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

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.

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

“…The TGF-β family comprises 33 members. While TGF-β2 plays an important role in biliary fibrogenesis, TGF-β1 is the most widely investigated isoform in liver fibrogenesis [134]. TGF-β is synthetized as a latent precursor by a variety of cells including endothelial cells, macrophages, and hepatocytes.…”

Hepatitis C virus–induced tumor‐initiating cancer stem–like cells activate stromal fibroblasts in a xenograft tumor model

“…On the other hand, TGF‐β3 blocks Smad4 through up‐regulation of Smad7 phosphorylation, which is an inhibitor of TGF‐β superfamily signaling . There are reports on the differences between TGF‐β1 and TGF‐β2 in the liver: TGF‐β1 induces Smad1 phosphorylation, but TGF‐β2 has less affinity for Smad1 phosphorylation . We know from our previous results that EMT is induced in HCV‐infected hepatocytes and generates TGF‐β .…”

“…(45) There are reports on the differences between TGF-b1 and TGF-b2 in the liver: TGF-b1 induces Smad1 phosphorylation, but TGF-b2 has less affinity for Smad1 phosphorylation. (46) We know from our previous results that EMT is induced in HCV-infected hepatocytes and generates TGF-b. (8) CM from HCVinfected hepatocytes promotes human HSC activation for fibrosis markers.…”

Serum coding and non‐coding RNAs as biomarkers of NAFLD and fibrosis severity

“…Validation of candidate coding/non‐coding RNAs both in an independent internal cohort of 88 study subjects (63 NAFLD and 25 CTRL) and an in external cohort of 50 NAFLD patients was performed through real‐time PCR assays (Power SYBR Green RNA‐to‐CT1‐Step Kit Thermo Fisher Scientific) according to the manufacturer's protocol. Candidate transcripts were selected according to the following three criteria: (i) high levels of fluorescence microarray signals; (ii) low P ‐value in severe NAFLD vs mild NAFLD comparison ( P ≤ 0.02); (iii) involvement in oxidative stress, inflammatory, apoptotic, authophagy or fibrogenic pathways according to the literature data . Validated transcript expression was also analysed, through real‐time PCR assays, in liver biopsies and in NAFL/NASH in vitro models at intracellular and extracellular level.…”

“…Candidate transcripts were selected according to the following three criteria: (i) high levels of fluorescence microarray signals; (ii) low P-value in severe NAFLD vs mild NAFLD comparison (P ≤ 0.02); (iii) involvement in oxidative stress, inflammatory, apoptotic, authophagy or fibrogenic pathways according to the literature data. [29][30][31][32][33][34] Validated transcript expression was also analysed, through real-time PCR assays, in liver biopsies and in NAFL/ NASH in vitro models at intracellular and extracellular level.…”