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Inhibition of skin carcinogenesis by suppression of NF-κB dependent ITGAV and TIMP-1 expression in IL-32γ overexpressed condition
- Source :
- Journal of Experimental & Clinical Cancer Research, Vol 37, Iss 1, Pp 1-16 (2018), Journal of Experimental & Clinical Cancer Research : CR
- Publication Year :
- 2018
- Publisher :
- BMC, 2018.
-
Abstract
- Background Interleukin-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. Methods We 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. Results Carcinogen-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. Conclusions These 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. Electronic supplementary material The online version of this article (10.1186/s13046-018-0943-8) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Cancer Research
Skin Neoplasms
Carcinogenesis
Skin tumor development
DMBA
Mice, Transgenic
medicine.disease_cause
Transfection
lcsh:RC254-282
NF-κB
03 medical and health sciences
Mice
TIMP-1
ITGAV
Cell Line, Tumor
medicine
Animals
Humans
Gene Regulatory Networks
Tumor microenvironment
Tissue Inhibitor of Metalloproteinase-1
integumentary system
Chemistry
Interleukins
Research
NF-kappa B
Cancer
Integrin alphaV
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Mice, Inbred C57BL
030104 developmental biology
Oncology
Apoptosis
Cancer cell
Cancer research
Neoplastic Stem Cells
Skin cancer
IL-32γ
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 17569966
- Volume :
- 37
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental & Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....a9cdf7384d4137f34b74c7f3dd78d773