Epithelial gp130/Stat3 functions: An intestinal signaling node in health and disease

Ernst, Matthias; Thiem, Stefan; Nguyen, Paul M.; Eissmann, Moritz F.; Putoczki, Tracy L.

doi:10.1016/j.smim.2013.12.006

Cited by 56 publications

(48 citation statements)

References 69 publications

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“…STAT3 Y705 phosphorylation was consistently higher in Δp/np than in F/F tumours and correlated with the expression of the GP130 subunit of the IL6 receptor (Fig. 3a), which has been implicated in gastrointestinal tumourigenesis22. The expression of βcatenin, frequently activated in HCC, was slightly elevated in tumours of both genotypes (Fig.…”

Section: Resultsmentioning

confidence: 80%

“…Increased GP130 expression selectively supports the activation of STAT3 by proinflammatory cytokines of the IL6 family, but not by those of the IL10 family, broadly speaking anti-inflammatory in nature; the importance of the GP130/STAT3 axis in epithelial inflammation and gastrointestinal tumourigenesis22 and of GP130 in liver tumours47144041 has been amply documented. Besides the cell-autonomous proliferation phenotype, RAF1-deficient DIH are much more efficient than controls in attracting macrophages; they also produce higher amounts of CCL2, a STAT3 target gene42, and of CXCL1, upregulated by YAP1 in breast cancer cell lines43.…”

Section: Discussionmentioning

confidence: 99%

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A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

et al. 2016

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Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies. Currently, the only therapeutic option for advanced HCC is Sorafenib, an inhibitor whose targets include RAF. Unexpectedly, RAF1 expression is reduced in human HCC samples. Modelling RAF1 downregulation by RNAi increases the proliferation of human HCC lines in xenografts and in culture; furthermore, RAF1 ablation promotes chemical hepatocarcinogenesis and the proliferation of cultured (pre)malignant mouse hepatocytes. The phenotypes depend on increased YAP1 expression and STAT3 activation, observed in cultured RAF1-deficient cells, in HCC xenografts, and in autochthonous liver tumours. Thus RAF1, although essential for the development of skin and lung tumours, is a negative regulator of hepatocarcinogenesis. This unexpected finding highlights the contribution of the cellular/tissue environment in determining the function of a protein, and underscores the importance of understanding the molecular context of a disease to inform therapy design.

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

et al. 2016

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“…Meanwhile, genetic manipulations that reduce or ablate STAT3 expression or activation, or ablate IL6 production in myeloid cells reduces tumor incidence and growth (20,23). Collectively, these findings suggest that epithelial GP130/STAT3 signaling may act as a "rheostat" for WNT signaling-mediated wound healing of the intestinal epithelium (26). Consistent with this, homozygous gp130…”

Section: Stat3 Signaling During Epithelial Homeostasis and Tumor Formmentioning

confidence: 66%

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

Ernst

Putoczki

2014

Clinical Cancer Research

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Emerging evidence suggests that cytokines produced by inflammatory cells act as rheostats to link the degree of wounding and local inflammation to epithelial cell survival, proliferation, and metabolism that collectively underpin the repair response. Among these cytokines, the GP130 family, which encompasses, among others, IL6 and IL11, plays a major role in orchestrating these complex processes through the activation of the latent signal transducer and activator of transcription 3 (STAT3) in the epithelium. However, many of the molecular mechanisms that govern and ensure effective epithelial wound healing and regeneration renewal also promote tumorigenesis and the progression of established cancers. Accordingly, GP130 cytokines endow the inflammatory tumor microenvironment with a capacity to promote "cancer hallmark capabilities" of the malignant epithelium, while simultaneously suppressing the antitumor response of innate and adaptive immune cells. Here, we review some recent insights derived from genetic and therapeutic inhibition of the IL6/IL11-GP130-STAT3 signaling cascade in the context of preclinical mouse models of cancer, which are likely to have implications to other solid malignancies. Clin Cancer Res; 20(22); 5579-88. Ó2014 AACR.

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“…Phosphorylated Stat3 translocates to the nucleus and activates genes involved in proliferation, survival, and mucosal defense (Bollrath et al, 2009;Pickert et al, 2009;Ernst et al, 2014). Mutations in STAT3 have been identified as susceptibility factors for inflammatory bowel disease (Bollrath et al, 2009;Anderson et al, 2011;Demaria et al, 2012), and in mice, upon DSSinduced colitis, epithelial Stat3 is required for mucosal wound healing (Pickert et al, 2009).…”

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confidence: 99%