Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature (Lond)

Inserm, U674, Génomique fonctionnelle des tumeurs solides, Paris F-75010, France.
Nature (Impact Factor: 41.46). 12/2008; 457(7226):200-4. DOI: 10.1038/nature07475
Source: PubMed


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.

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Available from: Jessica Zucman-Rossi, Oct 12, 2015
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    • "Therefore, those accumulated DNA damages occurred on tumor suppressor genes and oncogenes are important genetic events of HCC oncogenesis and progression. A few inactivated tumor suppressor genes such as TP53 and activated oncogenes such as β-catenin, gp130 resulted from somatic mutations play critical roles during hepatocarcinogenesis, as demonstrated by previous investigations 6-8. Recent sequencing analysis of exomes and genomes in multiple HCC cohorts has defined not only common events that target well-known cancer pathways including β-catenin/Axin, TP53, and RB/CDKN2A, as well as frequent aberrations in chromatin remodeling factors, but also a large amount of moderate and low frequency genetic lesions which may account for tumor heterogeneity and malignancy 9-13. "
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    • "Although sensitized to inflammatory liver injury, mice with hepatocyte-specific Il6st knockout do not develop liver pathologies under basal conditions (Streetz et al. 2003), suggesting that loss of expression in other cell types contributes to the phenotype in constitutive knockout mice. Given that IL-6 levels are typically increased in NAFLD-associated conditions such as obesity and type 2 diabetes (Goyal et al. 2012; Roytblat et al. 2000) and that activating mutations in IL6ST have been recurrently detected in human liver cancer (Rebouissou et al. 2009), these results seem somewhat counterintuitive. Additionally, enhanced production of IL-6 has been demonstrated to functionally contribute to chemically-induced hepatocarcinogenesis in mice (Naugler et al. 2007). "
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    • "The resulting small in-frame deletions were found in 60% of IHCAs and are located in one of the binding sites of gp130 for IL-6. In hepatic cells these gp130 mutants caused ligand-independent Stat3 phosphorylation [4]. Two years later it was reported that 12% of IHCAs lacking a mutation in the IL-6ST gene harbor somatic Stat3 mutations underscoring the role of the gp130-Stat3 axis in benign hepatocellular tumorigenesis [5]. "
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    ABSTRACT: Short in-frame deletions in the second extracellular domain of the cytokine receptor gp130 are the leading cause of inflammatory hepatocellular adenomas (IHCAs). The deletions render gp130 constitutively active. In this study we investigate the intracellular signaling potential of one of the most potent constitutively active gp130 mutants (CAgp130) found in IHCAs. Trafficking and signaling of CAgp130 were studied in stably transfected cell lines that allowed the inducible expression of CAgp130 fused to fluorescent proteins such as YFP and mCherry. In contrast to the predominantly highly glycosylated gp130 wild type (WTgp130), CAgp130 is preferentially found in the less glycosylated high-mannose form. Accordingly, the mutated receptor is retained intracellularly and therefore less prominently expressed at the cell surface. CAgp130 persistently activates Stat3 despite the presence of the feedback inhibitor SOCS3 but fails to activate Erk1/2. De novo synthesized CAgp130 signals already from the ER-Golgi compartment before having reached the plasma membrane. Cell surface expressed and endocytosed CAgp130 do not significantly contribute to signaling. As a consequence, Stat3 activation through CAgp130 cannot be inhibited by neutralizing gp130 antibodies but through overexpression of a dominant-negative Stat3 mutant. CAgp130 and WTgp130 differ significantly with respect to glycosylation, trafficking and signaling. As a consequence of intracellular signaling pharmacological inhibition of CAgp130 will not be achieved by targeting the receptor extracellularly but by compounds that act from within the cell.
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