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@ARTICLE{Dutruel:119893,
      author       = {C. Dutruel$^*$ and F. Bergmann and I. Rooman and M.
                      Zucknick$^*$ and D. Weichenhan$^*$ and L. Geiselhart$^*$ and
                      T. Kaffenberger and P. S. K. Rachakonda$^*$ and A. Bauer and
                      N. Giese and C. Hong and H. Xie and J. F. Costello and J.
                      Hoheisel$^*$ and R. Kumar$^*$ and M. Rehli and P.
                      Schirmacher and J. Werner and C. Plass$^*$ and O.
                      Popanda$^*$ and P. Schmezer$^*$},
      title        = {{E}arly epigenetic downregulation of {WNK}2 kinase during
                      pancreatic ductal adenocarcinoma development.},
      journal      = {Oncogene},
      volume       = {33},
      number       = {26},
      issn         = {1476-5594},
      address      = {Basingstoke},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-00484},
      pages        = {3401 - 3410},
      year         = {2014},
      abstract     = {Pancreatic ductal adenocarcinoma (PDAC) is usually
                      incurable. Contrary to genetic mechanisms involved in PDAC
                      pathogenesis, epigenetic alterations are ill defined. Here,
                      we determine the contribution of epigenetically silenced
                      genes to the development of PDAC. We analyzed enriched,
                      highly methylated DNAs from PDACs, chronic pancreatitis (CP)
                      and normal tissues using CpG island microarrays and
                      identified WNK2 as a prominent candidate tumor suppressor
                      gene being downregulated early in PDAC development. WNK2 was
                      further investigated in tissue microarrays, methylation
                      analysis of early pancreatic intraepithelial neoplasia
                      (PanIN), mouse models for PDAC and pancreatitis,
                      re-expression studies after demethylation, and cell growth
                      assays using WNK2 overexpression. Demethylation assays
                      confirmed the link between methylation and expression. WNK2
                      hypermethylation was higher in tumor than in surrounding
                      inflamed tissues and was observed in PanIN lesions as well
                      as in a PDAC mouse model. WNK2 mRNA and protein expressions
                      were lower in PDAC and CP compared with normal tissues both
                      in patients and mouse models. Overexpression of WNK2 led to
                      reduced cell growth, and WNK2 expression in tissues
                      correlated negatively with pERK1/2 expression, a downstream
                      target of WNK2 responsible for cell proliferation.
                      Downregulation of WNK2 by promoter hypermethylation occurs
                      early in PDAC pathogenesis and may support tumor cell growth
                      via the ERK-MAPK pathway.},
      keywords     = {RNA, Messenger (NLM Chemicals) / WNK2 protein, human (NLM
                      Chemicals) / Protein-Serine-Threonine Kinases (NLM
                      Chemicals) / Extracellular Signal-Regulated MAP Kinases (NLM
                      Chemicals)},
      cin          = {C010 / C060 / B070 / C050},
      ddc          = {610},
      cid          = {I:(DE-He78)C010-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)B070-20160331 / I:(DE-He78)C050-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:23912455},
      doi          = {10.1038/onc.2013.312},
      url          = {https://inrepo02.dkfz.de/record/119893},
}