ArticleThe Journal of experimental medicine2015
A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.
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Article in The Journal of experimental medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers.
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138 citing papers in PubMed, 224 citations in OpenAlex.
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- Vunakizumab for IL-17A-Mediated Diseases: A Review in Psoriasis and Spondyloarthritis.Biologics : targets & therapy · 2026Review
- The structure and functions of TRAF families and recent advances of TRAFs in leukemia.Frontiers in oncology · 2026Review
- Interleukin-17 receptor A drives cancer stem-like properties in colorectal cancer through STAT3 activation.Journal of Cancer · 2026Article
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- Unraveling the crucial role of CCL3 in nasopharyngeal carcinoma: bioinformatics and immunohistochemical insights.Journal of pathology and translational medicine · 2025Article
- The absence of IL17A favours cytotoxic cell function and improves antigen-specific immunotherapies in pancreatic adenocarcinoma.Clinical and translational medicine · 2025Article
- The Impact of Flavonoids and Omega-3 in Mitigating Frailty Syndrome to Improve Treatment Outcomes in Peripheral Artery Disease (PAD) Patients.Nutrients · 2025Review
- Effect of fecal microbiota transplantation on diabetic wound healing through the IL-17A-mTOR-HIF1α signaling axis.Applied and environmental microbiology · 2025Article
- An Evaluation of Prognostic Factors in Cutaneous Squamous Cell Carcinoma: A Single-Center Study of 237 Japanese Cases.Journal of clinical medicine · 2025Article
- Nerve Growth Factor Signaling Promotes Nuclear Translocation of TRAF4 to Enhance Tumor Stemness and Metastatic Dormancy Via C-Jun-mediated IL-8 Autocrine.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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- The IL-23/Th17 pathway inhibitors in the treatment of psoriasis and the risk of skin malignancies: a review.Postepy dermatologii i alergologii · 2024Review
78 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 8 institutions in 5 countries.
Ling WuDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Pathology and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Xing ChenDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Junjie ZhaoDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Pathology and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Bradley MartinDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Pathology and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Jarod A ZeppDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Pathology and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Jennifer S KoDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Chunfang GuDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Gang CaiDepartment of Laboratory Medicine, Ruijin Hospital, Shanghai Institute of Immunology, and Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Wenjun OuyangDepartment of Immunology, Genentech, South San Francisco, CA 94080.
Ganes SenDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
George R StarkDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Bing SuDepartment of Laboratory Medicine, Ruijin Hospital, Shanghai Institute of Immunology, and Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Laboratory Medicine, Ruijin Hospital, Shanghai Institute of Immunology, and Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Immunobiology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520.
Charlotte M VinesUniversity of Texas at El Paso, El Paso, TX 79968.
Cathy TournierUniversity of Manchester, Manchester M13 9PL, England, UK.
Thomas A HamiltonDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Allison VidimosDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Brian GastmanDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
Caini LiuDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 lix@ccf.org liuc@ccf.org.
Xiaoxia LiDepartment of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 lix@ccf.org liuc@ccf.org.
Cleveland Clinic · USCentre for Cancer Biology · AUShanghai Jiao Tong University · CNCase Western Reserve University · USCleveland Clinic Lerner College of Medicine · USThe University of Texas at El Paso · USUniversity of Manchester · GBUniversity School · US
Funding
TELOMERASE INACTIVATION BY RNASE L SIGNALS CELL DEATHP01CA062220 · NCI · CLEVELAND CLINIC LERNER COM-CWRU · PI LI, XIAOXIA, STARK, GEORGE ROBERT · 1994 to 2020
$35.6MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007250 · NIGMS · CASE WESTERN RESERVE UNIVERSITY · PI HUANG, ALEX YEE-CHEN · 1985 to 2023
$33.4MTargeting pathological hyaluronan matricesP01HL103453 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI REIZES, OFER · 2011 to 2020
$26.8MImmunology Training Program-PredoctoralT32AI089474 · NIAID · CASE WESTERN RESERVE UNIVERSITY · PI COBB, BRIAN A · 2010 to 2025
$3.4MCCR7 Chemotaxis Regulates Memory T Cell LocalizationSC1GM111172 · NIGMS · UNIVERSITY OF TEXAS EL PASO · PI VINES, CHARLOTTE M · 2015 to 2023
$3.0MMolecular and Cellular Mechanisms of IL-17 SignalingR01NS071996 · NINDS · CLEVELAND CLINIC LERNER COM-CWRU · PI LI, XIAOXIA · 2011 to 2015
$1.9MNCI NIH HHS P01 CA062220NCI NIH HHS P01CA062220-16A1NHLBI NIH HHS 1P01 HL103453NHLBI NIH HHS P01 HL103453NIAID NIH HHS T32 AI089474NIAID NIH HHS T32 AI 89474-1NIGMS NIH HHS SC1 GM111172NIGMS NIH HHS T32 GM007250NIGMS NIH HHS T32GM007250NINDS NIH HHS 1R01NS071996NINDS NIH HHS R01 NS071996Worldwide Cancer Research 10-0134
Abstract
Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.
Indexed as
Adaptor Proteins, Signal TransducingAnimalsCarcinoma, Squamous CellCell ProliferationFeedback, PhysiologicalHumansInterleukin-17KeratinocytesMAP Kinase Kinase Kinase 3Membrane ProteinsMice, Inbred C57BLMice, KnockoutMice, TransgenicMitogen-Activated Protein Kinase 7PhosphoproteinsReceptors, Interleukin-17Adaptor Proteins, Signal TransducingInterleukin-17Map3k3 protein, mouseMAP Kinase Kinase Kinase 3Membrane ProteinsMitogen-Activated Protein Kinase 7PhosphoproteinsReceptors, Interleukin-17Tiarp protein, mouseTNF Receptor-Associated Factor 4Traf3ip2 protein, mouseTraf4 protein, mouseTrans-ActivatorsTrp63 protein, mouse
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