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@ARTICLE{Li:180198,
      author       = {X. Li$^*$ and B. Michels$^*$ and O. E. Tosun$^*$ and J.
                      Jung$^*$ and J. Kappes$^*$ and S. Ibing$^*$ and N. B.
                      Nataraj and S. Sahay and M. Schneider$^*$ and A. Wörner$^*$
                      and C. Becki$^*$ and N. Ishaque and L. Feuerbach$^*$ and B.
                      Heßling$^*$ and D. Helm$^*$ and R. Will$^*$ and Y. Yarden
                      and K. Müller-Decker$^*$ and S. Wiemann$^*$ and C.
                      Körner$^*$},
      title        = {5'isomi{R}-183-5p|+2 elicits tumor suppressor activity in a
                      negative feedback loop with {E}2{F}1.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {41},
      number       = {1},
      issn         = {0392-9078},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2022-01167},
      pages        = {190},
      year         = {2022},
      note         = {#EA:B050#LA:B050#},
      abstract     = {MicroRNAs (miRNAs) and isomiRs play important roles in
                      tumorigenesis as essential regulators of gene expression.
                      5'isomiRs exhibit a shifted seed sequence compared to the
                      canonical miRNA, resulting in different target spectra and
                      thereby extending the phenotypic impact of the respective
                      common pre-miRNA. However, for most miRNAs, expression and
                      function of 5'isomiRs have not been studied in detail yet.
                      Therefore, this study aims to investigate the functions of
                      miRNAs and their 5'isomiRs.The expression of 5'isomiRs was
                      assessed in The Cancer Genome Atlas (TCGA) breast cancer
                      patient dataset. Phenotypic effects of miR-183
                      overexpression in triple-negative breast cancer (TNBC) cell
                      lines were investigated in vitro and in vivo by quantifying
                      migration, proliferation, tumor growth and metastasis.
                      Direct targeting of E2F1 by miR-183-5p|+2 was validated with
                      a 3'UTR luciferase assay and linked to the phenotypes of
                      isomiR overexpression.TCGA breast cancer patient data
                      indicated that three variants of miR-183-5p are highly
                      expressed and upregulated, namely miR-183-5p|0,
                      miR-183-5p|+1 and miR-183-5p|+2. However, TNBC cell lines
                      displayed reduced proliferation and invasion upon
                      overexpression of pre-miR-183. While invasion was reduced
                      individually by all three isomiRs, proliferation and cell
                      cycle progression were specifically inhibited by
                      overexpression of miR-183-5p|+2. Proteomic analysis revealed
                      reduced expression of E2F target genes upon overexpression
                      of this isomiR, which could be attributed to direct
                      targeting of E2F1, specifically by miR-183-5p|+2. Knockdown
                      of E2F1 partially phenocopied the effect of miR-183-5p|+2
                      overexpression on cell proliferation and cell cycle. Gene
                      set enrichment analysis of TCGA and METABRIC patient data
                      indicated that the activity of E2F strongly correlated with
                      the expression of miR-183-5p, suggesting transcriptional
                      regulation of the miRNA by a factor of the E2F family.
                      Indeed, in vitro, expression of miR-183-5p was regulated by
                      E2F1. Hence, miR-183-5p|+2 directly targeting E2F1 appears
                      to be part of a negative feedback loop potentially
                      fine-tuning its activity.This study demonstrates that
                      5'isomiRs originating from the same arm of the same
                      pre-miRNA (i.e. pre-miR-183-5p) may exhibit different
                      functions and thereby collectively contribute to the same
                      phenotype. Here, one of three isomiRs was shown to
                      counteract expression of the pre-miRNA by negatively
                      regulating a transcriptional activator (i.e. E2F1). We
                      speculate that this might be part of a regulatory mechanism
                      to prevent uncontrolled cell proliferation, which is
                      disabled during cancer progression.},
      keywords     = {Cell cycle (Other) / E2F1 (Other) / IsomiRs (Other) /
                      MiR-183-5p (Other) / MicroRNAs (Other) / Triple-negative
                      breast cancer (Other)},
      cin          = {B050 / B330 / W120 / W420},
      ddc          = {610},
      cid          = {I:(DE-He78)B050-20160331 / I:(DE-He78)B330-20160331 /
                      I:(DE-He78)W120-20160331 / I:(DE-He78)W420-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35655310},
      doi          = {10.1186/s13046-022-02380-8},
      url          = {https://inrepo02.dkfz.de/record/180198},
}