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• Dr. Göktuna’s article has been published in the Cancer Research

Dr. Göktuna has published his research article entitled “The pro-survival IKK-related kinase IKKepsilon integrates LPS and IL-17A signaling cascades to promote Wnt-dependent tumor development in the intestine.” in the Cancer Research Journal in March, 2016. This article Published in American Association for Cancer Research in March 15, 2015 with doi: 


Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor-promoting environment has not been extensively studied. Therefore, we assessed the relationship between the pro-inflammatory Ikk-related kinase, Ikkepsilon, in Wnt-driven tumor development. We found that Ikkepsilon was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkepsilon in APC or β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkepsilon to limited TNF-dependent apoptosis using transformed intestinal epithelial cells. Additionally, Ikkepsilon was also required for lipopolysaccharide (LPS) and IL-17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides, including IL-17A, were downregulated in Ikkepsilon-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages. Further studies revealed that IL-17A synergized with commensal bacteria to trigger Ikkepsilon phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL-17A-dependent signaling pathways converge on Ikkepsilon to promote cell survival and establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.