Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature (Reprinted with permission.)
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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 b-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.
Hepatic adenomas are rare benign liver tumours that are usually found in younger women using oral contraceptives without underlying liver disease. Recently, three subgroups were identified having different risks for malignant transformation. These groups are characterized by inactivation of hepatic nuclear factor 1α, an activating β-catenin mutation, or the histological presence of inflammation (inflammatory hepatocellular adenoma [IHAC]).1
IHACs are defined by the presence of inflammatory infiltrates, which are highly polymorphous, and no general pattern has been described. The chemokine CCL20 is highly expressed in these tumors and acts as a chemoattractant for immune cells, including B, T, and dendritic cells. Immunohistochemistry reveals a strong expression of serum amyloid A (SAA) and C-reactive protein (CRP) restricted exclusively to tumor hepatocytes. Nuclear phospho-STAT3 expression was found in all tumor samples. No signs of an acute phase response could be detected in surrounding liver tissue.
Interleukin-6 (IL-6) is a typical proinflammatory cytokine that regulates acute phase gene expression2, 3 and is involved in liver regeneration4 but also in carcinogenesis. Despite the inflammatory infiltrate, no elevated IL-6 expression could be detected in IHACs. These initial findings inspired Zucman-Rossi's group to screen for genomic mutations in the IL6ST gene coding for the gp130 cell surface receptor. After ligand binding, gp130 is the essential signal transduction molecule used by all IL-6 family members.
In 60% (26/43) of all the IHACs included in this study, an IL6ST gene mutation was present. These mutations were not observed in the surrounding normal liver tissue. All the mutations found in IHACs had a common pattern as they had an altered D2 domain; a gp130 area essential for IL-6–gp130 interaction. Therefore, these findings indicated that these mutations may have an impact on gp130 homodimerization. Interestingly, transfection of these gp130 mutants in the hepatoma cell line Hep3B triggered activation of CRP, SAA2, and SOCS3 without IL-6 stimulation. These findings suggest that gain-of-function mutations in the gp130 receptor have been selected in IHACs resulting in STAT3 phosphorylation without classical IL-6 ligand binding (Fig. 1A).
In recent years, molecular mechanisms of liver cancerogenesis have increasingly been a focus of interest. Several of these studies suggested that IL-6 may play an important role in their pathogenesis. First evidence was gathered in 1998 in double transgenic mice overexpressing IL-6 and soluble IL-6 receptor (sgp80). These animals showed a hyperstimulation of IL-6/gp130–dependent signaling in hepatocytes and developed nodular regenerative hyperplasia and spontaneous hepatic adenomas.5
A more recent study investigated the important role of IL-6 in the DEN model. In this model, the authors concluded that IL-6 is an essential factor for HCC development and also might be involved in explaining the sex difference as males more readily develop HCCs. On a molecular level, DEN-induced cellular debris triggers IL-6 production in Kupffer cells via the Toll-like receptor and MyD88 activation. IL-6 promotes an inflammatory response and a sustained proliferation signal, which is essential to trigger hepatocancerogenesis. In this setting, estrogens have a negative regulatory effect on IL-6 expression and thus reduce the proproliferative response in female livers and thus tumor growth.6
A marked activation of IL-6–dependent signaling and STAT3 activation has also been described in human HCC, suggesting that HCC could arise from IL-6–driven transformed stem cells combined with inactivated transforming growth factor β signaling.7
The present study provides a direct molecular link that hyperstimulation of the gp130 pathway via an in vivo selected gain-of-function mutation results in liver tumorigenesis. The IHAC-related gp130 mutant allows to homodimerize or heterodimerize with the wild-type gp130, whereas the wild-type alone cannot homodimerize without ligand binding. The mutant activity driven by its homodimerization can be competed by higher expression of the wild-type protein. From these experiments, the authors conclude that expression of the gain-of-function gp130 mutations alone account for the inflammatory response and tumor growth found in IHACs (Fig. 1B).
A gp130 mutation is only present in 60% of all IHACs. The remaining tumors have a similar expression profile showing STAT3 activation without mutations in gp130 or sgp80. However, a higher expression of wild-type gp130 could be detected in these IHACs. At present, the molecular mechanism of STAT3 activation in these tumors has not yet been elucidated (Fig. 1C). These results indicate that the gp130/STAT3 axis is also relevant for pathogenesis in either mutated and nonmutated IHACs, and thus the third group of hepatic adenomas represents a homogenous group linked to this signaling cascade.
Only in two of the cases was malignant transformation observed. In these IHACs, the combination of mutations in gp130 and the β-catenin pathway were detected. However, this mechanism is a rare event in HCC cancerogenesis. The incidence of gp130 mutations in HCCs was 1.8% (2/111). Those cases also had the combination with a mutation in the β-catenin pathway. Together, these results suggest that gp130 can induce malignant transformation and thus represent a rather rare event in a potential small HCC subclass.
In summary, gp130 mutations or gp130 wild-type overexpression in hepatocytes are associated with inflammatory benign liver tumor leading to STAT3 activation (Fig. 1). However, single gp130 mutations or overexpression in hepatocytes alone are not sufficient to trigger malignant transformation. The present data suggest that a second hit is required to trigger HCC development. Further studies are needed to clarify the mechanism of gp130 overexpression in benign liver tumors and in HCC. Therefore, gp130 could be a potential target in some of the hepatic adenomas and in a subclass of HCCs.