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.
Your institute does not have access to this article
Open Access articles citing this article.
Nature Communications Open Access 29 June 2022
Cellular and Molecular Life Sciences Open Access 18 December 2021
Seminars in Immunopathology Open Access 28 May 2021
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bioulac-Sage, P. et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 46, 740–748 (2007)
Zucman-Rossi, J. et al. Genotype–phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 43, 515–524 (2006)
Grivennikov, S. & Karin, M. Autocrine IL-6 signaling: a key event in tumourigenesis? Cancer Cell 13, 7–9 (2008)
Akira, S. et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77, 63–71 (1994)
Wegenka, U. M., Buschmann, J., Lutticken, C., Heinrich, P. C. & Horn, F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol. Cell. Biol. 13, 276–288 (1993)
Hibi, M. et al. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149–1157 (1990)
Boulanger, M. J., Chow, D. C., Brevnova, E. E. & Garcia, K. C. Hexameric structure and assembly of the interleukin-6/IL-6α-receptor/gp130 complex. Science 300, 2101–2104 (2003)
Ward, L. D. et al. High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130. J. Biol. Chem. 269, 23286–23289 (1994)
Lutticken, C. et al. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263, 89–92 (1994)
Murakami, M. et al. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 260, 1808–1810 (1993)
Stahl, N. et al. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components. Science 263, 92–95 (1994)
Coulouarn, C. et al. Genome-wide response of the human Hep3B hepatoma cell to proinflammatory cytokines, from transcription to translation. Hepatology 42, 946–955 (2005)
Kishimoto, T., Akira, S., Narazaki, M. & Taga, T. Interleukin-6 family of cytokines and gp130. Blood 86, 1243–1254 (1995)
Chow, D., He, X., Snow, A. L., Rose-John, S. & Garcia, K. C. Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291, 2150–2155 (2001)
Skiniotis, G., Boulanger, M. J., Garcia, K. C. & Walz, T. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nature Struct. Mol. Biol. 12, 545–551 (2005)
Li, H. & Nicholas, J. Identification of amino acid residues of gp130 signal transducer and gp80α receptor subunit that are involved in ligand binding and signaling by human herpesvirus 8-encoded interleukin-6. J. Virol. 76, 5627–5636 (2002)
Ernst, M. et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumourigenesis in gp130 receptor mutant mice. J. Clin. Invest. 118, 1727–1738 (2008)
Maione, D. et al. Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J. 17, 5588–5597 (1998)
Judd, L. M. et al. Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology 126, 196–207 (2004)
Judd, L. M. et al. STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumourigenesis. Gastroenterology 131, 1073–1085 (2006)
Tebbutt, N. C. et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nature Med. 8, 1089–1097 (2002)
Boulton, T. G., Stahl, N. & Yancopoulos, G. D. Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J. Biol. Chem. 269, 11648–11655 (1994)
Croker, B. A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. . Nature Immunol. 4, 540–545 (2003)
Bioulac-Sage, P. et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology 128, 1211–1218 (2005)
Schutyser, E., Struyf, S. & Van Damme, J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 14, 409–426 (2003)
Bluteau, O. et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nature Genet. 32, 312–315 (2002)
Chen, Y. W., Jeng, Y. M., Yeh, S. H. & Chen, P. J. P53 gene and Wnt signaling in benign neoplasms: β-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology 36, 927–935 (2002)
Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007)
Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007)
Rebouissou, S. et al. HNF1α inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation. J. Biol. Chem. 282, 14437–14446 (2007)
Gautier, L., Cope, L., Bolstad, B. M. & Irizarry, R. A. Affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20, 307–315 (2004)
Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004)
Li, C. & Hung Wong, W. Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol. 2, Research0032 (2001)
Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003)
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.
About this article
Cite this article
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
Nature Reviews Gastroenterology & Hepatology (2022)
Cellular and Molecular Life Sciences (2022)
Nature Communications (2022)
Nature Reviews Gastroenterology & Hepatology (2021)
Seminars in Immunopathology (2021)