Mesothelin/Mucin 16 Signaling in Activated Portal Fibroblasts Drives the Development of Cholestatic Fibrosis and Hepatocellular Carcinoma in Aged Female Multidrug Resistance Protein 2 Knockout Mice

BACKGROUND & AIMS: The contribution of activated hepatic stellate cells (aHSCs) to cholestatic fibrosis and cancer is well-documented, but the role of portal fibroblasts (PFs), and especially mesothelin (Msln)-mucin 16 (Muc16)- Thy-1 cell surface antigen (Thy-1) signaling in activated portal fibroblasts (aPFs), is unknown. METHODS: ) mice, which mimic primary biliary cholangitis with biliary fibrosis. RESULTS: aPFs was linked to increased hepatocyte proliferation. Based on in vitro studies, MMP3-mediated shedding of hepatic HGFR (c-Met) was identified as one of the mechanisms by which aPFs suppress HGF-c-Met-induced phosphorylation of AKT, ERK, p38, resulting in proliferation of primary human hepatocytes. In turn, proliferation of MMP3-stimulated human hepatocytes was restored in the presence of MMP3 inhibitor. CONCLUSIONS: These findings demonstrate that aPFs mediate the crosstalk between cholangiocytes and hepatocytes, regulate hepatocyte functions, and that Msln-Muc16 signaling in aPFs is pathogenic for cholestatic fibrosis and HCC. Msln and Muc16 may become novel targets for anti-fibrotic therapy and patients with HCC and sclerosis cholangitis.