# Molecular and cellular mechanism of IL-17 signaling in tumorigenesis

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $450,732

## Abstract

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.

## Key facts

- **NIH application ID:** 9891021
- **Project number:** 5P01CA062220-25
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Xiaoxia Li
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,732
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891021

## Citation

> US National Institutes of Health, RePORTER application 9891021, Molecular and cellular mechanism of IL-17 signaling in tumorigenesis (5P01CA062220-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9891021. Licensed CC0.

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