P611 GAS6/AXL AXIS AS PROGNOSTIC AND THERAPEUTIC TARGET IN LIVER DISEASE

Abstract

Background and Aims: AXL, a receptor tyrosin kinase, and its ligand GAS6 are related to processes leading to cell differentiation and carcinogenesis. The role of GAS6/AXL signaling in hepatic stellate cell (HSC) transformation during liver disease has been insufficiently addressed. Methods: HSCs were isolated from wild-type and AXL knockout (KO) mice. HSCs and LX2 human activated HSCs were exposed to recombinant GAS6, AXL inhibitor (BGB324, BerGenBio) or siRNA silencing. p-AXL, p-AKT and HSC transformation were evaluated by western blotting and qPCR. CCl4-induced fibrosis was analyzed in wild-type and AXL KO mice. Gas6 and soluble AXL (sAXL) levels were measured by ELISA in serum from alcoholic patients with normal liver, compensated cirrhosis and decompensated cirrhosis, and in control individuals (n = 10, each group). Results: Recombinant GAS6 stimulated AXL and AKT activation, inducing phenotypic changes in primary HSCs. HSCs from AXL KO mice displayed reduced capacity to be activated in vitro, and AXL inhibition (BGB324, Bergenbio) reduced HSC activation and proliferation. Similar results were obtained in LX2 cells and after RNA silencing of AXL. Chronic CCl4 administration increased serum levels of sAXL and GAS6, while AXL deficient mice exhibited reduced liver fibrosis. More importantly, AXL inhibition (BGB324) efficiently diminished CCl4-induced liver fibrosis in wild-type mice. In parallel, GAS6 and sAXL levels in serum were increased in alcoholic liver disease (ALD) patients, inversely correlating with liver functionality. Conclusions: AXL inhibitors have clinical interest since AXL targeting is effective to treat experimental liver fibrosis. In addition, GAS6 and sAXL levels could be proposed as early prognostic markers in liver disease.