Abstract
The therapeutic approach of liver fibrosis is still an unsolved clinical problem worldwide. Notably, the accumulation of extracellular matrix (ECM) in the liver is mediated by the production of cytokines and growth factors, such as transforming growth factor-β1 (TGF-β1) in hepatic stellate cells (HSCs). Ring finger protein 2 (RNF2) was identified as the catalytic subunit of polycomb repressive complex 1 (PRC1), mediating the monoubiquitination of histone H2A. In recent years, a growing amount of evidence suggests that RNF2 may play an important role in multiple pathological processes involved in cancer. Here, we explored the role of RNF2 in liver fibrogenesis and its potential mechanisms. The results showed that RNF2 was up-regulated in human fibrotic liver tissue. Knockdown of RNF2 led to a decreasing expression of collagen1 and α-smooth muscle actin (α-SMA) in LX-2 cells, which was upregulated by RNF2 overexpression. Moreover, RNF2 overexpression significantly promoted TGF-β1-induced LX-2 cell proliferation but decreased apoptosis. Furthermore, knockdown of RNF2 inhibited the activation of ERK/p38 signaling pathways induced by TGF-β1. These data suggested that RNF2 is an effective pro-fibrogenic factor for HSC activation via ERK/p38 signaling pathway. RNF2 inhibition might be a promising therapeutic target for liver fibrosis.
Highlights
Liver fibrosis is a severe health problem worldwide resulting from chronic liver injury and viral hepatitis, comprising viral Hepatitis B (HBV) and hepatitis (HCV), alcoholic steatohepatitis (ASH), and non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver dysfunction, and even hepatocellular carcinoma (HCC) (Hernandez-Gea and Friedman, 2011; Sun and Kisseleva, 2015; Zoubek et al, 2017)
The expression level of Ring finger protein 2 (RNF2) was observed at different concentrations and times with transforming growth factor-β1 (TGF-β1) stimulation in LX-2 cells
Western blotting results indicated that the noteworthy upregulation protein level of RNF2 were observed at 20 ng/mL in TGF-β1-induced LX-2 cells (Figure 2A)
Summary
Liver fibrosis is a severe health problem worldwide resulting from chronic liver injury and viral hepatitis, comprising viral Hepatitis B (HBV) and hepatitis (HCV), alcoholic steatohepatitis (ASH), and non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver dysfunction, and even hepatocellular carcinoma (HCC) (Hernandez-Gea and Friedman, 2011; Sun and Kisseleva, 2015; Zoubek et al, 2017). Considerable evidence has revealed that the accumulation of excessive extracellular matrix (ECM) is a critical characteristic of liver fibrosis. The activation and proliferation of hepatic stellate cells (HSCs) may lead to the production of a large amount of ECM, which may result in an imbalance between synthesis and degradation, leading to liver fibrosis (Liu et al, 2019; Zhao et al, 2019). Recent studies have shown that HSCs are highly responsive to pro-inflammatory cytokines, and may exert specific effect on the regulation of inflammation during liver fibrosis (Seki and Schwabe, 2015). It is promising to find an intrinsic target for regulating inflammatory response and produce of ECM. RNF2 in HSC in HSCs. targeting chronic inflammation under the circumstance of fibrogenesis will be a novel way to investigate the progress of liver fibrosis
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