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: 42.35). 12/2008; 457(7226):200-4. DOI: 10.1038/nature07475
Source: PubMed

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.

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    • "International Journal of Hepatology is the coreceptor of IL6R. Activating mutations of gp130 led to the constitutive activation of the JAK/STAT pathway in the absence of the IL6 ligand [42] [48]. A small subset of HCC exhibited both gp130 and í µí»½í µí»½-catenin-activating mutations. "
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    ABSTRACT: Hepatocellular adenomas (HCAs) are benign tumors developed in normal liver most frequently in women before menopause. HCAs lead to diagnostic pitfalls and several difficulties to assess the risk of malignant transformation in these young patients. Recent advances in basic knowledge have revealed a molecular classification related to risk factors, pathological features, and risk of transformation in hepatocellular carcinoma. Three major molecular pathways have been identified altered in specific HCA subgroups that are defined by either (1) inactivation of hepatocyte nuclear factor 1A (HNF1A) transcription factor, (2) activation of the WNT/β-catenin by CTNNB1 mutations, or (3) activation of the IL6/STAT3 pathway by somatic mutation of IL6ST, GNAS, or STAT3. Here, we will review the different molecular classes of HCA.
    01/2013; 2013(6):315947. DOI:10.1155/2013/315947
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    • "As a member of signal transducer and activator of transcription (STAT) family proteins, STAT3 is constitutively activated in various types of cancer (Bromberg et al. 1999) and plays an important role in inflammation-associated tumorigenesis initiated by genetic changes (Gao et al. 2007; Rebouissou et al. 2009) and environmental factors (Hodge et al. 2005; Yu et al. 2009). Among inflammatory factors, interleukin-6 (IL-6) is essentially required for STAT3 activation (Zhong et al. 1994). "
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    ABSTRACT: BACKGROUND: Aberrant expression of interleukin-6 (IL-6) may play an important role in lung carcinogenesis. Whether IL-6 promoter haplotypes are associated with lung cancer risk and their functions have not yet been studied. We tested the hypothesis that single-nucleotide polymorphism (SNP) and/or haplotypes of IL-6 promoter are associated with risk of lung cancer. METHODS: Two functional IL-6 promoter SNPs (-6331T>C and -572C>G) were genotyped in the discovery group including 622 patients and 614 controls, and the results were replicated in an independent validation group including 615 patients and 638 controls. Luciferase reporter gene assays were conducted to examine the function of IL-6 promoter haplotypes. RESULTS: None of the functional IL-6 promoter SNPs were associated with lung cancer risk in either study. However, a two-SNP CC (-6331C and -572C) IL-6 promoter haplotype was significantly more common among cases than among controls in both groups (P = 0.031 and P = 0.035, respectively), indicating that this haplotype is associated with increased lung cancer risk {adjusted odds ratio [OR], 1.56 [95 % confidence interval (95 % CI), 1.04-2.34] and 1.51 [95 % CI, 1.03-2.22], respectively}. Combined analysis of both studies showed a strong association of this two-SNP haplotype with increased lung cancer risk (adjusted OR, 1.53; 95 % CI, 1.16-2.03; P = 0.003). Comparably, luciferase reporter assays of A549 lung cancer cell lines transfected with the CC haplotype revealed that the two-SNP haplotype had significantly higher IL-6 transcriptional activity compared with cells transfected with the common haplotype. CONCLUSIONS: This is the first evidence of identifying an IL-6 promoter haplotype (CC) associated with increased risk of lung cancer.
    Journal of Cancer Research and Clinical Oncology 10/2012; DOI:10.1007/s00432-012-1314-z · 3.01 Impact Factor
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    • "HCA is divided into 3 subgroups according to 3 different genetic mutations: hepatocellular nuclear factor-1α (HNF1α) genemutated type HCA, β-catenin gene-mutated type HCA, and inflammatory type HCA (IHCA) which contains a somatic mutation of IL6ST gene. The latter mutation, encoding gp130, is found in 60% of IHCA, and a somatic mutation of STAT3 gene is found in 12% of IHCA [4] [5]. A fourth group represents HCA without any of these mutations. "
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    ABSTRACT: The inflammatory type hepatocellular adenoma (IHCA) is a subtype of HCA which is a benign liver tumor, predominantly occurring in young women in an otherwise normal liver. IHCA contains either a mutation of gp130 or STAT3. Both mutations lead to a similar morphologic phenotype and to increased expression of C-reactive protein (CRP) and/or serum amyloid-A (SAA). IHCA comprised about 40% of all HCAs and is associated with obesity. We investigated the histomorphological and immunophenotypical changes of the nontumorous liver of 32 resected IHCA specimens. Similar types of changes are present in samples taken adjacent to tumor and distant ones. The lobular architecture is well preserved. Mild/moderate steatosis is found in a high frequency which is in accordance with the median BMI of 32 in our cases. Of note are the regular findings of sinusoidal dilatation, single arteries, and minute CRP foci which are all features of HCA. These distinct CRP foci are mostly found in cases of multiple IHCA which indicates that the remnant liver may also contain IHCA foci. These findings show that the nonlesional liver in IHCA does contain abnormalities, and this may have consequences for the followup, especially since it is known that obesity may stimulate malignant growth.
    09/2012; 2012:805621. DOI:10.1155/2012/805621
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