Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis

Li, Yang; Haar, Colin de; Chen, Min; Deuring, J. Jasper; Gerrits, Monique M.; Smits, Ron; Xia, Bing; Kuipers, Ernst J.; Woude, Christien J. van der

doi:10.1136/gut.2009.184176

Cited by 289 publications

(222 citation statements)

References 43 publications

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“…Interleukin-6 (IL-6), a pro-inflammatory cytokine, has been shown to regulate cancer cell growth and thereby contribute to tumor promotion and progression (5). has been demonstrated to be associated with an unfavorable prognosis in patients with various types of cancers including both sporadic and colitis-associated CRC (6). However, despite clear evidence implicating IL-6 in causation of CRC, molecular mechanisms underlying this phenomenon are still incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

Han

Meng

et al. 2015

International Journal of Oncology

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Abstract. Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.

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Section: Introductionmentioning

confidence: 99%

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

Han

Meng

et al. 2015

International Journal of Oncology

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“…Finally, Li et al (2010) investigated the expression of IL-6 and its epithelial targets in patients with UC who had progressed to CRC. They found that the expression of both IL-6 and STAT3 was greater in both patients with active UC and those who had progressed to CAC, compared with both patients with inactive disease and control patients.…”

Section: Cytokinesmentioning

confidence: 99%

Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin–Yang interplay between inflammation and cancer

Danese¹,

2010

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Colon cancer represents a paradigm for the connection between inflammation and cancer in terms of epidemiology and mechanistic studies in preclinical models. Key components of cancer promoting inflammation include master transcription factors (for example, nuclear factor jB, STAT3), proinflammatory cytokines (for example, tumor necrosis factor, interleukin-6 (IL-6)), cyclooxygenase-2 and selected chemokines (for example, CCL2). Of no less importance are mediators that keep inflammation in check, including IL-10, transforming growth factorb, toll-like receptor and the IL-1 receptor inhibitor TIR8/ SIGIRR, and the chemokine decoy and scavenger receptor D6. Dissection of molecular pathways involved in colitis-associated cancer may offer opportunities for innovative therapeutic strategies.

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“…Although these studies imply a key role for STAT3 in mediating the potent anti-inflammatory effects of IL-10, the role of STAT3 in facilitating proinflammatory responses of IL-6 and other STAT3-activating cytokines remains ill-defined with current Stat3 gene knock-out mouse models. Moreover, considering persistent STAT3 activation is a feature of numerous human inflammatory diseases (e.g., human ulcerative colitis, RA) (25,26), there is a growing need for genetically defined mouse models displaying hyperactivated levels of endogenous STAT3 to investigate the mechanisms by which STAT3 promotes the pathogenesis of inflammatory diseases.…”

mentioning

confidence: 99%

IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3

Greenhill

Rose-John

Lissilaa

et al. 2011

The Journal of Immunology

245

159

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Innate immune responses triggered by the prototypical inflammatory stimulus LPS are mediated by TLR4 and involve the coordinated production of a multitude of inflammatory mediators, especially IL-6, which signals via the shared IL-6 cytokine family receptor subunit gp130. However, the exact role of IL-6, which can elicit either proinflammatory or anti-inflammatory responses, in the pathogenesis of TLR4-driven inflammatory disorders, as well as the identity of signaling pathways activated by IL-6 in a proinflammatory state, remain unclear. To define the contribution of gp130 signaling events to TLR4-driven inflammatory responses, we combined genetic and therapeutic approaches based on a series of gp130F/F knock-in mutant mice displaying hyperactivated IL-6–dependent JAK/STAT signaling in an experimental model of LPS/TLR4-mediated septic shock. The gp130F/F mice were markedly hypersensitive to LPS, which was associated with the specific upregulated production of IL-6, but not TNF-α. In gp130F/F mice, either genetic ablation of IL-6, Ab-mediated inhibition of IL-6R signaling or therapeutic blockade of IL-6 trans-signaling completely protected mice from LPS hypersensitivity. Furthermore, genetic reduction of STAT3 activity in gp130F/F:Stat3+/− mice alleviated LPS hypersensitivity and reduced LPS-induced IL-6 production. Additional genetic approaches demonstrated that the TLR4/Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130F/F mice. Collectively, these data demonstrate for the first time, to our knowledge, that IL-6 trans-signaling via STAT3 is a critical modulator of LPS-driven proinflammatory responses through cross-talk regulation of the TLR4/Mal signaling pathway, and potentially implicate cross-talk between JAK/STAT and TLR pathways as a broader mechanism that regulates the severity of the host inflammatory response.

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Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis

Abstract: The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.

Cited by 289 publications

References 43 publications

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin–Yang interplay between inflammation and cancer

IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3

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