Inflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes1,2. Here we show a marked activation of the interleukin (IL)-6 signalling pathway in this tumour type; sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signalling co-receptor gp130. Indeed, 60% of inflammatory hepatocellular adenomas harbour small in-frame deletions that target the binding site of gp130 for IL-6, and expression of four different gp130 mutants in hepatocellular cells activates signal transducer and activator of transcription 3 (STAT3) in the absence of ligand. Furthermore, analysis of hepatocellular carcinomas revealed that rare gp130 alterations are always accompanied by β-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas fully explains activation of the acute inflammatory phase observed in tumourous hepatocytes, and suggests that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation.
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We are indebted to P. Bois and O. Bernard for scientific discussion and critical reading of this manuscript. We thank C. Thomas and G. Cubel for their participation to this work. We also thank J. Saric, C. Laurent, A. Sa Cunha, B. Le Bail and A. Rullier for contributing to the tissue collection (CHU Bordeaux). This work was supported by Inserm (Réseaux de Recherche Clinique et Réseaux de Recherche en Santé des Populations), the Ligue Nationale Contre le Cancer (“Cartes d’Identité des Tumeurs” program), ARC (grant 5158), and the Fondation de France. S.R. and M.A. are supported by a fellowship from la Ligue Nationale Contre le Cancer and the Inca, respectively. J.Z.-R. is supported by an interface contract between Inserm and Bordeaux hospital. T.I. is supported by the National Institutes of Health grants GM071596, AI055894 and AI067949.
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Rebouissou, S., Amessou, M., Couchy, G. et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457, 200–204 (2009). https://doi.org/10.1038/nature07475
Cell & Bioscience (2022)
Nature Reviews Gastroenterology & Hepatology (2022)
Cellular and Molecular Life Sciences (2022)
Nature Communications (2022)
Nature Reviews Gastroenterology & Hepatology (2021)