EGFR-STAT3 signaling in cholestatic liver injury and fibrosis

Cholestatic liver diseases in humans lead to bile acid-induced liver damage, biliary fibrosis, liver cirrhosis and formation of hepatocellular carcinomas. We have recently employed the Mdr2-/- mouse model for sclerosing cholangitis to investigate functions of the transcription factor STAT3 in cholestatic liver injury. Conditional ablation of STAT3 in hepatocytes and cholangiocytes (STAT3 hc ) of Mdr2-/- mice strongly aggravated cholestasis and liver fibrosis. The molecular mechanisms that underlie this hepatoprotective activity of STAT3 in cholestatic liver diseases were identified by Affymetrix microarray experiments. These analyses demonstrated that STAT3 negatively regulates genes for bile acid biosynthesis and positively regulates expression of several hepatoprotective genes including epidermal growth factor receptor (EGFR)1,2 . We employed a genetic approach to evaluate if EGFR is a crucial hepatoprotective downstream target of STAT3 in cholestatic liver injury and conditionally deleted EGFR in hepatocytes and cholangiocytes (EGFR hc ) of Mdr2-/- mice. Importantly, EGFRhc Mdr2-/- mice phenocopied the severe liver fibrosis observed in STAT3hc Mdr2-/- mice. This indicates that induction of EGFR expression by STAT3 is a crucial hepatoprotective event in cholestatic liver disease. The goal of this proposal is the identification of molecular mechanisms that underly the hepatoprotective activity of STAT3-EGFR signaling in cholestatic liver disease, its potential for hepatoprotective therapies and its implication in formation of hepatocellular carcinomas.

Chronic cholestatic liver diseases lead to retention of toxic bile acids in the liver (cholestasis). This results in liver injury, infiltration of immune cells, liver fibrosis (replacement of liver tissue by connective tissue), liver cirrhosis (loss of the typical liver architecture) and eventually formation of liver cancer. Liver fibrosis is characterized by deposition of collagen and other extracellular matrix components that is orchestrated by several cell types including Kupffer cells (macrophages in the liver) and stellate cells. The latter are fibroblast-like cells that are activated by Kupffer cell- or immune cell-derived cytokines and deposit collagen in various parts of the liver lobes. Despite profound knowledge about the responsible cell types, little is known about molecular mechanisms that protect from cholestatic liver injury and formation of liver cancer. We have recently shown that the transcription factor STAT3 and the STAT3- inducing cytokine interleukin-6 (IL-6) protect form cholestatic liver injury. As a molecular mechanism, we proposed that STAT3 regulates the expression of the epidermal growth factor receptor (EGFR) which is supposed to protect from cholestatic liver injury. Our FWF project demonstrated on the one hand that EGFR signaling in hepatocytes protects from cholestatic liver injury and on the other hand that EGFR signaling in myeloid cells drives formation of liver cancer. These results have important clinical implications because patients with various types of cancers (e.g. lung cancer) are treated with EGFR inhibitors. These inhibitors might lead to aggravated liver damage in cancer patients with simultaneously appearing cholestatic liver disease. Moreover, we showed that myeloid EGFR expression in the stroma of liver tumors is a bad prognostic factor for liver cancer patients. Therefore, the presence of EGFR-positive myeloid cells in the stroma of liver tumors might be used as a predictive marker for a positive outcome of EGFR-based tumor therapy.