Abstract
BackgroundInterleukin-32 (IL-32) has been associated with various diseases. Previous studies have shown that IL-32 inhibited the development of several tumors. However, the role of IL-32γ, an isotype of IL-32, in skin carcinogenesis remains unknown.MethodsWe compared 7,12-Dimethylbenz[a]anthracene/12-O-Tetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis in wild type (WT) and IL-32γ-overexpressing mice to evaluate the role of IL-32γ. We also analyzed cancer stemness and NF-κB signaling in skin cancer cell lines with or without IL-32γ expression by western blotting, quantitative real-time PCR and immunohistochemistry analysis.ResultsCarcinogen-induced tumor incidence in IL-32γ mice was significantly reduced in comparison to that in WT mice. Infiltration of inflammatory cells and the expression levels of pro-inflammatory mediators were decreased in the skin tumor tissues of IL-32γ mice compared with WT mice. Using a genome-wide association study analysis, we found that IL-32 was associated with integrin αV (ITGAV) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are critical factor for skin carcinogenesis. Reduced expression of ITGAV and TIMP-1 were identified in DMBA/TPA-induced skin tissues of IL-32γ mice compared to that in WT mice. NF-κB activity was also reduced in DMBA/TPA-induced skin tissues of IL-32γ mice. IL-32γ decreased cancer cell sphere formation and expression of stem cell markers, and increased chemotherapy-induced cancer cell death. IL-32γ also downregulated expression of ITGAV and TIMP-1, accompanied with the inhibition of NF-κB activity. In addition, IL-32γ expression with NF-κB inhibitor treatment further reduced skin inflammation, epidermal hyperplasia, and cancer cell sphere formation and downregulated expression levels of ITGAV and TIMP-1.ConclusionsThese findings indicated that IL-32γ suppressed skin carcinogenesis through the inhibition of both stemness and the inflammatory tumor microenvironment by the downregulation of TIMP-1 and ITGAV via inactivation of NF-κB signaling.
Highlights
Interleukin-32 (IL-32), formerly known as natural killer cell transcript 4, has six splice variants, namely IL-32α, −32β, −32γ, −32δ, −32ε, and -32ζ, all of which demonstrate distinct functional differences [1, 2]
With the data analysis using a genome-wide association study (GWAS), we found that IL-32 was closely related to many cancers (Additional file 1: Figure S1), and further analysis showed that IL-32 was closely associated with several genes including Integrin αV (ITGAV) and tissue inhibitor of metalloproteinase-1 (TIMP-1) (Additional file 2: Figure S2A and S2B), which have been implicated in skin tumor development
Expression levels of ITGAV and TIMP-1 are associated with the inhibition of IL-32γ-induced cancer stemness Using the GWAS analysis, we found that IL-32 was associated with ITGAV and TIMP-1
Summary
Interleukin-32 (IL-32), formerly known as natural killer cell transcript 4, has six splice variants, namely IL-32α, −32β, −32γ, −32δ, −32ε, and -32ζ, all of which demonstrate distinct functional differences [1, 2]. IL-32β lacks the second exon, is spliced form between exons 3 and 4 of IL-32γ. IL-32δ lacks the second exon, which results in a shift in the ATG codon in the third exon. IL-32ζ lacks the second and third exons, and the ATG codon of IL-32ζ is shifted in the fourth exons. It has been reported that IL-32 was critically associated with the development of several cancers [9, 10]. It was reported that IL-32α induces cell apoptosis in human melanoma cells and inhibits EMT in pancreatic cancer cells [14, 15]. The role of IL-32γ in carcinogen-induced skin tumor growth and its mechanisms of action have not yet been reported. The role of IL-32γ, an isotype of IL-32, in skin carcinogenesis remains unknown
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