It has long been appreciated that chronic inflammation poses a potential risk for the development of cancer. However, it is still an evolving research area for how inflammation and tissue repair are intrinsically linked to cancer. IL-17A (IL-17), a signature cytokine produced by a subset of T helper cells termed Th17 cells, plays essential roles in host defense and contributes to autoimmune inflammatory diseases. High IL-17A levels in hepatocellular carcinoma, colorectal cancer, non-small cell lung cancer and squamous cell carcinoma (SCC) are indicative of poorer prognosis. While IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. We now discovered a novel IL-17-induced Act1/TRAF4-mediated ERK5 cascade that directly stimulates epidermal stem cell expansion, epidermal hyperplasia and tumor formation. While Act1 (the adaptor for the IL-17 receptor) interacts with TRAF6 and TRAF2/5, to activate NF-?B and mediate posttranscriptional control of inflammatory genes (including IL-6), respectively; TRAF4 binds Act1 to promote ERK5 activation. While Act1, TRAF4 or ERK5 deficiency resulted in a loss of IL-17-induced epidermal hyperplasia, epidermal-specific deletion of Act1 or TRAF4 deficiency was sufficient to protect mice from DMBA/TPA-induced carcinogenesis. Mechanistically, Act1/TRAF4-dependent ERK5 activation was achieved through the interaction of IL-17 receptor (IL-17R) with EGFR, resulting in MEKK3-MEK5-ERK5 activation. While IL-17A stimulation induced EGFR phosphorylation, epidermal EGFR- deficiency specifically blocked IL-17A-induced ERK5 activation, epidermal proliferation and tumor formation. Based on these results, we hypothesize that EGFR is recruited to IL-17R to mediate ERK5 activation in tumor initiating cells, contributing to epidermal proliferation and skin tumorigenesis. The direct impact of IL-17 signaling on tumor cells is synergized by pro-inflammatory action of IL-17 (e.g. IL-6 production) in stromal cells. To test this hypothesis, we will (1) Investigate the molecular mechanism by which IL-17R interacts with EGFR to mediate the activation of ERK5; (2) Investigate the target genes of the IL-17A-induced TRAF4-ERK5 axis that promote cell proliferation and tumorigenesis; (3) Study the cellular mechanism by which the IL-17R-EGFR- ERK5 pathway contributes to chemical- and wound-induce tumorigenesis. The completion of this study will provide mechanistic insight into IL-17-dependent tumorigenesis, which will lead to new therapeutic strategies for cancer treatments.
This proposal aims to study the relationship between inflammation and cancer. Specifically we will investigate the pathogenic role of pro-inflammatory interleukin-17 in chemical- and wound-induced tumor formation. The completion of the proposal will help to develop new therapeutic strategies for treatment of cancer.
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