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@ARTICLE{Lesina:129041,
      author       = {M. Lesina and S. M. Wörmann and J. Morton and K. N.
                      Diakopoulos and O. Korneeva and M. Wimmer and H. Einwächter
                      and J. Sperveslage and I. E. Demir and T. Kehl$^*$ and D.
                      Saur and B. Sipos and M. Heikenwälder$^*$ and J. M. Steiner
                      and T. C. Wang and O. J. Sansom and R. M. Schmid and H.
                      Algül},
      title        = {{R}el{A} regulates {CXCL}1/{CXCR}2-dependent
                      oncogene-induced senescence in murine {K}ras-driven
                      pancreatic carcinogenesis.},
      journal      = {The journal of clinical investigation},
      volume       = {126},
      number       = {8},
      issn         = {1558-8238},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2017-05046},
      pages        = {2919 - 2932},
      year         = {2016},
      abstract     = {Tumor suppression that is mediated by oncogene-induced
                      senescence (OIS) is considered to function as a safeguard
                      during development of pancreatic ductal adenocarcinoma
                      (PDAC). However, the mechanisms that regulate OIS in PDAC
                      are poorly understood. Here, we have determined that nuclear
                      RelA reinforces OIS to inhibit carcinogenesis in the Kras
                      mouse model of PDAC. Inactivation of RelA accelerated
                      pancreatic lesion formation in Kras mice by abrogating the
                      senescence-associated secretory phenotype (SASP) gene
                      transcription signature. Using genetic and pharmacological
                      tools, we determined that RelA activation promotes OIS via
                      elevation of the SASP factor CXCL1 (also known as KC), which
                      activates CXCR2, during pancreatic carcinogenesis. In Kras
                      mice, pancreas-specific inactivation of CXCR2 prevented OIS
                      and was correlated with increased tumor proliferation and
                      decreased survival. Moreover, reductions in CXCR2 levels
                      were associated with advanced neoplastic lesions in tissue
                      from human pancreatic specimens. Genetically disabling OIS
                      in Kras mice caused RelA to promote tumor proliferation,
                      suggesting a dual role for RelA signaling in pancreatic
                      carcinogenesis. Taken together, our data suggest a pivotal
                      role for RelA in regulating OIS in preneoplastic lesions and
                      implicate the RelA/CXCL1/CXCR2 axis as an essential
                      mechanism of tumor surveillance in PDAC.},
      keywords     = {Chemokine CXCL1 (NLM Chemicals) / Cxcl1 protein, mouse (NLM
                      Chemicals) / RNA, Messenger (NLM Chemicals) / Receptors,
                      Interleukin-8B (NLM Chemicals) / Rela protein, mouse (NLM
                      Chemicals) / Transcription Factor RelA (NLM Chemicals) / ras
                      Proteins (NLM Chemicals)},
      cin          = {V155 / F180},
      ddc          = {610},
      cid          = {I:(DE-He78)V155-20160331 / I:(DE-He78)F180-20160331},
      pnm          = {316 - Infections and cancer (POF3-316)},
      pid          = {G:(DE-HGF)POF3-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27454298},
      pmc          = {pmc:PMC4966329},
      doi          = {10.1172/JCI86477},
      url          = {https://inrepo02.dkfz.de/record/129041},
}