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IL-32γ suppresses lung cancer stem cell growth via inhibition of ITGAV-mediated STAT5 pathway.

ABSTRACT: The cancer stem cells (CSCs) are thought to be responsible for cancer initiation, recurrence, and metastasis via a multifactorial process. IL-32γ has been known to inhibit several tumor developments. However, the role of IL-32γ in CSCs is unknown. The role of IL-32γ on tumor development was assessed in IL-32γ transgenic (Tg) mice allograft and xenograft model. In the in vitro assay, we analyzed CSC growth and apoptosis in cells with IL-32γ overexpression by cell viability assay and tumor-sphere formation assay. In addition, expression of cell proliferation, apoptosis markers, and signaling molecules was determined by western blot analysis. IL-32γ suppressed CD133+ CSC-induced allograft model in IL-32γ Tg mice and xenograft model. Tumor-sphere formation and cell viability assay revealed a greater inhibition of CSC proliferation and antineoplastic activity of IL-32γ in CD133+ CSCs as compared with normal cancer cells. The inhibitory effects of IL-32γ on tumor development were associated with inhibition of the STAT5 pathway. In addition, inhibition of STAT5 increased cleavage of caspase-3, but suppressed CD133 expression and colony formation. Web-based gene network analysis showed that IL-32 is correlated with ITGAV, an integrin gene. Our result revealed that knockdown of ITGAV by siRNA inhibited the phosphorylation of STAT5. Moreover, we identified that ITGAV overexpression reversed the effect of IL-32γ on phosphorylation of STAT5 and the expression of CD133. Our results demonstrate that IL-32γ negatively regulates CD133+ CSC proliferation and tumor development and suggest that IL-32γ has great potential for use in the treatment of cancer progression.

SUBMITTER: Lee YS

PROVIDER: S-EPMC6602938 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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IL-32γ suppresses lung cancer stem cell growth via inhibition of ITGAV-mediated STAT5 pathway.

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