TGF-β1 and TGF-β2 abundance in liver diseases of mice and men
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Anne Dropmann1, Tatjana Dediulia1, Katja Breitkopf-Heinlein2, Hanna Korhonen3 Michel Janicot3, Susanne N. Weber4, Maria Thomas5,6, Albrecht Piiper7, Esther Bertran8, Isabel Fabregat8, Kerstin Abshagen9, Jochen Hess10,11, Peter Angel12, Cédric Coulouarn13, Steven Dooley1, Nadja M. Meindl-Beinker1
1Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
2Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
3Isarna Therapeutics GmbH, Munich, Germany
4Department of Medicine II, Saarland University Medical Center, Homburg, Germany
5Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
6University of Tuebingen, Tuebingen, Germany
7Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
8Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona. L’Hospitalet, Barcelona, Spain
9Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
10Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
11Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
12Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
13Institut National de la Santé et de la Recherche Médicale UMR991, University of Rennes, Pontchaillou University Hospital, Rennes, France
Nadja M. Meindl-Beinker, e-mail: [email protected]
Keywords: TGF-β isoform, mouse models, HCC, fibrosis, regeneration
Received: July 14, 2015 Accepted: January 01, 2016 Published: January 21, 2016
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.
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