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@ARTICLE{Nwaeburu:130259,
      author       = {C. C. Nwaeburu and N. Bauer and Z. Zhao and A. Abukiwan and
                      J. Gladkich and A. Benner$^*$ and I. Herr},
      title        = {{U}p-regulation of micro{RNA} let-7c by quercetin inhibits
                      pancreatic cancer progression by activation of {N}umbl.},
      journal      = {OncoTarget},
      volume       = {7},
      number       = {36},
      issn         = {1949-2553},
      address      = {[S.l.]},
      publisher    = {Impact Journals LLC},
      reportid     = {DKFZ-2017-05339},
      pages        = {58367 - 58380},
      year         = {2016},
      abstract     = {Pancreatic Ductal Adenocarcinoma (PDA) is a highly
                      malignant tumor with poor prognosis. MicroRNAs (miRs) may
                      offer novel therapeutic approaches to treatment. The
                      polyphenol quercetin, present in many fruits and vegetables,
                      possesses anti-carcinogenic properties. To unravel the
                      effect of quercetin to miR signaling we performed miR
                      profiling in PDA cells before and after quercetin treatment,
                      followed by biostatistical analysis. miR let-7c was among
                      the top up-regulated candidates after quercetin treatment,
                      as measured by qRT-PCR and confirmed in two established and
                      one primary PDA cell lines. By computational analysis we
                      identified the Notch-inhibitor Numbl as let-7c target gene.
                      This was strengthened by luciferase assays, where lipofected
                      let-7c mimics induced a Numbl 3-UTR wild type construct, but
                      not the mutated counterpart. Let-7c induced Numbl mRNA and
                      protein expression but inhibited Notch just like quercetin.
                      It also inhibited colony formation, wound healing, and
                      protein expression of progression markers. In vivo
                      xenotransplantation of PDA cells and subsequent intravenous
                      injection of let-7c resulted in a significant decrease in
                      tumor mass without obvious toxic effects in the fertilized
                      chick egg model. The delivery rate of the miR mimics to the
                      tumor mass was $80\%,$ whereas minor amounts were present in
                      host tissue. By immunohistochemistry we demonstrated that
                      let-7c inhibited Notch and progression markers but
                      up-regulated Numbl. These findings show that
                      quercetin-induced let-7c decreases tumor growth by
                      posttranscriptional activation of Numbl and indirect
                      inhibition of Notch.},
      cin          = {C060},
      ddc          = {610},
      cid          = {I:(DE-He78)C060-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27521217},
      pmc          = {pmc:PMC5295436},
      doi          = {10.18632/oncotarget.11122},
      url          = {https://inrepo02.dkfz.de/record/130259},
}