Publication Date:
2008-11-21
Description:
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. 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 beta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695248/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695248/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rebouissou, Sandra -- Amessou, Mohamed -- Couchy, Gabrielle -- Poussin, Karine -- Imbeaud, Sandrine -- Pilati, Camilla -- Izard, Tina -- Balabaud, Charles -- Bioulac-Sage, Paulette -- Zucman-Rossi, Jessica -- AI055894/AI/NIAID NIH HHS/ -- AI067949/AI/NIAID NIH HHS/ -- GM071596/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jan 8;457(7226):200-4. doi: 10.1038/nature07475. Epub 2008 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Inserm, U674, Genomique fonctionnelle des tumeurs solides, Paris F-75010, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020503" target="_blank"〉PubMed〈/a〉
Keywords:
Adenoma, Liver Cell/*genetics/*pathology
;
Cell Line, Tumor
;
Cytokine Receptor gp130/*genetics/*metabolism
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic
;
Humans
;
Inflammation/genetics/pathology
;
Interferons/metabolism
;
Interleukin-6/metabolism
;
STAT3 Transcription Factor/metabolism
;
Sequence Deletion/*genetics
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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