Expression of growth differentiation factor 5 in liver fibrosis and cancer

 

The activation of hepatic stellate cells (HSC) is the key event of hepatic fibrosis and activated HSC also play a critical role in the progression of hepatocellular cancer (HCC). Growth differentiation factor 5 (GDF5) belongs to the TGF-β/BMP-superfamily. So far, GDF5 has been mostly studied in the context of cartilage development and repair.

The aim of this study was to assess the expression and function of GDF5 in liver fibrosis and cancer.

Methods and results GDF5 expression-levels increased during in vitro activation of primary human HSC and in different murine models of hepatic fibrosis. Furthermore, there is a significant correlation between the expression of GDF5 and alpha-smooth-muscle actin (a-sma) in human HCC as well as non-tumorous liver tissues. RNAi mediated GDF5-suppression in activated HSC resulted in reduced a-sma and collagen-expression, while treatment with recombinant GDF5 induced a-sma and collagen-expression. In human HCC cell-lines treatment with recombinant GDF5 induced the phosphorylation of Smad1/5/8 and the expression of the transcription factors inhibitor of differentiation 1 (ID1), a known promoters of HCC-progression. In line with this, GDF5 induced the proliferation and colony formation of HCC cells.

Summary and conclusion Our data indicate activated HSC as major cellular source of enhanced GDF5 expression in fibrotic liver disease and HCC and show that GDF5 exhibits pro-fibrogenic as well as pro-tumorigenic effect. Future analyses will reveal the potential of this soluble growth-factor as therapeutic target or prognostic marker for fibrosis and HCC-progression in patients with chronic liver disease.

Publication History

Article published online:
18 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany