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.
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Research Article|
March 17 2015
Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma
Teng Feng;
Teng Feng
1
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Johanna Dzieran;
Johanna Dzieran
1
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Xing Gu;
Xing Gu
1
†Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
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Silke Marhenke;
Silke Marhenke
‡Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany
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Arndt Vogel;
Arndt Vogel
‡Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany
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Keigo Machida;
Keigo Machida
§Department of Molecular Microbiology and Immunology and Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, U.S.A.
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Thomas S. Weiss;
Thomas S. Weiss
║Department of Pediatrics and Juvenile Medicine, Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany
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Petra Ruemmele;
Petra Ruemmele
¶Institute of Pathology, University of Regensburg, Regensburg, Germany
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Otto Kollmar;
Otto Kollmar
2
**Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany
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Patrick Hoffmann;
Patrick Hoffmann
††Saarland University Medical School, Institute of Virology, Homburg/Saar, Germany
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Friedrich Grässer;
Friedrich Grässer
††Saarland University Medical School, Institute of Virology, Homburg/Saar, Germany
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Heike Allgayer;
Heike Allgayer
‡‡Department of Experimental Surgery, University of Heidelberg, Mannheim and Molecular Oncology of Solid Tumors, DKFZ, Heidelberg, Germany
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Jasmin Fabian;
Jasmin Fabian
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Hong Lei Weng;
Hong Lei Weng
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Andreas Teufel;
Andreas Teufel
§§Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg, Regensburg, Germany
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Thorsten Maass;
Thorsten Maass
§§Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg, Regensburg, Germany
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Christoph Meyer;
Christoph Meyer
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Ulrich Lehmann;
Ulrich Lehmann
║║Institute of Pathology, Medical School Hannover, Hannover, Germany
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Cheng Zhu;
Cheng Zhu
¶¶Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
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Peter R. Mertens;
Peter R. Mertens
¶¶Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
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Chun Fang Gao;
Chun Fang Gao
1
†Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
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Steven Dooley;
Steven Dooley
1
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Nadja M. Meindl-Beinker
Nadja M. Meindl-Beinker
1
*Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Correspondence: Dr Nadja Meindl-Beinker (email nadja.meindl-beinker@medma.uni-heidelberg.de).
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Publisher: Portland Press Ltd
Received:
September 25 2014
Revision Received:
January 13 2015
Accepted:
January 20 2015
Accepted Manuscript online:
January 20 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 128 (11): 761–774.
Article history
Received:
September 25 2014
Revision Received:
January 13 2015
Accepted:
January 20 2015
Accepted Manuscript online:
January 20 2015
Citation
Teng Feng, Johanna Dzieran, Xing Gu, Silke Marhenke, Arndt Vogel, Keigo Machida, Thomas S. Weiss, Petra Ruemmele, Otto Kollmar, Patrick Hoffmann, Friedrich Grässer, Heike Allgayer, Jasmin Fabian, Hong Lei Weng, Andreas Teufel, Thorsten Maass, Christoph Meyer, Ulrich Lehmann, Cheng Zhu, Peter R. Mertens, Chun Fang Gao, Steven Dooley, Nadja M. Meindl-Beinker; Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma. Clin Sci (Lond) 1 June 2015; 128 (11): 761–774. doi: https://doi.org/10.1042/CS20140606
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