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Oncotarget. 2016 Apr 12;7(15):19499-518. doi: 10.18632/oncotarget.6967.

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

Author information

1
Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
2
Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
3
Isarna Therapeutics GmbH, Munich, Germany.
4
Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
5
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
6
University of Tuebingen, Tuebingen, Germany.
7
Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
8
Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona L'Hospitalet, Barcelona, Spain.
9
Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.
10
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany.
12
Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Institut National de la Santé et de la Recherche Médicale UMR991, University of Rennes, Pontchaillou University Hospital, Rennes, France.

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.

KEYWORDS:

HCC; TGF-β isoform; fibrosis; mouse models; regeneration

PMID:
26799667
PMCID:
PMC4991397
DOI:
10.18632/oncotarget.6967
[Indexed for MEDLINE]
Free PMC Article

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