PROJECT 3: PROJECT SUMMARY 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-κB 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.