Skip to main content
SpringerLink
Log in

Oncogenic functions of ZEB1 in pediatric solid cancers: interplays with microRNAs and long noncoding RNAs

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activities in cell function and embryonic development, including driving epithelial-mesenchymal transition. Several aspects of ZEB1 function can be regulated by its functional interactions with noncoding RNA types, namely microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Increasing evidence indicates that ZEB1 importantly influences cancer initiation, tumor progression, metastasis, and resistance to treatment. Cancer is the main disease-related cause of death in children and adolescents. Although the role of ZEB1 in pediatric cancer is still poorly understood, emerging findings have shown that it is expressed and regulates childhood solid tumors including osteosarcoma, retinoblastoma, neuroblastoma, and central nervous system tumors. Here, we review the evidence supporting a role for ZEB1, and its interplays with miRNAs and lncRNAs, in pediatric cancers.

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
Fig. 3

Similar content being viewed by others

References

  1. Lawlor ER, Thiele CJ (2012) Epigenetic changes in pediatric solid tumors: promising new targets. Clin Cancer Res 18:2768–2779. https://doi.org/10.1158/1078-0432.CCR-11-1921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Marshall GM, Carter DR, Cheung BB et al (2014) The prenatal origins of cancer. Nat Rev Cancer 14(4):277–289. https://doi.org/10.1038/nrc3679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nieto MA, Huang RY, Jackson RA, Thiery JP (2016) EMT: 2016. Cell 166:21–45. https://doi.org/10.1016/j.cell.2016.06.028

    Article  CAS  PubMed  Google Scholar 

  4. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890. https://doi.org/10.1016/j.cell.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  5. Wang H, Xiao Z, Zheng J et al (2019) ZEB1 represses neural differentiation and cooperates with CTBP2 to dynamically regulate cell migration during neocortex development. Cell Rep 27:2335-2353.e6. https://doi.org/10.1016/j.celrep.2019.04.081

    Article  CAS  PubMed  Google Scholar 

  6. Caramel J, Ligier M, Puisieux A (2018) Pleiotropic roles for ZEB1 in cancer. Cancer Res 78:30–35. https://doi.org/10.1158/0008-5472.CAN-17-2476

    Article  CAS  PubMed  Google Scholar 

  7. Funahashi J, Kamachi Y, Goto K, Kondoh H (1991) Identification of nuclear factor δEF1 and its binding site essential for lens-specific activity of the δ1-crystallin enhancer. Nucleic Acids Res 19:3543–3547. https://doi.org/10.1093/nar/19.13.3543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Williams TM, Moolten D, Burlein J et al (1991) Identification of a zinc finger protein that inhibits IL-2 gene expression. Science 254:1791–1794. https://doi.org/10.1126/science.1840704

    Article  CAS  PubMed  Google Scholar 

  9. Lai Z, Fortini ME, Rubin GM (1991) The embryonic expression patterns of zfh-1 and zfh-2, two Drosophila genes encoding novel zinc-finger homeodomain proteins. Mech Dev 34:2–3. https://doi.org/10.1016/0925-4773(91)90049-C

    Article  Google Scholar 

  10. Funahashi J, Sekido R, Murai K, Kamachi Y, Kondoh H (1993) Delta-crystallin enhancer binding protein delta EF1 is a zinc finger-homeodomain protein implicated in postgastrulation embryogenesis. Development 119:433–446

    Article  CAS  Google Scholar 

  11. Takagi T, Moribe H, Kondoh H, Higashi Y (1998) DeltaEF1, a zinc finger and homeodomain transcription factor, is required for skeleton patterning in multiple lineages. Development 125:21–31

    Article  CAS  Google Scholar 

  12. Remacle JE, Kraft H, Lerchner W et al (1999) New mode of DNA binding of multi-zinc finger transcription factors: δEF1 family members bind with two hands to two target sites. EMBO J 18:5073–5084. https://doi.org/10.1093/emboj/18.18.5073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu HT, Zhong HT, Li GW et al (2020) Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer. J Transl Med 18:51. https://doi.org/10.1186/s12967-020-02240-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fortini ME, Lai ZC, Rubin GM (1991) The Drosophila zfh-1 and zfh-2 genes encode novel proteins containing both zinc-finger and homeodomain motifs. Mech Dev 34(2–3):113–122. https://doi.org/10.1016/0925-4773(91)90048-b

    Article  CAS  PubMed  Google Scholar 

  15. Gheldof A, Hulpiau P, van Roy F, De Craene B, Berx G (2012) Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cell Mol Life Sci 69(15):2527–2541. https://doi.org/10.1007/s00018-012-0935-3

    Article  CAS  PubMed  Google Scholar 

  16. Zhang S, Liao W, Wu Q, Huang X, Pan Z, Chen W, Gu S, Huang Z, Wang Y, Tang X, Liang S, Zhang X, Chen Y, Chen S, Chen W, Jiang Y, Chen C, Qiu G (2020) LINC00152 upregulates ZEB1 expression and enhances epithelial-mesenchymal transition and oxaliplatin resistance in esophageal cancer by interacting with EZH2. Cancer Cell Int 20(1):569. https://doi.org/10.1186/s12935-020-01620-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Llorens MC, Lorenzatti G, Cavallo NL et al (2016) Phosphorylation regulates functions of ZEB1 transcription factor. J Cell Physiol 231:2205–2217. https://doi.org/10.1002/jcp.25338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Siles L, Ninfali C, Cortés M, Darling DS, Postigo A (2019) ZEB1 protects skeletal muscle from damage and is required for its regeneration. Nat Commun 10:1364. https://doi.org/10.1038/s41467-019-08983-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fouani L, Huang MLH, Cole L, Jansson PJ, Kovacevic Z, Richardson DR (2020) During mitosis ZEB1 “switches” from being a chromatin-bound epithelial gene repressor, to become a microtubule-associated protein. Biochim Biophys Acta Mol Cell Res 1867:118673. https://doi.org/10.1016/j.bbamcr.2020.118673

    Article  CAS  PubMed  Google Scholar 

  20. Vandewalle C, Van Roy F, Berx G (2009) The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 66(5):773–787. https://doi.org/10.1007/s00018-008-8465-8

    Article  CAS  PubMed  Google Scholar 

  21. Lazarova DL, Bordonaro M, Sartorelli AC (2001) Transcriptional regulation of the vitamin D(3) receptor gene by ZEB. Cell Growth Differ 12:319–326

    CAS  PubMed  Google Scholar 

  22. Ponticos M, Partridge T, Black CM, Abraham DJ, Bou-Gharios G (2004) Regulation of collagen type I in vascular smooth muscle cells by competition between Nkx2.5 and deltaEF1/ZEB1. Mol Cell Biol 24:6151–6161. https://doi.org/10.1128/MCB.24.14.6151-6161.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yasui DH, Genetta T, Kadesch T, Williams TM, Swain SL, Tsui LV, Huber BT (1998) Transcriptional repression of the IL-2 gene in Th cells by ZEB. J Immunol 160:4433–4440

    CAS  PubMed  Google Scholar 

  24. Vannier C, Mock K, Brabletz T, Driever W (2013) Zeb1 regulates E-cadherin and Epcam (epithelial cell adhesion molecule) expression to control cell behavior in early zebrafish development. J Biol Chem 288:18643–18659. https://doi.org/10.1074/jbc.M113.467787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gu Y, Zhao Y, Zhou Y, Xie Y, Ju P, Long Y et al (2016) Zeb1 is a potential regulator of Six2 in the proliferation, apoptosis and migration of metanephric mesenchyme cells. Int J Mol Sci 17:1283. https://doi.org/10.3390/ijms17081283

    Article  CAS  PubMed Central  Google Scholar 

  26. Cencioni C, Spallotta F, Savoia M et al (2018) Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells. Nat Commun 9:1281. https://doi.org/10.1038/s41467-018-03668-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luo Z, Wen G, Wang G et al (2013) MicroRNA-200C and -150 play an important role in endothelial cell differentiation and vasculogenesis by targeting transcription repressor ZEB1. Stem Cells 31:1749–1762. https://doi.org/10.1002/stem.1448

    Article  CAS  PubMed  Google Scholar 

  28. Lim W, Song G (2015) Novel genes and hormonal regulation for gonadal development during embryogenesis in chickens. Gen Comp Endocrinol 211:20–27. https://doi.org/10.1016/j.ygcen.2014.11.009

    Article  CAS  PubMed  Google Scholar 

  29. Yang S, Zhao L, Yang J (2007) deltaEF1 represses BMP-2-induced differentiation of C2C12 myoblasts into the osteoblast lineage. J Biomed Sci 14:663–679. https://doi.org/10.1007/s11373-007-9155-5

    Article  CAS  PubMed  Google Scholar 

  30. Jiang Y, Yan L, Xia L (2018) Zinc finger E-box-binding homeobox 1 (ZEB1) is required for neural differentiation of human embryonic stem cells. J Biol Chem 293:19317–19329. https://doi.org/10.1074/jbc.RA118.005498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kahlert UD, Suwala AK, Raabe EH et al (2015) ZEB1 promotes invasion in human fetal neural stem cells and hypoxic glioma neurospheres. Brain Pathol 25:724–732. https://doi.org/10.1111/bpa.12240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Singh S, Howell D, Trivedi N et al (2016) Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition. Elife 5:e12717. https://doi.org/10.7554/eLife.12717

    Article  PubMed  PubMed Central  Google Scholar 

  33. Cheng L, Zhou MY, Gu YJ, Chen L, Wang Y (2021) ZEB1: new advances in fibrosis and cancer. Mol Cell Biochem 476(4):1643–1650. https://doi.org/10.1007/s11010-020-04036-7

    Article  CAS  PubMed  Google Scholar 

  34. Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y (2013) Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat 138:81–90. https://doi.org/10.1007/s10549-013-2442-0

    Article  CAS  PubMed  Google Scholar 

  35. Lehmann W, Mossmann D, Kleemann J (2016) ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat Commun 7:10498. https://doi.org/10.1038/ncomms10498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu Y, El-Naggar S, Darling DS, Higashi Y, Dean DC (2008) Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135:579–588. https://doi.org/10.1242/dev.007047

    Article  CAS  PubMed  Google Scholar 

  37. Liu Y, Lu X, Huang L et al (2014) Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis. Nat Commun 5:5660. https://doi.org/10.1038/ncomms6660

    Article  PubMed  Google Scholar 

  38. Larsen JE, Nathan V, Osborne JK et al (2016) ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Invest 126:3219–3235. https://doi.org/10.1172/JCI76725

    Article  PubMed  PubMed Central  Google Scholar 

  39. Caramel J, Papadogeorgakis E, Hill L (2013) A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24:466–480. https://doi.org/10.1016/j.ccr.2013.08.018

    Article  CAS  PubMed  Google Scholar 

  40. Gregory PA, Bert AG, Paterson EL et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601. https://doi.org/10.1038/ncb1722

    Article  CAS  PubMed  Google Scholar 

  41. Wellner U, Schubert J, Burk UC et al (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11:1487–1495. https://doi.org/10.1038/ncb1998

    Article  CAS  PubMed  Google Scholar 

  42. Pauli A, Rinn JL, Schier AF (2011) Non-coding RNAs as regulators of embryogenesis. Nat Rev Genet 12:136–149. https://doi.org/10.1038/nrg2904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bicker S, Schratt G (2008) MicroRNAs: tiny regulators of synapse function in development and disease. J Cell Mol Med 12(5A):1466–1476. https://doi.org/10.1111/j.1582-4934.2008.00400.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fiore R, Siegel G, Schratt G (2008) MicroRNA function in neuronal development, plasticity and disease. Biochim Biophys Acta 1779:471–478. https://doi.org/10.1016/j.bbagrm.2007.12.006

    Article  CAS  PubMed  Google Scholar 

  45. Schratt G (2009) Fine-tuning neural gene expression with microRNAs. Curr Opin Neurobiol 19:213–219. https://doi.org/10.1016/j.conb.2009.05.015

    Article  CAS  PubMed  Google Scholar 

  46. Bredy TW, Lin Q, Wei W, Baker-Andresen D, Mattick JS (2011) MicroRNA regulation of neural plasticity and memory. Neurobiol Learn Mem 96:89–94. https://doi.org/10.1016/j.nlm.2011.04.004

    Article  CAS  PubMed  Google Scholar 

  47. Mercer TR, Mattick JS (2013) Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol 20:300–307. https://doi.org/10.1038/nsmb.2480

    Article  CAS  PubMed  Google Scholar 

  48. Briggs JA, Wolvetang EJ, Mattick JS, Rinn JL, Barry G (2015) Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron 88:861–877. https://doi.org/10.1016/j.neuron.2015.09.045

    Article  CAS  PubMed  Google Scholar 

  49. Ashrafizadeh M, Ang HL, Moghadam ER (2020) MicroRNAs and their influence on the ZEB family: mechanistic aspects and therapeutic applications in cancer therapy. Biomolecules 10:1040. https://doi.org/10.3390/biom10071040

    Article  CAS  PubMed Central  Google Scholar 

  50. Chen G, Huang P, Xie J, Li R (2018) MicroRNA-211 suppresses the growth and metastasis of cervical cancer by directly targeting ZEB1. Mol Med Rep 17:1275–1282. https://doi.org/10.3892/mmr.2017.8006

    Article  CAS  PubMed  Google Scholar 

  51. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196. https://doi.org/10.1038/nrm3758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma Z, Li Y, Xu J, Ren Q, Yao J, Tian X (2016) MicroRNA-409-3p regulates cell invasion and metastasis by targeting ZEB1 in breast cancer. IUBMB Life 68:394–402. https://doi.org/10.1002/iub.1494

    Article  CAS  PubMed  Google Scholar 

  53. Liang TC, Fu WG, Zhong YS (2019) MicroRNA-1236-3p inhibits proliferation and invasion of breast cancer cells by targeting ZEB1. Eur Rev Med Pharmacol Sci 23:9988–9995. https://doi.org/10.26355/eurrev_201911_19565

    Article  PubMed  Google Scholar 

  54. Krebs AM, Mitschke J, Lasierra Losada M 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. https://doi.org/10.1038/ncb3513

    Article  CAS  PubMed  Google Scholar 

  55. Hur K, Toiyama Y, Takahashi M et al (2013) MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut 62:1315–1326. https://doi.org/10.1136/gutjnl-2011-301846

    Article  CAS  PubMed  Google Scholar 

  56. Chen L, Gibbons DL, Goswami S (2014) Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 5:5241. https://doi.org/10.1038/ncomms6241

    Article  CAS  PubMed  Google Scholar 

  57. Li T, Xie J, Shen C et al (2016) Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma. Oncogene 35:1575–1584. https://doi.org/10.1038/onc.2015.223

    Article  CAS  PubMed  Google Scholar 

  58. Su W, Xu M, Chen X et al (2017) Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer. Mol Cancer 16:142. https://doi.org/10.1186/s12943-017-0711-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zuo XL, Cai J, Chen ZQ et al (2018) The utility of long non-coding RNA ZEB1-AS1 as a prognostic biomarker in human solid tumors: a meta-analysis. Clin Chim Acta 485:14–20. https://doi.org/10.1016/j.cca.2018.06.018

    Article  CAS  PubMed  Google Scholar 

  60. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629. https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang P, Wei Y, Wang L (2014) ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol 16:864–875. https://doi.org/10.1038/ncb3013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Siebzehnrubl FA, Silver DJ, Tugertimur B (2013) The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Mol Med 5:1196–1212. https://doi.org/10.1002/emmm.201302827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zou J, Liu L, Wang Q (2017) Downregulation of miR-429 contributes to the development of drug resistance in epithelial ovarian cancer by targeting ZEB1. Am J Transl Res 9:1357–1368

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang M, Zhang R, Zhang S, Xu R, Yang Q (2019) MicroRNA-574-3p regulates epithelial mesenchymal transition and cisplatin resistance via targeting ZEB1 in human gastric carcinoma cells. Gene 700:110–119. https://doi.org/10.1016/j.gene.2019.03.043

    Article  CAS  PubMed  Google Scholar 

  65. Meidhof S, Brabletz S, Lehmann W et al (2015) ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med 7:831–847. https://doi.org/10.15252/emmm.201404396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang Z, Lee JC, Lin L et al (2012) Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44:852–860. https://doi.org/10.1038/ng.2330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Haddad Y, Choi W, McConkey DJ (2009) Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines. Clin Cancer Res 15:532–542. https://doi.org/10.1158/1078-0432.CCR-08-1733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Richard G, Dalle S, Monet MA et al (2016) ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol Med 8:1143–1161. https://doi.org/10.15252/emmm.201505971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang J, Zhang W (2013) New molecular insights into osteosarcoma targeted therapy. Curr Opin Oncol 25(2013):398–406. https://doi.org/10.1097/CCO.0b013e3283622c1b

    Article  CAS  PubMed  Google Scholar 

  70. Mei Q, Li F, Quan H, Liu Y, Xu H (2014) Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo. Cancer Sci 105:755–762. https://doi.org/10.1111/cas.12436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Xu XM, Liu W, Cao ZH, Liu MX (2017) Effects of ZEB1 on regulating osteosarcoma cells via NF-κB/iNOS. Eur Rev Med Pharmacol Sci 21:1184–1190

    PubMed  Google Scholar 

  72. Yu XJ, Guo XZ, Li C et al (2019) SIRT1-ZEB1-positive feedback promotes epithelial-mesenchymal transition process and metastasis of osteosarcoma. J Cell Biochem 120:3727–3735. https://doi.org/10.1002/jcb.27653

    Article  CAS  PubMed  Google Scholar 

  73. Liu J, Wu Q, Wang Y et al (2018) Ovol2 induces mesenchymal-epithelial transition via targeting ZEB1 in osteosarcoma. Onco Targets Ther 11:2963–2973. https://doi.org/10.2147/OTT.S157119

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ming H, Chuang Q, Jiashi W et al (2018) Naringin targets Zeb1 to suppress osteosarcoma cell proliferation and metastasis. Aging (Albany NY) 10:4141–4151. https://doi.org/10.18632/aging.101710

    Article  CAS  Google Scholar 

  75. Han X, Liu F, Zhang C, Ren Z, Li L, Wang G (2019) SIAH1/ZEB1/IL-6 axis is involved in doxorubicin (Dox) resistance of osteosarcoma cells. Biol Chem 400:545–553. https://doi.org/10.1515/hsz-2018-0292

    Article  CAS  PubMed  Google Scholar 

  76. Wang D, Qian G, Wang J (2019) Visfatin is involved in the cisplatin resistance of osteosarcoma cells via upregulation of Snail and Zeb1. Cancer Biol Ther 20:999–1006. https://doi.org/10.1080/15384047.2019.1591675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang T, Wang D, Zhang L et al (2019) The TGFβ-miR-499a-SHKBP1 pathway induces resistance to EGFR inhibitors in osteosarcoma cancer stem cell-like cells. J Exp Clin Cancer Res 38:226. https://doi.org/10.1186/s13046-019-1195-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li Y, Zeng C, Tu M et al (2016) MicroRNA-200b acts as a tumor suppressor in osteosarcoma via targeting ZEB1. Onco Targets Ther 9:3101–3111. https://doi.org/10.2147/OTT.S96561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Al-Khalaf HH, Aboussekhra A (2014) MicroRNA-141 and microRNA-146b-5p inhibit the prometastatic mesenchymal characteristics through the RNA-binding protein AUF1 targeting the transcription factor ZEB1 and the protein kinase AKT. J Biol Chem 289:31433–31447. https://doi.org/10.1074/jbc.M114.593004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Deng Y, Luan F, Zeng L, Zhang Y, Ma K (2017) MiR-429 suppresses the progression and metastasis of osteosarcoma by targeting ZEB1. EXCLI J 16:618–627. https://doi.org/10.17179/excli2017-258

    Article  PubMed  PubMed Central  Google Scholar 

  81. Yi L, Liu M, Tang Z (2017) MicroRNA-130a inhibits growth and metastasis of osteosarcoma cells by directly targeting ZEB1. Mol Med Rep 16:3606–3612. https://doi.org/10.3892/mmr.2017.6968

    Article  CAS  PubMed  Google Scholar 

  82. Xu J, Wang Z, Liao Z, Dai D, Ma X (2017) MicroRNA-150 functions as an antioncogenic regulator in osteosarcoma. Oncol Lett 14:2483–2490. https://doi.org/10.3892/ol.2017.6393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. He J, Xiang D, Lin Y (2019) MicroRNA-708 inhibits the proliferation and invasion of osteosarcoma cells by directly targeting ZEB1. Mol Med Rep 19:3948–3954. https://doi.org/10.3892/mmr.2019.10013

    Article  CAS  PubMed  Google Scholar 

  84. Wu L, Zhang Y, Huang Z et al (2019) MiR-409-3p inhibits cell proliferation and invasion of osteosarcoma by targeting zinc-finger e-box-binding homeobox-1. Front Pharmacol 10:137. https://doi.org/10.3389/fphar.2019.00137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Feng T, Zhu Z, Jin Y et al (2020) The microRNA-708-5p/ZEB1/EMT axis mediates the metastatic potential of osteosarcoma. Oncol Rep 43:491–502. https://doi.org/10.3892/or.2019.7452

    Article  CAS  PubMed  Google Scholar 

  86. Wang H, Xing D, Ren D et al (2017) MicroRNA-643 regulates the expression of ZEB1 and inhibits tumorigenesis in osteosarcoma. Mol Med Rep 16:5157–5164. https://doi.org/10.3892/mmr.2017.7273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yan H, Zhang B, Fang C, Chen L (2018) miR-340 alleviates chemoresistance of osteosarcoma cells by targeting ZEB1. Anticancer Drugs 29:440–448. https://doi.org/10.1097/CAD.0000000000000614

    Article  CAS  PubMed  Google Scholar 

  88. Liu C, Lin J (2016) Long noncoding RNA ZEB1-AS1 acts as an oncogene in osteosarcoma by epigenetically activating ZEB1. Am J Transl Res 8:4095–4105

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu C, Pan C, Cai Y, Wang H (2017) Interplay between long noncoding RNA ZEB1-AS1 and miR-200s regulates osteosarcoma cell proliferation and migration. J Cell Biochem 118:2250–2260. https://doi.org/10.1002/jcb.25879

    Article  CAS  PubMed  Google Scholar 

  90. Han F, Wang C, Wang Y, Zhang L (2017) Long noncoding RNA ATB promotes osteosarcoma cell proliferation, migration and invasion by suppressing miR-200s. Am J Cancer Res 7:770–783

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang Y, Kong D (2018) Knockdown of lncRNA MEG3 inhibits viability, migration, and invasion and promotes apoptosis by sponging miR-127 in osteosarcoma cell. J Cell Biochem 119:669–679. https://doi.org/10.1002/jcb.26230

    Article  CAS  PubMed  Google Scholar 

  92. Zhu C, Cheng D, Qiu X, Zhuang M, Liu Z (2018) Long noncoding RNA SNHG16 promotes cell proliferation by sponging microRNA-205 and upregulating ZEB1 expression in osteosarcoma. Cell Physiol Biochem 51:429–440. https://doi.org/10.1159/000495239

    Article  CAS  PubMed  Google Scholar 

  93. Wang B, Qu XL, Liu J, Lu J, Zhou ZY (2019) HOTAIR promotes osteosarcoma development by sponging miR-217 and targeting ZEB1. J Cell Physiol 234:6173–6181. https://doi.org/10.1002/jcp.27394

    Article  CAS  PubMed  Google Scholar 

  94. Jin H, Jin X, Chai W et al (2019) Long non-coding RNA MIAT competitively binds miR-150-5p to regulate ZEB1 expression in osteosarcoma. Oncol Lett 17:1229–1236. https://doi.org/10.3892/ol.2018.9671

    Article  CAS  PubMed  Google Scholar 

  95. Yao H, Hou G, Wang QY et al (2020) LncRNA SPRY4-IT1 promotes progression of osteosarcoma by regulating ZEB1 and ZEB2 expression through sponging of miR-101 activity. Int J Oncol 56:85–100. https://doi.org/10.3892/ijo.2019.4910

    Article  CAS  PubMed  Google Scholar 

  96. Wu K, Feng Q, Li L et al (2020) Long-noncoding RNA PCAT6 aggravates osteosarcoma tumourigenesis via the MiR-143-3p/ZEB1 axis. Onco Targets Ther 13:8705–8714. https://doi.org/10.2147/OTT.S258415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhou Y, Li X, Yang H (2020) LINC00612 functions as a ceRNA for miR-214-5p to promote the proliferation and invasion of osteosarcoma in vitro and in vivo. Exp Cell Res 392:112012. https://doi.org/10.1016/j.yexcr.2020.112012

    Article  CAS  PubMed  Google Scholar 

  98. Liu L, Zheng M, Wang X, Gao Y, Gu Q (2020) LncRNA NR_136400 suppresses cell proliferation and invasion by acting as a ceRNA of TUSC5 that is modulated by miR-8081 in osteosarcoma. Front Pharmacol 11:641. https://doi.org/10.3389/fphar.2020.00641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kivelä T (2009) The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol 93:1129–1131. https://doi.org/10.1136/bjo.2008.150292

    Article  PubMed  Google Scholar 

  100. Avior Y, Lezmi E, Yanuka D, Benvenisty N (2017) Modeling developmental and tumorigenic aspects of trilateral retinoblastoma via human embryonic stem cells. Stem Cell Reports 8:1354–1365. https://doi.org/10.1016/j.stemcr.2017.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang Y, Luo Y, Guan W, Zhao H (2018) Role of miR-23a/Zeb1 negative feedback loop in regulating epithelial-mesenchymal transition and tumorigenicity of intraocular tumors. Oncol Lett 16:2462–2470. https://doi.org/10.3892/ol.2018.8940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Asnaghi L, White DT, Key N (2019) ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma. Oncogene 38:2056–2075. https://doi.org/10.1038/s41388-018-0543-2

    Article  CAS  PubMed  Google Scholar 

  103. Cheng Y, Chang Q, Zheng B et al (2019) LncRNA XIST promotes the epithelial to mesenchymal transition of retinoblastoma via sponging miR-101. Eur J Pharmacol 843:210–216. https://doi.org/10.1016/j.ejphar.2018.11.028

    Article  CAS  PubMed  Google Scholar 

  104. Fetahu IS, Taschner-Mandl S (2021) Neuroblastoma and the epigenome. Cancer Metastasis Rev 40:173–189. https://doi.org/10.1007/s10555-020-09946-y

    Article  PubMed  PubMed Central  Google Scholar 

  105. Almeida VR, Vieira IA, Buendia M et al (2017) Combined treatments with a retinoid receptor agonist and epigenetic modulators in human neuroblastoma cells. Mol Neurobiol 54:7610–7619. https://doi.org/10.1007/s12035-016-0250-3

    Article  CAS  PubMed  Google Scholar 

  106. Ragusa M, Majorana A, Banelli B et al (2010) MIR152, MIR200B, and MIR338, human positional and functional neuroblastoma candidates, are involved in neuroblast differentiation and apoptosis. J Mol Med (Berl) 88:1041–1053. https://doi.org/10.1007/s00109-010-0643-0

    Article  CAS  Google Scholar 

  107. Wu J, Cheng P, Huang Z, Tan Q, Qu Y (2019) Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1. BioFactors 45:355–363. https://doi.org/10.1002/biof.1505

    Article  CAS  PubMed  Google Scholar 

  108. Yang J, Shao X, Wang L et al (2019) Angelica polysaccharide exhibits antitumor effect in neuroblastoma cell line SH-SY5Y by up-regulation of miR-205. BioFactors. https://doi.org/10.1002/biof.1586

    Article  PubMed  Google Scholar 

  109. Northcott PA, Robinson GW, Kratz CP et al (2019) Medulloblastoma. Nat Rev Dis Primers 5:11. https://doi.org/10.1038/s41572-019-0063-6

    Article  PubMed  Google Scholar 

  110. Thomaz A, Jaeger M, Brunetto AL et al (2020) Neurotrophin signaling in medulloblastoma. Cancers (Basel) 12:2542. https://doi.org/10.3390/cancers12092542

    Article  CAS  Google Scholar 

  111. Malgulwar PB, Nambirajan A, Pathak P et al (2018) Epithelial-to-mesenchymal transition-related transcription factors are up-regulated in ependymomas and correlate with a poor prognosis. Hum Pathol 82:149–157. https://doi.org/10.1016/j.humpath.2018.07.018

    Article  CAS  PubMed  Google Scholar 

  112. Simonson B, Das S (2015) MicroRNA therapeutics: the next magic bullet? Mini Rev Med Chem 15:467–474. https://doi.org/10.2174/1389557515666150324123208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Authors are supported by the National Council for Scientific and Technological Development (CNPq; Grant No. 305647/2019-9 to R.R.); PRONON/Ministry of Health, Brazil (Grant No. 25000.162.034/2014-21); the Children’s Cancer Institute (ICI); the Coordination for the Improvement of Higher Education Personnel (CAPES); the Clinical Hospital institutional research fund (FIPE/HCPA); InbetweenEars; the Brain Tumour North West Research Consortium; and the University of Central Lancashire.

Author information

Authors and Affiliations

  1. Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-003, Brazil

    Lívia Fratini, Mariane Jaeger, Caroline Brunetto de Farias, André T. Brunetto, Algemir L. Brunetto & Rafael Roesler

  2. Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS, 90050-170, Brazil

    Lívia Fratini & Rafael Roesler

  3. Children’s Cancer Institute, Porto Alegre, RS, 90620-110, Brazil

    Mariane Jaeger, Caroline Brunetto de Farias, André T. Brunetto & Algemir L. Brunetto

  4. School of Pharmacy and Biomedical Sciences, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE, Lancashire, UK

    Lisa Shaw

Authors
  1. Lívia Fratini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariane Jaeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caroline Brunetto de Farias
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. André T. Brunetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Algemir L. Brunetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lisa Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rafael Roesler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LF was responsible for the article conception and writing of the first draft. All authors contributed to the writing and revision of this article.

Corresponding authors

Correspondence to Lívia Fratini or Rafael Roesler.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Fratini, L., Jaeger, M., de Farias, C.B. et al. Oncogenic functions of ZEB1 in pediatric solid cancers: interplays with microRNAs and long noncoding RNAs. Mol Cell Biochem 476, 4107–4116 (2021). https://doi.org/10.1007/s11010-021-04226-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04226-x

Keywords

Search

Navigation