CoChat
Sign Up
Cited by 21Retinal Diseases and TreatmentsMicroRNA in disease regulationRetinal Development and Disorders

c-Jun-mediated microRNA-302d-3p induces RPE dedifferentiation by targeting p21Waf1/Cip1

Open access
Jiang, Chao, Xie, Ping, Sun, Ruxu, Sun, Xiantao, Liu, Guohua, Ding, Sijia, Zhu, Meidong, Yan, Biao +3 more·2018·Cell Death & Disease
DOI 10.1038/s41419-018-0481-5PMC PMC5906557
Open this paper in CoChat — free accountOpen PDF

Abstract

Dedifferentiation of retinal pigment epithelium (RPE) cells and choroidal neovascularization (CNV) contributes to the pathogenesis of age-related macular degeneration (AMD). MicroRNAs (miRNAs) have crucial roles in AMD onset and progression. We thus aim to investigate the effects of miRNAs on RPE dedifferentiation and endothelium cell (EC) behavior, and analyze its downstream pathways. We have previously identified miR-302d-3p as the most downregulated miRNA signature along with RPE differentiation. Herein, in vitro study supported that miR-302d-3p induces RPE dedifferentiation typified by reduction of RPE characteristic markers, interrupts its phagocytosis, and promotes its migration, proliferation, and cell-cycle progression. c-Jun was identified as a potential upstream transcript factor for MIR302D, which might modulate RPE function by regulating miR-302d-3p expression. P21 Waf1/Cip1, a cyclin-dependent kinase inhibitor encoded by the CDKN1A gene, was identified as a downstream target of miR-302d-3p. Our data suggested that p21 Waf1/Cip1 could promote RPE differentiation, and inhibit its proliferation, migration, and cell-cycle progression. We also demonstrated that miR-302d-3p suppresses RPE differentiation through directly targeting p21 Waf1/Cip1. In addition, the miR-302d-3p/CDKN1A axis was also involved in regulating tube formation of ECs, indicating its potential involvement in CNV formation. Taken together, our study implies that miR-302d-3p, regulated by c-Jun, contributes to the pathogenesis of both atrophic and exudative AMD. MiR-302d-3p promotes RPE dedifferentiation, migration, proliferation and cell-cycle progression, inhibits RPE phagocytosis, and induces abnormal EC behavior by targeting p21 Waf1/Cip1. Pharmacological miR-302d-3p inhibitors are prospective therapeutic options for prevention and treatment of AMD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41419-018-0481-5

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • miR-302d-3p is overexpressed in RPEs of AMD patients and targets CDNK1A and p21Waf1/Cip1, inducing RPE dedifferentiation, cell cycle progression, proliferation, migration, and inhibiting phagocytosis.

    “MiR-302d-3p is overexpressed in RPEs of AMD patients. It targets products of CDNK1A and p21Waf1/Cip1, inducing RPE dedifferentiation, cell cycle progression, proliferation, migration, and inhibiting phagocytosis [272].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [272]

    The Results sections on CDKN1A targeting and RPE phagocytosis, together with the Discussion, support the reported effects on RPE differentiation, cell-cycle progression, proliferation, migration, and phagocytosis. They do not establish that miR-302d-3p is overexpressed in RPE cells from AMD patients; the experiments described used cultured RPE cells. The gene is CDKN1A (not CDNK1A), and p21Waf1/Cip1 is its encoded protein, not a separate target. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 58

  1. [1]Strauss O The retinal pigment epithelium in visual function Physiol. Rev. 2005 85 845 881 10.1152/physrev.00021.2004 15987797 · DOI · Paper page
  2. [2]Ambati J Fowler BJ Mechanisms of age-related macular degeneration Neuron 2012 75 26 39 10.1016/j.neuron.2012.06.018 22794258 PMC3404137 · DOI
  3. [3]Gehrs KM Anderson DH Johnson LV Hageman GS Age-related macular degeneration–emerging pathogenetic and therapeutic concepts Ann. Med. 2006 38 450 471 10.1080/07853890600946724 17101537 PMC4853957 · DOI
  4. [4]Lim LS Mitchell P Seddon JM Holz FG Wong TY Age-related macular degeneration Lancet 2012 379 1728 1738 10.1016/S0140-6736(12)60282-7 22559899 · DOI
  5. [5]Du H JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration Proc. Natl Acad. Sci. USA 2013 110 2377 2382 10.1073/pnas.1221729110 23341606 PMC3568328 · DOI · Paper page
  6. [6]Wormald, R., Evans, J., Smeeth, L. & Henshaw, K. Photodynamic therapy for neovascular age-related macular degeneration. Cochrane Database Syst. Rev. CD002030, 3, (2007). 17636693
  7. [7]Frampton JE Ranibizumab: a review of its use in the treatment of neovascular age-related macular degeneration Drugs Aging 2013 30 331 358 10.1007/s40266-013-0077-9 23539234 · DOI
  8. [8]Kodjikian L Bevacizumab and ranibizumab for neovascular age-related macular degeneration: an updated meta-analysis of randomised clinical trials Graefes Arch. Clin. Exp. Ophthalmol. 2014 252 1529 1537 10.1007/s00417-014-2764-6 25142373 PMC4180904 · DOI
  9. [9]Martin DF Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results Ophthalmology 2012 119 1388 1398 10.1016/j.ophtha.2012.03.053 22555112 PMC3389193 · DOI · Paper page
  10. [10]Heier JS Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration Ophthalmology 2012 119 2537 2548 10.1016/j.ophtha.2012.09.006 23084240 · DOI · Paper page
  11. [11]Yang S Zhao J Sun X Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review Drug Des. Dev.Ther. 2016 10 1857 1867 10.2147/DDDT.S115121 PMC4898027 27330279 · DOI
  12. [13]Bartel DP MicroRNAs: genomics, biogenesis, mechanism, and function Cell 2004 116 281 297 10.1016/S0092-8674(04)00045-5 14744438 · DOI
  13. [14]Vasudevan S Tong Y Steitz JA Switching from repression to activation: microRNAs can upregulate translation Science 2007 318 1931 1934 10.1126/science.1149460 18048652 · DOI
  14. [15]Xiao M MicroRNAs activate gene transcription epigenetically as an enhancer trigger RNA Biol. 2016 14 1326 1334 10.1080/15476286.2015.1112487 26853707 PMC5711461 · DOI
  15. [16]Sundermeier TR Palczewski K The impact of microRNA gene regulation on the survival and function of mature cell types in the eye FASEB J. 2016 30 23 33 10.1096/fj.15-279745 26399786 PMC4684546 · DOI
  16. [17]Friedman RC Farh KK Burge CB Bartel DP Most mammalian mRNAs are conserved targets of microRNAs Genome Res. 2009 19 92 105 10.1101/gr.082701.108 18955434 PMC2612969 · DOI · Paper page
  17. [18]ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome Nature 2012 489 57 74 10.1038/nature11247 22955616 PMC3439153 · DOI · Paper page
  18. [19]Adijanto J Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression J. Biol. Chem. 2012 287 20491 20503 10.1074/jbc.M112.354761 22523078 PMC3370234 · DOI
  19. [20]Jiang C MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway Oncotarget 2016 7 52340 52353 27418134 PMC5239556
  20. [21]Lin SL Regulation of somatic cell reprogramming through inducible mir-302 expression Nucleic Acids Res. 2011 39 1054 1065 10.1093/nar/gkq850 20870751 PMC3035461 · DOI
  21. [22]Lipchina I Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response Genes Dev. 2011 25 2173 2186 10.1101/gad.17221311 22012620 PMC3205587 · DOI
  22. [23]Lin SL Chang DC Ying SY Leu D Wu DT MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways Cancer Res. 2010 70 9473 9482 10.1158/0008-5472.CAN-10-2746 21062975 · DOI
  23. [24]Zhang H Shykind B Sun T Approaches to manipulating microRNAs in neurogenesis Front. Neurosci. 2012 6 196 23335878 PMC3547386
  24. [25]Martinez J Patkaniowska A Urlaub H Luhrmann R Tuschl T Single-stranded antisense siRNAs guide target RNA cleavage in RNAi Cell 2002 110 563 574 10.1016/S0092-8674(02)00908-X 12230974 · DOI
  25. [26]Tian B Atorvastatin promotes phagocytosis and attenuates pro-inflammatory response in human retinal pigment epithelial cells Sci. Rep. 2017 7 2329 10.1038/s41598-017-02407-7 28539592 PMC5443823 · DOI
  26. [27]Li W Phagocyte dysfunction, tissue aging and degeneration Ageing Res. Rev. 2013 12 1005 1012 10.1016/j.arr.2013.05.006 23748186 PMC3842398 · DOI
  27. [29]Ishibashi T Sorgente N Patterson R Ryan SJ Pathogenesis of drusen in the primate Invest. Ophthalmol. Vis. Sci. 1986 27 184 193 2417981
  28. [30]Liu Y Taz-tead1 links cell-cell contact to zeb1 expression, proliferation, and dedifferentiation in retinal pigment epithelial cells Invest. Ophthalmol. Vis. Sci. 2010 51 3372 3378 10.1167/iovs.09-4321 20207963 PMC2904003 · DOI
  29. [31]Yang S Yao H Li M Li H Wang F Long non-coding RNA MALAT1 mediates transforming growth factor beta1-induced epithelial–mesenchymal transition of retinal pigment epithelial cells PLoS ONE 2016 11 e0152687 10.1371/journal.pone.0152687 27019196 PMC4809592 · DOI
  30. [32]Messeguer X PROMO: detection of known transcription regulatory elements using species-tailored searches Bioinformatics 2002 18 333 334 10.1093/bioinformatics/18.2.333 11847087 · DOI
  31. [33]Farre D Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN Nucleic Acids Res. 2003 31 3651 3653 10.1093/nar/gkg605 12824386 PMC169011 · DOI
  32. [34]Crooks GE Hon G Chandonia JM Brenner SE WebLogo: a sequence logo generator Genome Res. 2004 14 1188 1190 10.1101/gr.849004 15173120 PMC419797 · DOI
  33. [35]Kim JY MicroRNA-302 induces proliferation and inhibits oxidant-induced cell death in human adipose tissue-derived mesenchymal stem cells Cell Death Dis. 2014 5 e1385 10.1038/cddis.2014.344 25144720 PMC4454318 · DOI
  34. [36]Wang Y Overexpression p21WAF1/CIP1 in suppressing retinal pigment epithelial cells and progression of proliferative vitreoretinopathy via inhibition CDK2 and cyclin E BMC Ophthalmol. 2014 14 144 10.1186/1471-2415-14-144 25421815 PMC4255444 · DOI
  35. [37]Marneros AG Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms EMBO Mol. Med. 2016 8 208 231 10.15252/emmm.201505613 26912740 PMC4772957 · DOI
  36. [38]Gao J NLRP3 inflammasome: activation and regulation in age-related macular degeneration Mediat. Inflamm. 2015 2015 690243 10.1155/2015/690243 PMC4324923 25698849 · DOI
  37. [39]Ehlken, C. et al. Expression of angiogenic and inflammatory factors in choroidal neovascularisation-derived retinal pigment epithelium. Ophthalmic Res. (2017). 10.1159/000481260. 29050001 · DOI
  38. [40]Emde A Hornstein E miRNAs at the interface of cellular stress and disease EMBO J. 2014 33 1428 1437 24867813 PMC4194087
  39. [41]Sundermeier TR MicroRNA-processing enzymes are essential for survival and function of mature retinal pigmented epithelial cells in mice J. Biol. Chem. 2017 292 3366 3378 10.1074/jbc.M116.770024 28104803 PMC5336169 · DOI
  40. [42]Ohana R MicroRNAs are essential for differentiation of the retinal pigmented epithelium and maturation of adjacent photoreceptors Development 2015 142 2487 2498 10.1242/dev.121533 26062936 · DOI
  41. [43]Corydon TJ Antiangiogenic eye gene therapy Hum. Gene. Ther. 2015 26 525 537 10.1089/hum.2015.064 26222377 · DOI
  42. [44]Askou AL Suppression of choroidal neovascularization in mice by subretinal delivery of multigenic lentiviral vectors encoding anti-angiogenic microRNAs Hum. Gene Ther. Methods 2017 28 222 233 10.1089/hgtb.2017.079 28817343 · DOI
  43. [46]Ho TT Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines Nucleic Acids Res. 2015 43 e17 10.1093/nar/gku1198 25414344 PMC4330338 · DOI
  44. [47]Scheel AH Beyer U Agami R Dobbelstein M Immunofluorescence-based screening identifies germ cell associated microRNA 302 as an antagonist to p63 expression Cell Cycle 2009 8 1426 1432 10.4161/cc.8.9.8324 19342891 · DOI
  45. [48]Lin SL Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state RNA 2008 14 2115 2124 10.1261/rna.1162708 18755840 PMC2553732 · DOI
  46. [49]Parchem RJ miR-302 is required for timing of neural differentiation, neural tube closure, and embryonic viability Cell Rep. 2015 12 760 773 10.1016/j.celrep.2015.06.074 26212322 PMC4741278 · DOI
  47. [50]Wang L MicroRNA-302b suppresses cell proliferation by targeting EGFR in human hepatocellular carcinoma SMMC-7721 cells BMC Cancer 2013 13 448 10.1186/1471-2407-13-448 24083596 PMC3850949 · DOI
  48. [51]Cai N Wang YD Zheng PS The microRNA-302-367 cluster suppresses the proliferation of cervical carcinoma cells through the novel target AKT1 RNA 2013 19 85 95 10.1261/rna.035295.112 23185040 PMC3527729 · DOI
  49. [52]Fareh M 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. 2012 19 232 244 10.1038/cdd.2011.89 21720384 PMC3263498 · DOI
  50. [53]Buccarello L The c-jun N-terminal kinase plays a key role in ocular degenerative changes in a mouse model of Alzheimer disease suggesting a correlation between ocular and brain pathologies Oncotarget 2017 8 83038 83051 29137322 PMC5669948
  51. [54]Kamata H Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases Cell 2005 120 649 661 10.1016/j.cell.2004.12.041 15766528 · DOI · Paper page
  52. [55]Hu S MicroRNA-302 increases reprogramming efficiency via repression of NR2F2 Stem Cells 2013 31 259 268 10.1002/stem.1278 23136034 PMC3572288 · DOI
  53. [56]Chang HM Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation Nat. Commun. 2012 3 923 10.1038/ncomms1909 22735451 PMC3518406 · DOI
  54. [57]Dolezalova D MicroRNAs regulatep21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells Stem Cells 2012 30 1362 1372 10.1002/stem.1108 22511267 · DOI
  55. [58]Chen X PRPF4 mutations cause autosomal dominant retinitis pigmentosa Hum. Mol. Genet. 2014 23 2926 2939 10.1093/hmg/ddu005 24419317 · DOI
  56. [59]Zhao C Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs Am. J. Hum. Genet. 2009 85 617 627 10.1016/j.ajhg.2009.09.020 19878916 PMC2775825 · DOI
  57. [60]Liu Y SPP2 mutations cause autosomal dominant retinitis pigmentosa Sci. Rep. 2015 5 14867 10.1038/srep14867 26459573 PMC4602186 · DOI
  58. [61]Chen X LncRNA ZNF503-AS1 promotes RPE differentiation by downregulating ZNF503 expression Cell Death Dis. 2017 8 e3046 10.1038/cddis.2017.382 28880276 PMC5636965 · DOI

Cited by

Sorted by citations

Authors
Jiang, C., Xie, P., Sun, R., Sun, X., Liu, G., Ding, S., Zhu, M., Yan, B., Liu, Q., Chen, X., & Zhao, C.
Affiliations
  • Jiangsu Province Hospital (CN)
  • Zhengzhou Children's Hospital (CN)
  • Shandong University (CN)
  • The University of Sydney (AU)
  • Shanghai Medical College of Fudan University (CN)
Corresponding author
  • Chen, Xue
  • Zhao, Chen
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2018-04-18
Volume
9
Issue
5
Pages
451-451
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-018-0481-5
PMC
PMC5906557
OpenAlex
W2800610903
Cited by
21
References
3
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 4 · 2019: 2
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (81525006, 81700877, 81730025, 81670864)
  • Government of Jiangsu Province
  • Natural Science Foundation of Jiangsu Province (BK20171087)
  • Nanjing Medical University
  • Priority Academic Program Development of Jiangsu Higher Education Institutions
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords
c-Jun, p21, choroidal neovascularization, age-related macular degeneration, endothelial tube formation, cell proliferation and migration, cell cycle progression, microRNA target regulation
MeSH terms
Cell Cycle, Epithelial Cells, Humans, Macular Degeneration, Proto-Oncogene Proteins c-jun, MicroRNAs, Cyclin-Dependent Kinase Inhibitor p21, Cell Dedifferentiation, Retinal Pigment Epithelium, Human Umbilical Vein Endothelial Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review