Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours.
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.
Rebouissou
Sandra
S
Inserm, U674, Génomique fonctionnelle des tumeurs solides, Paris F-75010, France.
Amessou
Mohamed
M
Couchy
Gabrielle
G
Poussin
Karine
K
Imbeaud
Sandrine
S
Pilati
Camilla
C
Izard
Tina
T
Balabaud
Charles
C
Bioulac-Sage
Paulette
P
Zucman-Rossi
Jessica
J
D018248:Adenoma, Liver Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007372:Interferons / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D015398:Signal Transduction
C494199:IL6ST protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D007372:Interferons