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Hepatocellular carcinoma (HCC), a primary malignancy of the liver, is the second leading cause of cancer mortality worldwide. Fibroblast Growth Factor 19 ( FGF19 ) is one of the most frequently amplified genes in HCC patients. Moreover, mice expressing an  FGF19  transgene have been shown to develop HCC. However, the downstream signalling pathways that mediate  FGF19 -dependent tumorigenesis remain to be deciphered. Here we show that FGF19 triggers a previously unsuspected, non-cell-autonomous program to activate STAT3 signalling in hepatocytes through IL-6 produced in the liver microenvironment. We show that the hepatocyte-specific deletion of  Stat3 , genetic ablation of  Il6 , treatment with a neutralizing anti-IL-6 antibody or administration of a small-molecule JAK inhibitor, abolishes FGF19-induced tumorigenesis, while the regulatory functions of FGF19 in bile acid, glucose and energy metabolism remain intact. Collectively, these data reveal a key role for the IL-6/STAT3 axis in potentiating FGF19-driven HCC in mice, a finding which may have translational relevance in HCC pathogenesis.

Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis