Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

• Published in: Nature 2009-01, Vol.457 (7226), p.200-204
• Main Authors: Rebouissou, Sandra, Amessou, Mohamed, Couchy, Gabrielle, Poussin, Karine, Imbeaud, Sandrine, Pilati, Camilla, Izard, Tina, Balabaud, Charles, Bioulac-Sage, Paulette, Zucman-Rossi, Jessica
• Format: Article
• Language: English
• Subjects: Adenoma, Liver Cell; Adenoma, Liver Cell - genetics; Adenoma, Liver Cell - pathology; Binding sites; Biological and medical sciences; Cell Line, Tumor; Cells; Cellular signal transduction; Crystal structure; Cytokine Receptor gp130; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; gp130; heaptocellular carcinoma; hepatocellular adenoma; Human health and pathology; Humanities and Social Sciences; Humans; Hépatology and Gastroenterology; Immune response; Inflammation; Inflammation - genetics; Inflammation - pathology; Interferons; Interferons - metabolism; Interleukin-6; Interleukin-6 - metabolism; Kinases; letter; Life Sciences; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; multidisciplinary; Mutation; oncogene; Proteins; Regulation; Rodents; Science; Science (multidisciplinary); Sequence Deletion; Sequence Deletion - genetics; Signal Transduction; STAT3 Transcription Factor; STAT3 Transcription Factor - metabolism; Studies; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature07475

Inflammation and cancer It is know that there is a link between some types of chronic inflammation and certain cancers. Now a genetic study of liver tumour tissues has identified gain-of-function mutations in the IL6ST gene, part of an inflammatory signalling pathway that codes for the interleukin-6 co-receptor gp130, as a possible early step on the development of benign liver tumours. This mutation in IL6ST was frequently found together with mutations in β-catenin, suggesting that they may cooperate in promoting tumorigenesis. Inflammatory heptocellular adenomas (IHCAs) show activation of an acute-phase inflammatory response signalling pathways, and it is found that this is due to gain-of function mutations in the IL6ST gene encoding gp130, a coreceptor for IL-6 and other cytokines that activate inflammatory signalling pathways. These mutations lead to constitutive activation of STAT3 signalling, contributing to the inflammatory phenotype of IHACs. Inflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes 1 , 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.