Advertisement

MicroRNAs in Drosophila Cancer Models

  • Moritz Sander
  • Héctor HerranzEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1167)

Abstract

MiRNAs are post-transcriptional regulators of gene expression which have been implicated in virtually all biological processes. MiRNAs are frequently dysregulated in human cancers. However, the functional consequences of aberrant miRNA levels are not well understood. Drosophila is emerging as an important in vivo tumor model, especially in the identification of novel cancer genes. Here, we review Drosophila studies which functionally dissect the roles of miRNAs in tumorigenesis. Ultimately, these advances help to understand the implications of miRNA dysregulation in human cancers.

Keywords

Drosophila Cancer Animal models miRNAs Oncogenic cooperation Bantam let-7 miR-7 miR-8 

Abbreviations

Ago-1

Argonaute-1

Brat

Brain tumor

CSC

Cancer stem cell

Dcr-1

Dicer-1

Dl

Delta

Dpp

Decapentaplegic

EGFR

Epidermal growth factor receptor

GSC

Germline stem cell

JAK/STAT

Janus kinase/Signal transducer and activator of transcription proteins

let-7

lethal-7

Lgl

Lethal giant larvae

Pnut

Peanut

RNAi

RNA interference

Scrib

Scribbled

Socs36E

Suppressor of cytokine signaling at 36E

YAP

Yes associated protein

Yki

Yorkie

Notes

Acknowledgements

This work was supported by the Novo Nordisk Foundation (grant number NNF0052223), a grant from the Neye Foundation for genetic models for cancer gene discovery, and a grant by Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Legat.

References

  1. 1.
    Cohen S (2010) Editorial. Semin Cell Dev Biol 21:727PubMedCrossRefGoogle Scholar
  2. 2.
    Friedman RC, Farh KKH, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Vidigal JA, Ventura A (2015) The biological functions of miRNAs: lessons from in vivo studies. Trends Cell Biol 25:137–147PubMedCrossRefGoogle Scholar
  4. 4.
    Miska EA, Alvarez-Saavedra E, Abbott AL, Lau NC, Hellman AB, McGonagle SM, Bartel DP, Ambros VR, Horvitz HR (2007) Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet 3:2395–2403CrossRefGoogle Scholar
  5. 5.
    Alvarez-Saavedra E, Horvitz HR (2010) Many families of C. elegans MicroRNAs are not essential for development or viability. Curr Biol 20:367–373PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Chen Y-W, Song S, Weng R, Verma P, Kugler J-M, Buescher M, Rouam S, Cohen SM (2014) Systematic study of Drosophila MicroRNA functions using a collection of targeted knockout mutations. Dev Cell 31:784–800PubMedCrossRefGoogle Scholar
  7. 7.
    Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RHA (2007) Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biol 5:1738–1749CrossRefGoogle Scholar
  8. 8.
    Park CY, Jeker LT, Carver-Moore K, Oh A, Liu HJ, Cameron R, Richards H, Li Z, Adler D, Yoshinaga Y et al (2012) A resource for the conditional ablation of microRNAs in the mouse. Cell Rep 1:385–391PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ebert MS, Sharp PA (2012) Roles for MicroRNAs in conferring robustness to biological processes. Cell 149:505–524CrossRefGoogle Scholar
  10. 10.
    Herranz H, Cohen SM (2010) MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev 24:1339–1344PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Posadas DM, Carthew RW (2014) MicroRNAs and their roles in developmental canalization. Curr Opin Genet Dev 27:1–6PubMedCrossRefGoogle Scholar
  12. 12.
    Mendell JT, Olson EN (2012) MicroRNAs in stress signaling and human disease. Cell 148:1172–1187PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Riffo-Campos ÁL, Riquelme I, Brebi-Mieville P (2016) Tools for sequence-based miRNA target prediction: what to choose? Int J Mol Sci 17:424PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Pinzón N, Li B, Martinez L, Sergeeva A, Presumey J, Apparailly F, Seitz H (2017) microRNA target prediction programs predict many false positives. Genome Res 27:234–245PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Pal AS, Kasinski AL (2017) Animal models to study MicroRNA function. Adv Cancer Res 135:53–118PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Chandra S, Vimal D, Sharma D, Rai V, Gupta SC, Chowdhuri DK (2017) Role of miRNAs in development and disease: lessons learnt from small organisms. Life Sci 185:8–14PubMedCrossRefGoogle Scholar
  17. 17.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866PubMedCrossRefGoogle Scholar
  18. 18.
    Ventura A, Jacks T (2009) miRNAs and cancer: a little RNA goes a long way. Cell 136:586–591PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Iorio MV, Croce CM (2012) MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 4:143–159PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Peng Y, Croce CM (2016) The role of MicroRNAs in human cancer. Signal Transduct Target Ther 1:15004PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Jansson MD, Lund AH (2012) MicroRNA and cancer. Mol Oncol 6:590–610PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Frixa T, Donzelli S, Blandino G (2015) Oncogenic MicroRNAs: key players in malignant transformation. Cancers (Basel) 7:2466–2485CrossRefGoogle Scholar
  23. 23.
    Hayes J, Peruzzi PP, Lawler S (2014) MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med 20:460–469PubMedCrossRefGoogle Scholar
  24. 24.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedCrossRefGoogle Scholar
  25. 25.
    Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci 103:2257–2261PubMedCrossRefGoogle Scholar
  26. 26.
    Wang J, Chen J, Sen S (2016) MicroRNA as biomarkers and diagnostics. J Cell Physiol 231:25–30PubMedCrossRefGoogle Scholar
  27. 27.
    Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Publ Gr 16:203–221Google Scholar
  28. 28.
    Kasinski AL, Slack FJ (2011) MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 11:849–864PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Hanahan D, Weinberg R a (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefGoogle Scholar
  30. 30.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, Colaprico A, Wendl MC, Kim J, Reardon B et al (2018) Comprehensive characterization of Cancer driver genes and mutations. Cell 173:371–385.e18PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science (80–) 331:1553–1558PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Richardson HE, Portela M (2018) Modelling cooperative tumorigenesis in Drosophila. Biomed Res Int 2018:1–29CrossRefGoogle Scholar
  34. 34.
    Sonoshita M, Cagan RL (2017) Modeling human cancers in Drosophila. Curr Top Dev Biol 121:287–309PubMedCrossRefGoogle Scholar
  35. 35.
    Polesello C, Roch F, Gobert V, Haenlin M, Waltzer L (2011) Modeling cancers in Drosophila. Prog Mol Biol Transl Sci 100:51–82PubMedCrossRefGoogle Scholar
  36. 36.
    Herranz H, Eichenlaub T, Cohen SM (2016) Cancer in Drosophila: imaginal discs as a model for epithelial tumor formation. Curr Top Dev Biol 116:181–199PubMedCrossRefGoogle Scholar
  37. 37.
    Reiter LT, Potocki L, Chien S, Gribskov M, Bier E (2001) A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res 11:1114–1125PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Xu T, Wang W, Zhang S, Stewart RA, Yu W (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121:1053–1063PubMedPubMedCentralGoogle Scholar
  39. 39.
    Justice RW, Zilian O, Woods DF, Noll M, Bryant PJ (1995) The Drosophila tumor-suppressor gene warts encodes a homolog of human myotonic-dystrophy kinase and is required for the control of cell-shape and proliferation. Genes Dev 9:534–546PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Morgan TH (1917) The theory of the gene. Am Nat 51:513–544CrossRefGoogle Scholar
  41. 41.
    Nüsslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287:795–801PubMedCrossRefGoogle Scholar
  42. 42.
    Rudrapatna VA, Cagan RL, Das TK (2012) Drosophila cancer models. Dev Dyn 241:107–118PubMedCrossRefGoogle Scholar
  43. 43.
    Karim FD, Rubin GM (1998) Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. Development 125:1–9PubMedGoogle Scholar
  44. 44.
    Go MJ, D.S.E. and S.A.-T. (1998) Cell proliferation control by Notch signaling in Drosophila development. Development 125:2031–2040PubMedGoogle Scholar
  45. 45.
    Pagliarini RA (2003) A genetic screen in Drosophila for metastatic behavior. Science (80–) 302:1227–1231PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Brumby AM, Richardson HE (2003) Scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J 22:5769–5779PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Elsum I, Yates L, Humbert PO, Richardson HE (2012) The Scribble–Dlg–Lgl polarity module in development and cancer: from flies to man. Essays Biochem 53:141–168PubMedCrossRefGoogle Scholar
  48. 48.
    Kozomara A, Griffiths-Jones S (2014) MiRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42:68–73CrossRefGoogle Scholar
  49. 49.
    Bejarano F, Bortolamiol-Becet D, Dai Q, Sun K, Saj A, Chou Y-T, Raleigh DR, Kim K, Ni J-Q, Duan H et al (2012) A genome-wide transgenic resource for conditional expression of Drosophila microRNAs. Development 139:2821–2831PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Schertel C, Rutishauser T, Förstemann K, Basler K (2012) Functional characterization of Drosophila microRNAs by a novel in vivo library. Genetics 192:1543–1552PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Fulga TA, McNeill EM, Binari R, Yelick J, Blanche A, Booker M, Steinkraus BR, Schnall-Levin M, Zhao Y, Deluca T et al (2015) A transgenic resource for conditional competitive inhibition of conserved Drosophila microRNAs. Nat Commun 6:1–10CrossRefGoogle Scholar
  52. 52.
    Shu Z, Huang Y, Palmer WH, Tamori Y, Xie G, Wang H, Liu N, Deng W (2017) Systematic analysis reveals tumor-enhancing and -suppressing microRNAs in Drosophila epithelial tumors. Oncotarget 8:108825–108839PubMedPubMedCentralGoogle Scholar
  53. 53.
    Gateff E (1978) Malignant neoplasms of genetic origin in Drosophila melanogaster. Science (80–) 200:1448–1459PubMedCrossRefGoogle Scholar
  54. 54.
    Woodhouse E, Hersperger E, Shearn A (1998) Growth, metastasis, and invasiveness of Drosophila tumors caused by mutations in specific tumor suppressor genes. Dev Genes Evol 207:542–550PubMedCrossRefGoogle Scholar
  55. 55.
    Calleja M, Morata G, Casanova J (2016) Tumorigenic properties of Drosophila epithelial cells mutant for lethal giant larvae. Dev Dyn 245:834–843PubMedCrossRefGoogle Scholar
  56. 56.
    Daniel SG, Russ AD, Guthridge KM, Raina AI, Estes PS, Parsons LM, Richardson HE, Schroeder JA, Zarnescu DC (2018) miR-9a mediates the role of lethal giant larvae as an epithelial growth inhibitor in Drosophila. Biol Open 7:bio027391PubMedCrossRefGoogle Scholar
  57. 57.
    Nowek K, Wiemer EAC, Jongen-Lavrencic M, Nowek K, Wiemer EAC, Jongen-Lavrencic M, Nowek K, Wiemer EAC, Jongen-Lavrencic M (2018) The versatile nature of miR-9/9∗ in human cancer. Oncotarget 9:20838–20854PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J et al (2007) let-7 regulates self renewal and Tumorigenicity of breast Cancer cells. Cell 131:1109–1123PubMedCrossRefGoogle Scholar
  59. 59.
    Tsuchiya S, Fujiwara T, Sato F, Shimada Y, Tanaka E, Sakai Y, Shimizu K, Tsujimoto G (2011) MicroRNA-210 regulates cancer cell proliferation through targeting fibroblast growth factor receptor-like 1 (FGFRL1). J Biol Chem 286:420–428PubMedCrossRefGoogle Scholar
  60. 60.
    Banerjee A, Roy JK (2017) Study of bantam miRNA expression in brain tumour resulted due to loss of polarity modules in Drosophila melanogaster. J Genet 96:365–369PubMedCrossRefGoogle Scholar
  61. 61.
    Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113:25–36PubMedCrossRefGoogle Scholar
  62. 62.
    Reinhart BJ, Slack FJ, Basson M, Ruvkun G (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 5:91–103Google Scholar
  63. 63.
    Nair VS, Maeda LS, Ioannidis JPA (2012) Clinical outcome prediction by MicroRNAs in human cancer: a systematic review. J Natl Cancer Inst 104:528–540PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Jiang Y, Seimiya M, Schlumpf TB, Paro R (2018) An intrinsic tumour eviction mechanism in Drosophila mediated by steroid hormone signalling. Nat Commun 9:2–10CrossRefGoogle Scholar
  66. 66.
    Wu YC, Chen CH, Mercer A, Sokol NS (2012) Let-7-complex MicroRNAs regulate the temporal identity of Drosophila mushroom body neurons via chinmo. Dev Cell 23:202–209PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Flaherty MS, Salis P, Evans CJ, Ekas LA, Marouf A, Zavadil J, Banerjee U, Bach EA (2010) Chinmo is a functional effector of the JAK/STAT pathway that regulates eye development, tumor formation, and stem cell self-renewal in Drosophila. Dev Cell 18:556–568PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Doggett K, Turkel N, Willoughby LF, Ellul J, Murray MJ, Richardson HE, Brumby AM (2015) BTB-zinc finger oncogenes are required for ras and notch-driven tumorigenesis in drosophila. PLoS One 10:1–29CrossRefGoogle Scholar
  69. 69.
    Martinez A-M, Schuettengruber B, Sakr S, Janic A, Gonzalez C, Cavalli G (2009) Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nat Genet 41:1076–1082PubMedCrossRefGoogle Scholar
  70. 70.
    Classen A-K, Bunker BD, Harvey KF, Vaccari T, Bilder D (2009) A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling. Nat Genet 41:1150–1155PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Kozlova T, Thummel CS (2000) Steroid regulation of postembryonic development and reproduction in Drosophila. Trends Endocrinol Metab 11:276–280PubMedCrossRefGoogle Scholar
  72. 72.
    Sempere LF, Dubrovsky EB, Dubrovskaya VA, Berger EM, Ambros V (2002) The expression of the let-7 small regulatory RNA is controlled by ecdysone during metamorphosis in Drosophila melanogaster. Dev Biol 244:170–179PubMedCrossRefGoogle Scholar
  73. 73.
    Hipfner DR, Weigmann K, Cohen SM (2002) The bantam gene regulates Drosophila growth. Genetics 161:1527–1537PubMedPubMedCentralGoogle Scholar
  74. 74.
    Thompson BJ, Cohen SM (2006) The hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126:767–774PubMedCrossRefGoogle Scholar
  75. 75.
    Nolo R, Morrison CM, Tao C, Zhang X, Halder G (2006) The bantam MicroRNA is a target of the hippo tumor-suppressor pathway. Curr Biol 16:1895–1904PubMedCrossRefGoogle Scholar
  76. 76.
    Herranz H, Pérez L, Martín FA, Milán M (2008) A wingless and notch double-repression mechanism regulates G1-S transition in the Drosophila wing. EMBO J 27:1633–1645PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Becam I, Rafel N, Hong X, Cohen SM, Milan M (2011) Notch-mediated repression of bantam miRNA contributes to boundary formation in the Drosophila wing. Development 138:3781–3789PubMedCrossRefGoogle Scholar
  78. 78.
    Oh H, Irvine KD (2011) Cooperative regulation of growth by Yorkie and mad through bantam. Dev Cell 20:109–122PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Herranz H, Hong X, Cohen SM (2012) Mutual repression by bantam miRNA and Capicua links the EGFR/MAPK and Hippo pathways in growth control. Curr Biol 22:651–657PubMedCrossRefGoogle Scholar
  80. 80.
    Baker J (2017) A matter of life and death. J Med Ethics 43:427–434PubMedCrossRefGoogle Scholar
  81. 81.
    Herranz H, Hong X, Hung NT, Voorhoeve M, Cohen SM (2012) Oncogenic cooperation between SOCS family proteins and EGFR identified using a Drosophila epithelial transformation model. Genes Dev 26:1602–1611PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Herranz H, Weng R, Cohen SM (2014) Crosstalk between epithelial and mesenchymal tissues in tumorigenesis and imaginal disc development. Curr Biol 24:1476–1484PubMedCrossRefGoogle Scholar
  83. 83.
    Almudi I, Stocker H, Hafen E, Serras F (2009) SOCS36E speci fi cally interferes with sevenless signaling during Drosophila eye development. Dev Biol 326:212–223PubMedCrossRefGoogle Scholar
  84. 84.
    Callus BA, Mathey-Prevot B (2002) SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc. Oncogene 21:4812–4821PubMedCrossRefGoogle Scholar
  85. 85.
    Wu M, Pastor-Pareja JC, Xu T (2010) Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463:545–548PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Hong X, Nguyen HT, Chen Q, Zhang R, Hagman Z, Voorhoeve PM, Cohen SM (2014) Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover. EMBO J 33:2447–2457PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Sousa-Nunes R, Cheng LY, Gould AP (2010) Regulating neural proliferation in the Drosophila CNS. Curr Opin Neurobiol 20:50–57PubMedCrossRefGoogle Scholar
  88. 88.
    Doe CQ (2008) Neural stem cells: balancing self-renewal with differentiation. Development 135:1575–1587PubMedCrossRefGoogle Scholar
  89. 89.
    Song Y, Lu B (2011) Regulation of cell growth by Notch signaling and its differential requirement in normal vs. tumor-forming stem cells in Drosophila. Genes Dev 25:2644–2658PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Weng R, Cohen SM (2015) Control of Drosophila type I and type II central brain neuroblast proliferation by bantam microRNA. Development 142:3713–3720PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Ding R, Weynans K, Bossing T, Barros CS, Berger C (2016) The Hippo signalling pathway maintains quiescence in Drosophila neural stem cells. Nat Commun 7:1–12Google Scholar
  92. 92.
    Banerjee A, Roy JK (2017) Dicer-1 regulates proliferative potential of Drosophila larval neural stem cells through bantam miRNA based down-regulation of the G1/S inhibitor Dacapo. Dev Biol 423:57–65PubMedCrossRefGoogle Scholar
  93. 93.
    Wu YC, Lee KS, Song Y, Gehrke S, Lu B (2017) The bantam microRNA acts through Numb to exert cell growth control and feedback regulation of Notch in tumor-forming stem cells in the Drosophila brain. PLoS Genet 13:1–20Google Scholar
  94. 94.
    Shen S, Guo X, Yan H, Lu Y, Ji X, Li L, Liang T, Zhou D, Feng XH, Zhao JC et al (2015) A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis. Cell Res 25:997–1012PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Zhang W, Gao Y, Li P, Shi Z, Guo T, Li F, Han X, Feng Y, Zheng C, Wang Z et al (2014) VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res 24:331–343PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, He F, Wang Y, Zhang Z, Wang W et al (2014) A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 25:166–180PubMedCrossRefGoogle Scholar
  97. 97.
    Ma X, Wang H, Ji J, Xu W, Sun Y, Li W, Zhang X, Chen J, Xue L (2017) Hippo signaling promotes JNK-dependent cell migration. Proc Natl Acad Sci 114:1934–1939PubMedCrossRefGoogle Scholar
  98. 98.
    Artavanis-Tsakonas S, Matsuno K, Fortini M (1995) Notch signaling. Science (80–) 268:225–232PubMedCrossRefGoogle Scholar
  99. 99.
    Hori K, Sen A, Artavanis-Tsakonas S (2013) Notch signaling at a glance. J Cell Sci 126:2135–2140PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Domínguez M, de Celis JF (1998) A dorsal/ventral boundary established by Notch controls growth and polarity in the Drosophila eye. Nature 396:276–278PubMedCrossRefGoogle Scholar
  101. 101.
    Ferres-Marco D, Gutierrez-Garcia I, Vallejo DM, Bolivar J, Gutierrez-Aviño FJ, Dominguez M (2006) Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439:430–436CrossRefGoogle Scholar
  102. 102.
    Vallejo DM, Caparros E, Dominguez M (2011) Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells. EMBO J 30:756–769PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Da Ros VG, Gutierrez-Perez I, Ferres-Marco D, Dominguez M (2013) Dampening the signals transduced through Hedgehog via MicroRNA miR-7 facilitates Notch-induced Tumourigenesis. PLoS Biol 11:e1001554PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Aparicio R, Simoes Da Silva CJ, Busturia A (2015) MicroRNA miR-7 contributes to the control of Drosophila wing growth. Dev Dyn 244:21–30PubMedCrossRefGoogle Scholar
  105. 105.
    Yu J-Y, Reynolds SH, Hatfield SD, Shcherbata HR, Fischer KA, Ward EJ, Long D, Ding Y, Ruohola-Baker H (2009) Dicer-1-dependent Dacapo suppression acts downstream of insulin receptor in regulating cell division of Drosophila germline stem cells. Development 136:1497–1507PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Meza-Sosa KF, Pérez-García EI, Camacho-Concha N, López-Gutiérrez O, Pedraza-Alva G, Pérez-Martínez L (2014) MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4. PLoS One 9:e103987PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zhao J, Tao Y, Zhou Y, Qin N, Chen C, Tian D, Xu L (2015) MicroRNA-7: a promising new target in cancer therapy. Cancer Cell Int 15:1–8CrossRefGoogle Scholar
  108. 108.
    Li J, Qiu M, An Y, Huang J, Gong C (2018) miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the hedgehog pathway factor Gli3. Biochem Biophys Res Commun 503:2101–2107PubMedCrossRefGoogle Scholar
  109. 109.
    Svoronos AA, Engelman DM, Slack FJ (2016) OncomiR or tumor suppressor? The duplicity of MicroRNAs in cancer. Cancer Res 76:3666–3670PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S (1991) Specific EGF repeats of Notch mediate interactions with delta and serrate: implications for notch as a multifunctional receptor. Cell 67:687–699PubMedCrossRefGoogle Scholar
  111. 111.
    Humphries B, Yang C (2015) The microRNA-200 family: small molecules with novel roles in cancer development, progression and therapy. Oncotarget 6:6472–6498PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Feng X, Wang Z, Fillmore R, Xi Y (2014) MiR-200, a new star miRNA in human cancer. Cancer Lett 344:166–173PubMedCrossRefGoogle Scholar
  113. 113.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601PubMedCrossRefGoogle Scholar
  114. 114.
    Park SM, 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 22:894–907PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Antonello ZA, Reiff T, Ballesta-Illan E, Dominguez M (2015) Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8-Escargot switch. EMBO J 34:2025–2041PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Sossey-Alaoui K, Bialkowska K, Plow EF (2009) The miR200 family of microRNAs regulates WAVE3-dependent cancer cell invasion. J Biol Chem 284:33019–33029PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Sun Y, Shen S, Liu X, Tang H, Wang Z, Yu Z, Li X, Wu M (2014) MiR-429 inhibits cells growth and invasion and regulates EMT-related marker genes by targeting Onecut2 in colorectal carcinoma. Mol Cell Biochem 390:19–30PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Jurmeister S, Baumann M, Balwierz A, Keklikoglou I, Ward A, Uhlmann S, Zhang JD, Wiemann S, Sahin O (2012) MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F. Mol Cell Biol 32:633–651PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Bracken CP, Khew-Goodall Y, Goodall GJ (2015) Network-based approaches to understand the roles of miR-200 and other microRNAs in cancer. Cancer Res 75:2594–2599PubMedCrossRefGoogle Scholar
  120. 120.
    Loya CM, McNeill EM, Bao H, Zhang B, Van Vactor D (2014) miR-8 controls synapse structure by repression of the actin regulator enabled. Development 141:1864–1874PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Bolin K, Rachmaninoff N, Moncada K, Pula K, Kennell J, Buttitta L (2016) miR-8 modulates cytoskeletal regulators to influence cell survival and epithelial organization in Drosophila wings. Dev Biol 412:83–98PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Verrando P, Capovilla M, Rahmani R (2016) Trans-nonachlor decreases miR-141-3p levels in human melanocytes in vitro promoting melanoma cell characteristics and shows a multigenerational impact on miR-8 levels in Drosophila. Toxicology 368–369:129–141PubMedCrossRefGoogle Scholar
  123. 123.
    O’Brien SJ, Carter JV, Burton JF, Oxford BG, Schmidt MN, Hallion JC, Galandiuk S (2018) The role of the miR-200 family in epithelial–mesenchymal transition in colorectal cancer: a systematic review. Int J Cancer 142:2501–2511PubMedCrossRefGoogle Scholar
  124. 124.
    Pecot CV, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C, Wu S, Han HD, Shah MY, Rodriguez-Aguayo C et al (2013) Tumour angiogenesis regulation by the miR-200 family. Nat Commun 4:1–14CrossRefGoogle Scholar
  125. 125.
    Mateescu B, Batista L, Cardon M, Gruosso T, De Feraudy Y, Mariani O, Nicolas A, Meyniel JP, Cottu P, Sastre-Garau X et al (2011) MiR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med 17:1627–1635PubMedCrossRefGoogle Scholar
  126. 126.
    Li A, Omura N, Hong SM, Vincent A, Walter K, Griffith M, Borges M, Goggins M (2010) Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res 70:5226–5237PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Li Y, Sun J, Cai Y, Jiang Y, Wang X, Huang X, Yin Y, Li H (2016) MiR-200a acts as an oncogene in colorectal carcinoma by targeting PTEN. Exp Mol Pathol 101:308–313PubMedCrossRefGoogle Scholar
  128. 128.
    Yoneyama K, Ishibashi O, Kawase R, Kurose K, Takeshita T (2015) MiR-200a, miR-200b and miR-429 are onco-miRs that target the PTEN gene in endometrioid endometrial carcinoma. Anticancer Res 35:1401–1410PubMedGoogle Scholar
  129. 129.
    Eichenlaub T, Cohen SM, Herranz H (2016) Cell competition drives the formation of metastatic tumors in a Drosophila model of epithelial tumor formation. Curr Biol 26:1–9CrossRefGoogle Scholar
  130. 130.
    Sander M, Eichenlaub T, Herranz H (2018) Oncogenic cooperation between Yorkie and the conserved microRNA miR-8 in the wing disc of Drosophila. Development 4:11–21Google Scholar
  131. 131.
    Hyun S, Lee JH, Jin H, Nam J, Namkoong B, Lee G, Chung J, Kim VN (2009) Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K. Cell 139:1096–1108PubMedCrossRefGoogle Scholar
  132. 132.
    Bilder D (2004) Epithelial polarity and proliferation control: links from the Drosophila neoplastictumor suppressors. Genes Dev 18:1909–1925CrossRefGoogle Scholar
  133. 133.
    Morata G, Ripoll P (1975) Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev Biol 42:211–221PubMedCrossRefGoogle Scholar
  134. 134.
    Neufeld T (1994) The Drosophila peanut gene is required for cytokinesis and encodes a protein similar to yeast putative bud neck filament proteins. Cell 77:371–379PubMedCrossRefGoogle Scholar
  135. 135.
    Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, Lawrence MS, Zhang C, Wala J, Mermel CH et al (2013) Pan-cancer patterns of somatic copy number alteration. Nat Genet 45:1134–1140PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Gerlach SU, Eichenlaub T, Herranz H (2018) Yorkie and JNK control tumorigenesis in Drosophila cells with cytokinesis failure. Cell Rep 23:1491–1503PubMedCrossRefGoogle Scholar
  137. 137.
    Lin S, Gregory RI (2015) MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15:321–333PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419PubMedCrossRefGoogle Scholar
  139. 139.
    Denli A, Tops B, Plasterk R, Ketting R, Hannon GJ (2004) Processing of primary microRNAs by the microprocessor complex. Nature 97:207–224Google Scholar
  140. 140.
    Lee Y, Jeon K, Lee J, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21:4663–4670PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Förstemann K, Horwich MD, Wee L, Tomari Y, Zamore PD (2007) Drosophila microRNAs are sorted into functionally distinct Argonaute complexes after production by Dicer-1. Cell 130:287–297PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Tomari Y, Du T, Zamore PD (2007) Sorting of Drosophila small silencing RNAs. Cell 130:299–308PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Kawamata T, Tomari Y (2010) Making RISC. Trends Biochem Sci 35:368–376PubMedCrossRefGoogle Scholar
  144. 144.
    Liu N, Abe M, Sabin LR, Hendriks GJ, Naqvi AS, Yu Z, Cherry S, Bonini NM (2011) The exoribonuclease nibbler controls 3′ end processing of microRNAs in drosophila. Curr Biol 21:1888–1893PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Han BW, Hung JH, Weng Z, Zamore PD, Ameres SL (2011) The 3′-to-5′ exoribonuclease nibbler shapes the 3′ ends of microRNAs bound to drosophila argonaute1. Curr Biol 21:1878–1887PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Castillejo-López C, Cai X, Fahmy K, Baumgartner S (2018) Drosophila exoribonuclease nibbler is a tumor suppressor, acts within the RNAi machinery and is not enriched in the nuage during early oogenesis. Hereditas 155:12PubMedCrossRefGoogle Scholar
  147. 147.
    Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, Nelson DL, Moses K, Warren ST (2004) Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat Neurosci 7:113–117PubMedCrossRefGoogle Scholar
  148. 148.
    Zarnescu DC, Jin P, Betschinger J, Nakamoto M, Wang Y, Dockendorff TC, Feng Y, Jongens TA, Sisson JC, Knoblich JA et al (2005) Fragile X protein functions with Lgl and the PAR complex in flies and mice. Dev Cell 8:43–52PubMedCrossRefGoogle Scholar
  149. 149.
    Herranz H, Hong X, Pérez L, Ferreira A, Olivieri D, Cohen SM, Milán M (2010) The miRNA machinery targets Mei-P26 and regulates Myc protein levels in the Drosophila wing. EMBO J 29:1688–1698PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Ferreira A, Boulan L, Perez L, Milán M (2014) Mei-P26 mediates tissue-specific responses to the brat tumor suppressor and the dMyc proto-oncogene in Drosophila. Genetics 198:249–258PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Clavería C, Torres M (2016) Cell competition: mechanisms and physiological roles. Annu Rev Cell Dev Biol 32:411–439CrossRefGoogle Scholar
  152. 152.
    Di Gregorio A, Bowling S, Rodriguez TA (2016) Cell competition and its role in the regulation of cell fitness from development to Cancer. Dev Cell 38:621–634PubMedCrossRefGoogle Scholar
  153. 153.
    Moreno E, Basler K (2004) dMyc transforms cells into super-competitors. Cell 117:117–129PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA (2004) Drosophila Myc regulates organ size by inducing cell competition. Cell 117:107–116PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Hatfield SD, Shcherbata HR, Fischer KA, Nakahara K, Carthew RW, Ruohola-Baker H (2005) Stem cell division is regulated by the microRNA pathway. Nature 435:974–978PubMedCrossRefGoogle Scholar
  156. 156.
    Park JK, Liu X, Strauss TJ, McKearin DM, Liu Q (2007) The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells. Curr Biol 17:533–538PubMedCrossRefGoogle Scholar
  157. 157.
    Jin Z, Xie T (2007) Dcr-1 maintains Drosophila ovarian stem cells. Curr Biol 17:539–544PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Shcherbata HR, Ward EJ, Fischer KA, Yu JY, Reynolds SH, Chen CH, Xu P, Hay BA, Ruohola-Baker H (2007) Stage-specific differences in the requirements for germline stem cell maintenance in the Drosophila ovary. Cell Stem Cell 1:698–709PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Schwamborn JC, Berezikov E, Knoblich JA (2009) The TRIM-NHL protein TRIM32 activates MicroRNAs and prevents self-renewal in mouse neural progenitors. Cell 136:913–925PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Lazzari E, Meroni G (2016) TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: from muscular dystrophy to tumours. Int J Biochem Cell Biol 79:469–477PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Liu J, Zhang C, Wang XL, Ly P, Belyi V, Xu-Monette ZY, Young KH, Hu W, Feng Z (2014) E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. Cell Death Differ 21:1792–1804PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Bieging KT, Mello SS, Attardi LD (2014) Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 14:359–370PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Hermeking H (2012) MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer 12:613–626PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Liu J, Zhang C, Zhao Y, Feng Z (2017) MicroRNA control of p53. J Cell Biochem 118:7–14PubMedCrossRefGoogle Scholar
  165. 165.
    Barrio L, Dekanty A, Milán M (2014) MicroRNA-mediated regulation of Dp53 in the Drosophila fat body contributes to metabolic adaptation to nutrient deprivation. Cell Rep 8:528–541PubMedCrossRefGoogle Scholar
  166. 166.
    Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Cellular and Molecular MedicineUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations