Autor: |
Dropmann A; Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany., Dediulia T; Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany., Breitkopf-Heinlein K; Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany., Korhonen H; Isarna Therapeutics GmbH, Munich, Germany., Janicot M; Isarna Therapeutics GmbH, Munich, Germany., Weber SN; Department of Medicine II, Saarland University Medical Center, Homburg, Germany., Thomas M; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; University of Tuebingen, Tuebingen, Germany., Piiper A; Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany., Bertran E; Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona L'Hospitalet, Barcelona, Spain., Fabregat I; Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona L'Hospitalet, Barcelona, Spain., Abshagen K; Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany., Hess J; 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., Angel P; Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany., Coulouarn C; Institut National de la Santé et de la Recherche Médicale UMR991, University of Rennes, Pontchaillou University Hospital, Rennes, France., Dooley S; Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany., Meindl-Beinker NM; Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. |
Abstrakt: |
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. |