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.
Highlights
Liver transplantation is the only therapeutic option to fight terminal liver failure
TGF-β1 and TGF-β2 mRNA expression was first determined in mouse hepatocytes by qPCR (Figure 1A)
To translate our results to human hepatic stellate cell (HSC) and examine TGF-β1 and -β2 signaling in more detail, we examined the human HSC cell line Lieming Xu (LX)-2 with respect to TGF-β1 and -β2 expression
Summary
Liver transplantation is the only therapeutic option to fight terminal liver failure. Subsequent fibrosis is the onset of hepatic disease development including cirrhosis, HCC, or hepatic failure [1]. The TGF-β receptors type I, II and III (TGFβR-I, TGFβR-II, and TGFβR-III) are expressed in almost every mammalian cell type, including cancer cells [7]. TGFβR-I and -II are essential for provoking the biological response of TGF-β isoforms [8], but can bind TGF-β3 and TGF-β1 with higher affinity than TGF-β2 [9,10,11]. TGFβRs-III (Betaglycan and Endoglin) are described to stabilize TGF-βs in a conformation that is optimal for binding to the signaling receptors. Betaglycan binds all TGF-β isoforms with high affinity [9, 10, 12] and significantly enhances the binding efficacy of TGF-β2 to TGFβR-II (reviewed in Massagué [13]). Endoglin only binds TGF-β1 and TGF-β3, but not TGF-β2 [14]
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