Oncotarget

Research Papers:

TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

Anne Dropmann, Tatjana Dediulia, Katja Breitkopf-Heinlein, Hanna Korhonen, Michel Janicot, Susanne N. Weber, Maria Thomas, Albrecht Piiper, Esther Bertran, Isabel Fabregat, Kerstin Abshagen, Jochen Hess, Peter Angel, Cédric Coulouarn, Steven Dooley, Nadja M. Meindl-Beinker _

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Abstract

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

Correspondence to:

Nadja M. Meindl-Beinker, e-mail: Nadja.Meindl-Beinker@medma.uni-heidelberg.de

Keywords: TGF-β isoform, mouse models, HCC, fibrosis, regeneration

Received: July 14, 2015     Accepted: January 01, 2016     Published: January 21, 2016

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.

Author Information

Anne Dropmann

Tatjana Dediulia

Katja Breitkopf-Heinlein

Hanna Korhonen

Michel Janicot

Susanne N. Weber

Maria Thomas

Albrecht Piiper

Esther Bertran

Isabel Fabregat

Kerstin Abshagen

Jochen Hess

Peter Angel

Cédric Coulouarn

Steven Dooley

Nadja M. Meindl-Beinker
Primary Contact  _


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