Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis
Open Access
- 16 May 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 8 (1), 15433
- https://doi.org/10.1038/ncomms15433
Abstract
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.Keywords
This publication has 61 references indexed in Scilit:
- FGF19 action in the brain induces insulin-independent glucose loweringJCI Insight, 2013
- FGF15/19 Regulates Hepatic Glucose Metabolism by Inhibiting the CREB-PGC-1α PathwayCell Metabolism, 2011
- Ptpn11/Shp2 Acts as a Tumor Suppressor in Hepatocellular CarcinogenesisCancer Cell, 2011
- FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen SynthesisScience, 2011
- Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic ScreeningCancer Cell, 2011
- Liver-Directed Recombinant Adeno-Associated Viral Gene Delivery Rescues a Lethal Mouse Model of Methylmalonic Acidemia and Provides Long-Term Phenotypic CorrectionHuman Gene Therapy, 2010
- Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 ActivationCancer Cell, 2010
- Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF ExpressionCell, 2010
- EpCAM-Positive Hepatocellular Carcinoma Cells Are Tumor-Initiating Cells With Stem/Progenitor Cell FeaturesGastroenterology, 2009
- Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trialThe Lancet, 2008