrossRefPubMedGoogle Scholar
  15. 15.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872CrossRefPubMedGoogle Scholar
  16. 16.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920CrossRefPubMedGoogle Scholar
  17. 17.
    Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318:1920–1923CrossRefPubMedGoogle Scholar
  18. 18.
    Kim J, Chu J, Shen X, Wang J, Orkin SH (2008) An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132:1049–1061CrossRefPubMedGoogle Scholar
  19. 19.
    Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Simonsson S, Gurdon J (2004) DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nat Cell Biol 6:984–990CrossRefPubMedGoogle Scholar
  21. 21.
    Pick M, Stelzer Y, Bar-Nur O, Mayshar Y, Eden A, Benvenisty N (2009) Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells 27:2686–2690CrossRefPubMedGoogle Scholar
  22. 22.
    Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, Su H, Sun W, Chang H, Xu G, Gaudet F, Li E, Chen T (2009) The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 41:125–129CrossRefPubMedGoogle Scholar
  23. 23.
    Monk M, Boubelik M, Lehnert S (1987) Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 99:371–382PubMedGoogle Scholar
  24. 24.
    Hirasawa R, Chiba H, Kaneda M, Tajima S, Li E, Jaenisch R, Sasaki H (2008) Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development. Genes Dev 22:1607–1616CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Suh MR, Lee Y, Kim JY, Kim SK, Moon SH, Lee JY, Cha KY, Chung HM, Yoon HS, Moon SY, Kim VN, Kim KS (2004) Human embryonic stem cells express a unique set of microRNAs. Dev Biol 270:488–498CrossRefPubMedGoogle Scholar
  26. 26.
    Barroso-delJesus A, Romero-López C, Lucena-Aguilar G, Melen GJ, Sanchez L, Ligero G, Berzal-Herranz A, Menendez P (2008) Embryonic stem cell-specific miR302-367 cluster: human gene structure and functional characterization of its core promoter. Mol Cell Biol 28:6609–6619CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wilson KD, Venkatasubrahmanyam S, Jia F, Sun N, Butte AJ, Wu JC (2009) MicroRNA profiling of human-induced pluripotent stem cells. Stem Cells Dev 18:749–758CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ying SY, Lin SL (2004) Intron-derived microRNAs -- fine tuning of gene functions. Gene 342:25–28CrossRefPubMedGoogle Scholar
  29. 29.
    Lin SL, Kim H, Ying SY (2008) Intron-mediated RNA interference and microRNA (miRNA). Front Biosci 13:2216–2230CrossRefPubMedGoogle Scholar
  30. 30.
    Ciccone DN, Su H, Hevi S, Gay F, Lei H, Bajko J, Xu G, Li E, Chen T (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461:415–418CrossRefPubMedGoogle Scholar
  31. 31.
    Lee MG, Wynder C, Cooch N, Shiekhattar R (2005) An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437:432–435CrossRefPubMedGoogle Scholar
  32. 32.
    Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R (2006) Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol 13:563–567CrossRefPubMedGoogle Scholar
  33. 33.
  34. 34.
    Carlson LL, Page AW, Bestor TH (1992) Properties and localization of DNA methyltransferase in preimplantation mouse embryos: implications for genomic imprinting. Genes Dev 6:2536–2541CrossRefPubMedGoogle Scholar
  35. 35.
    Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2340CrossRefPubMedGoogle Scholar
  36. 36.
    Vassena R, Dee Schramm R, Latham KE (2005) Species-dependent expression patterns of DNA methyltransferase genes in mammalian oocytes and preimplantation embryos. Mol Reprod Dev 72:430–436CrossRefPubMedGoogle Scholar
  37. 37.
    Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM (2010) Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463:1042–1047CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Popp C, Dean W, Feng S, Cokus SJ, Andrews S, Pellegrini M, Jacobsen SE, Reik W (2010) Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463:1101–1105CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Conticello SG, Langlois MA, Yang Z, Neuberger MS (2007) DNA deamination in immunity: AID in the context of its APOBEC relatives. Adv Immunol 94:37–73CrossRefPubMedGoogle Scholar
  40. 40.
    Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK (2004) Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 279:52353–52360CrossRefPubMedGoogle Scholar
  41. 41.
    Morgan HD, Santos F, Green K, Dean W, Reik W (2005) Epigenetic reprogramming in mammals. Hum Mol Genet 1:R47–R58CrossRefGoogle Scholar
  42. 42.
    Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR (2008) DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135:1201–1212CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Privat E, Sowers LC (1996) Photochemical deamination and demethylation of 5-methylcytosine. Chem Res Toxicol 9:745–750CrossRefPubMedGoogle Scholar
  44. 44.
    Valinluck V, Sowers LC (2007) Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67:946–950CrossRefPubMedGoogle Scholar
  45. 45.
    Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A (2011) Tet1 and tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8:200–213CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW, Gao Q, Kim J, Choi SW, Page DC, Jaenisch R (2011) Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9:166–175CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Dawlaty MM, Breiling A, Le T, Raddatz G, Barrasa MI, Cheng AW, Gao Q, Powell BE, Li Z, Xu M, Faull KF, Lyko F, Jaenisch R (2013) Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 24:310–323CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Vincent JJ, Huang Y, Chen PY, Feng S, Calvopiña JH, Nee K, Lee SA, Le T, Yoon AJ, Faull K, Fan G, Rao A, Jacobsen SE, Pellegrini M, Clark AT (2013) Stage-specific roles for tet1 and tet2 in DNA demethylation in primordial germ cells. Cell Stem Cell 12:470–478CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Han DW, Do JT, Gentile L, Stehling M, Lee HT, Schöler HR (2008) Pluripotential reprogramming of the somatic genome in hybrid cells occurs with the first cell cycle. Stem Cells 26:445–454CrossRefPubMedGoogle Scholar
  51. 51.
    Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G (2008) Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2:160–169CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Rosa A, Spagnoli FM, Brivanlou AH (2009) The miR-430/427/302 family controls mesendodermal fate specification via species-specific target selection. Dev Cell 16:517–527CrossRefPubMedGoogle Scholar
  53. 53.
    Rosa A, Brivanlou AH (2011) A regulatory circuitry comprised of miR-302 and the transcription factors OCT4 and NR2F2 regulates human embryonic stem cell differentiation. EMBO J 30:237–248CrossRefPubMedGoogle Scholar
  54. 54.
    Fuhrmann G, Chung AC, Jackson KJ, Hummelke G, Baniahmad A, Sutter J, Sylvester I, Schöler HR, Cooney AJ (2001) Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev Cell 1:377–387CrossRefPubMedGoogle Scholar
  55. 55.
    Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, Young RA (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:521–533CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813CrossRefPubMedGoogle Scholar
  57. 57.
    Wakayama T, Perry AC, Zuccotti M, Johnson KR, Yanagimachi R (1998) Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394:369–374CrossRefPubMedGoogle Scholar
  58. 58.
  59. 59.
  60. 60.
    Barroso-delJesus A, Lucena-Aguilar G, Sanchez L, Ligero G, Gutierrez-Aranda I, Menendez P (2011) The nodal inhibitor lefty is negatively modulated by the microRNA miR-302 in human embryonic stem cells. FASEB J 25:1497–1508CrossRefPubMedGoogle Scholar
  61. 61.
    Lipchina I, Elkabetz Y, Hafner M, Sheridan R, Mihailovic A, Tuschl T, Sander C, Studer L, Betel D (2011) Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response. Genes Dev 25:2173–2186CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Constam DB, Robertson EJ (2000) SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Genes Dev 14:1146–1155PubMedPubMedCentralGoogle Scholar
  63. 63.
    Meno C, Ito Y, Saijoh Y, Matsuda Y, Tashiro K, Kuhara S, Hamada H (1997) Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells 2:513–524CrossRefPubMedGoogle Scholar
  64. 64.
    Brennan J, Lu CC, Norris DP, Rodriguez TA, Beddington RS, Robertson EJ (2001) Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411:965–969CrossRefPubMedGoogle Scholar
  65. 65.
    miRBase::Sequences program.
  66. 66.
    Lin SL, Chang D, Ying SY, Leu D, Wu DTS (2010) MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of CDK2 and CDK4/6 cell cycle pathways. Cancer Res 70:9473–9482CrossRefPubMedGoogle Scholar
  67. 67.
    Becker KA, Ghule PN, Therrien JA, Lian JB, Stein JL, van Wijnen AJ, Stein GS (2006) Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol 209:883–893CrossRefPubMedGoogle Scholar
  68. 68.
    Parry D, Bates S, Mann DJ, Peters G (1995) Lack of cyclin D–Cdk complexes in Rb-negative cells correlated with high levels of p16INK4/MTS1 tumor suppressor gene product. EMBO J 14:503–511PubMedPubMedCentralGoogle Scholar
  69. 69.
    Quelle DE, Zindy F, Ashmun RA, Sherr CJ (1995) Alternative reading frames of the NK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83:993–1000CrossRefPubMedGoogle Scholar
  70. 70.
    Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649–659CrossRefPubMedGoogle Scholar
  71. 71.
    Li Z, Yang CS, Nakashima K, Rana TM (2011) Small RNA-mediated regulation of iPS cell generation. EMBO J 30:823–834CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Zhang GM, Bao CY, Wan FN, Cao DL, Qin XJ, Zhang HL, Zhu Y, Dai B, Shi GH, Ye DW (2015) MicroRNA-302a suppresses tumor cell proliferation by inhibiting AKT in prostate cancer. PLoS One 10:e0124410. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Li HL, Wei JF, Fan LY, Wang SH, Zhu L, Li TP, Lin G, Sun Y, Sun ZJ, Ding J, Liang XL, Li J, Han Q, Zhao RC. (2016) miR-302 regulates pluripotency, teratoma formation and differentiation in stem cells via an AKT1/OCT4-dependent manner. Cell Death Dis. doi:
  74. 74.
    Wang Y, Zhao L, Xiao Q, Jiang L, He M, Bai X, Ma M, Jiao X, Wei M (2016) miR-302a/b/c/d cooperatively inhibit BCRP expression to increase drug sensitivity in breast cancer cells. Gynecol Oncol 141:592–601. PMID: 26644266CrossRefPubMedGoogle Scholar
  75. 75.
    Liang Z, Ahn J, Guo D, Votaw JR, Shim H (2013) MicroRNA-302 replacement therapy sensitizes breast cancer cells to ionizing radiation. Pharm Res 30:1008–1016CrossRefPubMedGoogle Scholar
  76. 76.
    Zhao L, Wang Y, Jiang L, He M, Bai X, Yu L, Wei M (2016) MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1). J Exp Clin Cancer Res 35:25. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Maadi H, Moshtaghian A, Taha MF, Mowla SJ, Kazeroonian A, Haass NK, Javeri A (2016) Multimodal tumor suppression by miR-302 cluster in melanoma and colon cancer. Int J Biochem Cell Biol 81(Pt A):121–132CrossRefPubMedGoogle Scholar
  78. 78.
    Fareh M, Turchi L, Virolle V, Debruyne D, Almairac F, de-la-Forest Divonne S, Paquis P, Preynat-Seauve O, Krause KH, Chneiweiss H, Virolle T (2012) The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network. Cell Death Differ 19:232–244CrossRefPubMedGoogle Scholar
  79. 79.
    Yang CM, Chiba T, Brill B, Delis N, von Manstein V, Vafaizadeh V, Oellerich T, Groner B (2015) Expression of the miR-302/367 cluster in glioblastoma cells suppresses tumorigenic gene expression patterns and abolishes transformation related phenotypes. Int J Cancer 137:2296–2309CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Cai D, He K, Chang S, Tong D, Huang C (2015) MicroRNA-302b enhances the sensitivity of hepatocellular carcinoma cell lines to 5-FU via targeting Mcl-1 and DPYD. Int J Mol Sci 16:23668. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Wang L, Yao J, Shi X, Hu L, Li Z, Song T, Huang C (2013) MicroRNA-302b suppresses cell proliferation by targeting EGFR in human hepatocellular carcinoma SMMC-7721 cells. BMC Cancer 13.
  82. 82.
    Koga C, Kobayashi S, Nagano H, Tomimaru Y, Hama N, Wada H, Kawamoto K, Eguchi H, Konno M, Ishii H, Umeshita K, Doki Y, Mori M (2014) Reprogramming using microRNA-302 improves drug sensitivity in hepatocellular carcinoma cells. Ann Surg Oncol 21(Suppl 4):S591–S600CrossRefPubMedGoogle Scholar
  83. 83.
    Chen L, Min L, Wang X, Zhao J, Chen H, Qin J, Chen W, Shen Z, Tang Z, Gan Q, Ruan Y, Sun Y, Qin X, Gu J (2015) Loss of RACK1 promotes metastasis of gastric cancer by inducing a miR-302c/IL8 signaling loop. Cancer Res 75:3832–3841CrossRefPubMedGoogle Scholar
  84. 84.
    Yan GJ, Yu F, Wang B, Zhou HJ, Ge QY, Su J, Hu YL, Sun HX, Ding LJ (2014) MicroRNA miR-302 inhibits the tumorigenicity of endometrial cancer cells by suppression of Cyclin D1 and CDK1. Cancer Lett 345:39–47CrossRefPubMedGoogle Scholar
  85. 85.
    Khodayari N, Mohammed KA, Lee H, Kaye F, Nasreen N (2016) MicroRNA-302b targets Mcl-1 and inhibits cell proliferation and induces apoptosis in malignant pleural mesothelioma cells. Am J Cancer Res 6:1996–2009PubMedPubMedCentralGoogle Scholar
  86. 86.
    Cai N, Wang YD, Zheng PS (2013) The microRNA-302-367 cluster suppresses the proliferation of cervical carcinoma cells through the novel target AKT1. RNA 19:85–95CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Galoian K, Qureshi A, D’Ippolito G, Schiller PC, Molinari M, Johnstone AL, Brothers SP, Paz AC, Temple HT (2015) Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide 1. Int J Oncol 47:465–472CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Bourguignon LY, Wong G, Earle C, Chen L (2012) Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. J Biol Chem 287:32800–32824CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of Integrative Anatomical Sciences, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Division of Regenerative MedicineWJWU & LYNN (W&L) Institute for Stem Cell ResearchSanta Fe SpringsUSA

Personalised recommendations