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@ARTICLE{Feng:126504,
      author       = {T. Feng and J. Dzieran and X. Gu and S. Marhenke and A.
                      Vogel and K. Machida and T. S. Weiss and P. Ruemmele and O.
                      Kollmar and P. Hoffmann and F. Grässer and H. Allgayer$^*$
                      and J. Fabian and H. L. Weng and A. Teufel and T. Maass and
                      C. Meyer and U. Lehmann and C. Zhu and P. R. Mertens and C.
                      F. Gao and S. Dooley and N. M. Meindl-Beinker},
      title        = {{S}mad7 regulates compensatory hepatocyte proliferation in
                      damaged mouse liver and positively relates to better
                      clinical outcome in human hepatocellular carcinoma.},
      journal      = {Clinical science},
      volume       = {128},
      number       = {11},
      issn         = {1470-8736},
      address      = {London},
      publisher    = {Portland},
      reportid     = {DKFZ-2017-02532},
      pages        = {761 - 774},
      year         = {2015},
      abstract     = {Transforming growth factor β (TGF-β) is cytostatic
                      towards damage-induced compensatory hepatocyte
                      proliferation. This function is frequently lost during
                      hepatocarcinogenesis, thereby switching the TGF-β role from
                      tumour suppressor to tumour promoter. In the present study,
                      we investigate Smad7 overexpression as a pathophysiological
                      mechanism for cytostatic TGF-β inhibition in liver damage
                      and hepatocellular carcinoma (HCC). Transgenic
                      hepatocyte-specific Smad7 overexpression in damaged liver of
                      fumarylacetoacetate hydrolase (FAH)-deficient mice increased
                      compensatory proliferation of hepatocytes. Similarly,
                      modulation of Smad7 expression changed the sensitivity of
                      Huh7, FLC-4, HLE and HLF HCC cell lines for cytostatic
                      TGF-β effects. In our cohort of 140 HCC patients, Smad7
                      transcripts were elevated in $41.4\%$ of HCC samples as
                      compared with adjacent tissue, with significant positive
                      correlation to tumour size, whereas low Smad7 expression
                      levels were significantly associated with worse clinical
                      outcome. Univariate and multivariate analyses indicate Smad7
                      levels as an independent predictor for overall (P<0.001) and
                      disease-free survival (P=0.0123). Delineating a mechanism
                      for Smad7 transcriptional regulation in HCC, we identified
                      cold-shock Y-box protein-1 (YB-1), a multifunctional
                      transcription factor. YB-1 RNAi reduced TGF-β-induced and
                      endogenous Smad7 expression in Huh7 and FLC-4 cells
                      respectively. YB-1 and Smad7 mRNA expression levels
                      correlated positively (P<0.0001). Furthermore, nuclear
                      co-localization of Smad7 and YB-1 proteins was present in
                      cancer cells of those patients. In summary, the present
                      study provides a YB-1/Smad7-mediated mechanism that
                      interferes with anti-proliferative/tumour-suppressive TGF-β
                      actions in a subgroup of HCC cells that may facilitate
                      aspects of tumour progression.},
      keywords     = {Smad7 Protein (NLM Chemicals) / Transforming Growth Factor
                      beta (NLM Chemicals) / Y-Box-Binding Protein 1 (NLM
                      Chemicals) / YBX1 protein, human (NLM Chemicals)},
      cin          = {G360},
      ddc          = {610},
      cid          = {I:(DE-He78)G360-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25602745},
      doi          = {10.1042/CS20140606},
      url          = {https://inrepo02.dkfz.de/record/126504},
}