title: TGF-β1 and TGF-β2 abundance in liver diseases of mice and men.
abstract: TGF-β1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-β2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-β2 expression correlates with fibrogenesis and liver cancer development.Using quantitative realtime PCR and ELISA, we show that TGF-β2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-β2 stimulation of the LX-2 cells led to upregulation of the TGF-β receptors 1, 2, and 3, whereas TGF-β1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-β2 expression was accompanied by TGF-β1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-β2 upregulation correlated with fibrotic markers and was more prominent than TGF-β1 expression. Accordingly, MDR2-KO mice showed significant TGF-β2 upregulation within 3 to 15 months but minor TGF-β1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-β2 expression and secretion were observed, with some cell lines even secreting more TGF-β2 than TGF-β1. TGF-β2 was also upregulated in tumors of TGFα/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-β2 as compared to normal liver.Our study demonstrates upregulation of TGF-β2 in liver disease and suggests TGF-β2 as a promising therapeutic target for tackling fibrosis and HCC.
authors.affiliation: Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Dropmann
authors.affiliation: Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dediulia
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.affiliation: Isarna Therapeutics GmbH, Munich, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Korhonen
authors.affiliation: Isarna Therapeutics GmbH, Munich, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Janicot
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: Susanne N
authors.initials: SN
authors.lastname: Weber
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Piiper
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona L'Hospitalet, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Bertran
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona L'Hospitalet, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fabregat
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.affiliation: Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.affiliation: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR991, University of Rennes, Pontchaillou University Hospital, Rennes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Coulouarn
authors.affiliation: Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nadja M
authors.initials: NM
authors.lastname: Meindl-Beinker
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2
keywords: HCC; TGF-β isoform; fibrosis; mouse models; regeneration