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      The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer

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      Author(s)
      Raza, U.
      Saatci, O.
      Uhlmann, S.
      Ansari, S. A.
      Eyüpoglu, E.
      Yurdusev, E.
      Mutlu, M.
      Ersan, P. G.
      Altundağ, M. K.
      Zhang, J. D.
      Dogan, H. T.
      Güler, G.
      Şahin, Ö.
      Date
      2016
      Source Title
      Oncotarget
      Print ISSN
      1949-2553
      Publisher
      Impact Journals LLC
      Volume
      7
      Issue
      31
      Pages
      49859 - 49877
      Language
      English
      Type
      Article
      Item Usage Stats
      254
      views
      176
      downloads
      Abstract
      Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPRCas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53- mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.
      Keywords
      CTBP1
      EMT
      MiRNAs
      P53
      Therapy resistance
      Carboxy terminal sequence binding protein 1
      Cyclin dependent kinase 1
      Cyclin dependent kinase inhibitor 1
      Cyclin dependent kinase inhibitor 1A
      Gefitinib
      Membrane protein
      MicroRNA
      MicroRNA 644a
      Protein Noxa
      Protein p21
      Tamoxifen
      Unclassified drug
      Alcohol dehydrogenase
      C-terminal binding protein
      DNA binding protein
      MicroRNA
      MIRN644 microRNA, human
      Protein p53
      TP53 protein, human
      Animal experiment
      Animal model
      Animal tissue
      Article
      Breast cancer
      Breast cancer cell line
      Cancer growth
      Cancer inhibition
      Cancer prognosis
      Cancer resistance
      Cell proliferation
      Cell survival
      Controlled study
      CRISPR Cas system
      Disease free survival
      Down regulation
      Epithelial mesenchymal transition
      Female
      G1 phase cell cycle checkpoint
      Gene identification
      Gene overexpression
      Gene targeting
      Human
      Human cell
      Metastasis potential
      Mouse
      Nonhuman
      Protein targeting
      Site directed mutagenesis
      Upregulation
      Animal
      Apoptosis
      Breast tumor
      Cancer transplantation
      Cell cycle
      Cell motion
      Cell survival
      Disease exacerbation
      Drug resistance
      Gene expression regulation
      Genetics
      MCF-7 cell line
      Metabolism
      Metastasis
      Mortality
      Mutation
      Nude mouse
      Tumor cell line
      Tumor recurrence
      Alcohol Oxidoreductases
      Animals
      Apoptosis
      Breast Neoplasms
      Cell Cycle
      Cell Line, Tumor
      Cell Movement
      Cell Survival
      Disease Progression
      DNA-Binding Proteins
      Drug Resistance, Neoplasm
      Epithelial-Mesenchymal Transition
      Female
      Gene Expression Regulation, Neoplastic
      Humans
      MCF-7 Cells
      Mice
      Mice, Nude
      MicroRNAs
      Mutation
      Neoplasm Metastasis
      Neoplasm Recurrence, Local
      Neoplasm Transplantation
      Tumor Suppressor Protein p53
      Permalink
      http://hdl.handle.net/11693/36664
      Published Version (Please cite this version)
      http://dx.doi.org/10.18632/oncotarget.10489
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