2. Academic Validation
  3. Interleukin-38 promotes skin tumorigenesis in an IL-1Rrp2-dependent manner

Interleukin-38 promotes skin tumorigenesis in an IL-1Rrp2-dependent manner

  • EMBO Rep. 2022 Jun 7;23(6):e53791. doi: 10.15252/embr.202153791.
Hong Zhou  # 1,  Qixiang Zhao  # 1,  Chengcheng Yue  # 1,  Jiadong Yu  # 1,  Huaping Zheng 1,  Jing Hu 1,  Zhonglan Hu 1,  Haozhou Zhang 1,  Xiu Teng 1,  Xiao Liu 1,  Xiaoqiong Wei 1,  Yuxi Zhou 2,  Fanlian Zeng 1,  Yan Hao 1,  Yawen Hu 1,  Xiaoyan Wang 1,  Chen Zhang 1,  Linna Gu 1,  Wenling Wu 1,  Yifan Zhou 1,  Kaijun Cui 3,  Nongyu Huang 1,  Wei Li 2,  Zhen Wang 1 4,  Jiong Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
  • 2 Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, China.
  • 3 Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
  • 4 Department of Liver Surgery & Liver Transplantation, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
  • # Contributed equally.
PMID: 35578812 DOI: 10.15252/embr.202153791
Abstract

Interleukin-38 (IL-38) is strongly associated with chronic inflammatory diseases; however, its role in tumorigenesis is poorly understood. We demonstrated that expression of IL-38, which exhibits high expression in the skin, is downregulated in human cutaneous squamous cell carcinoma and 7,12-dimethylbenzanthracene/12-O-tetradecanoyl phorbol-13-acetate-induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice displayed suppressed skin tumor formation and malignant progression. Keratinocyte-specific deletion of IL-38 was associated with reduced expression of inflammatory cytokines, leading to reduced myeloid cell infiltration into the local tumor microenvironment. IL-38 is dispensable for epidermal mutagenesis, but IL-38 keratinocyte-specific deletion reduces proliferative gene expression along with epidermal cell proliferation and hyperplasia. Mechanistically, we first demonstrated that IL-38 activates the c-Jun N-terminal kinase (JNK)/activator protein 1 signal transduction pathway to promote the expression of cancer-related inflammatory cytokines and proliferation and migration of tumor cells in an IL-1 receptor-related protein 2 (IL-1Rrp2)-dependent manner. Our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2/JNK and suggest IL-38/IL-1Rrp2 as a preventive and potential therapeutic target in skin Cancer.

Keywords

IL-1Rrp2; IL-38; skin carcinogenesis.

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