Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours.Report as inadecuate




Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. - Download this document for free, or read online. Document in PDF available to download.

* Corresponding author 1 Genomique Fonctionnelle des Tumeurs Solides 2 Labex Immuno-oncology 3 Genexpress, Génomique Fonctionnelle et Biologie Systémique pour la Santé 4 Department of Cancer Biology 5 Fibrose hépatique et cancer du foie 6 Service d-Hépato-Gastro-Entérologie 7 Service de pathologie Bordeaux

Abstract : 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.

keyword : hepatocellular adenoma heaptocellular carcinoma gp130 inflammation oncogene mutation





Author: Sandra Rebouissou - Mohamed Amessou - Gabrielle Couchy - Karine Poussin - Sandrine Imbeaud - Camilla Pilati - Tina Izard - Charle

Source: https://hal.archives-ouvertes.fr/



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