title: Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma.
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.
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Teng
authors.initials: T
authors.lastname: Feng
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Dzieran
authors.affiliation: †Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Gu
authors.affiliation: ‡Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Marhenke
authors.affiliation: ‡Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.affiliation: §Department of Molecular Microbiology and Immunology and Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, U.S.A.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.affiliation: ║Department of Pediatrics and Juvenile Medicine, Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.affiliation: ¶Institute of Pathology, University of Regensburg, Regensburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Ruemmele
authors.affiliation: **Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
authors.affiliation: ††Saarland University Medical School, Institute of Virology, Homburg/Saar, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: ††Saarland University Medical School, Institute of Virology, Homburg/Saar, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grässer
authors.affiliation: ‡‡Department of Experimental Surgery, University of Heidelberg, Mannheim and Molecular Oncology of Solid Tumors, DKFZ, Heidelberg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Fabian
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Hong Lei
authors.initials: HL
authors.lastname: Weng
authors.affiliation: §§Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg, Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.affiliation: §§Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg, Regensburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maass
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meyer
authors.affiliation: ║║Institute of Pathology, Medical School Hannover, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.affiliation: ¶¶Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: ¶¶Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.affiliation: †Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chun Fang
authors.initials: CF
authors.lastname: Gao
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: *Molecular Hepatology Alcohol Associated Diseases, Dept. of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Nadja M
authors.initials: NM
authors.lastname: Meindl-Beinker
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008875:Middle Aged; D015999:Multivariate Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human