IL-32 gamma reduces lung tumor development through upregulation of TIMP-3 overexpression and hypomethylation

The low expression of tissue inhibitor of metalloproteinase 3 (TIMP-3) is important in inflammatory responses. Therefore, inhibition of TIMP-3 may promote tumor development. Our study showed that expression of TIMP-3 was elevated in lL-32γ mice lung tissues. In this study, we investigated whether IL...

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Published in:Cell death & disease 2018-02, Vol.9 (3), p.306-12, Article 306
Main Authors: Yun, Jaesuk, Park, Mi Hee, Son, Dong Ju, Nam, Kyung Tak, Moon, Dae Bong, Ju, Jung Heun, Hwang, Ok Kyung, Choi, Jeong Soon, Kim, Tae Hoon, Jung, Young Suk, Hwang, Dae Yeon, Han, Sang Bae, Yoon, Do-Young, Hong, Jin Tae
Format: Article
Language:English
Subjects:
Apoptosis
Carcinogens
Cell growth
Cytosine
DNA (cytosine-5-)-methyltransferase
DNA methylation
DNA methyltransferase
DNMT1 protein
Gene expression
Inflammation
Lung cancer
Metalloproteinase
NF-κB protein
Tissue inhibitor of metalloproteinase 3
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Summary:The low expression of tissue inhibitor of metalloproteinase 3 (TIMP-3) is important in inflammatory responses. Therefore, inhibition of TIMP-3 may promote tumor development. Our study showed that expression of TIMP-3 was elevated in lL-32γ mice lung tissues. In this study, we investigated whether IL-32γ mice inhibited lung tumor development through overexpression of TIMP-3 and its methylation. To explore the possible underlying mechanism, lung cancer cells were transfected with IL-32γ cDNA plasmid. A marked increase in TIMP-3 expression was caused by promoter methylation. Mechanistic studies indicated that TIMP-3 overexpression reduced NF-κB activity, which led to cell growth inhibition in IL-32γ transfected lung cancer cells. We also showed that IL-32γ inhibits expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1). Moreover, IL-32γ inhibits the binding of DNMT1 to TIMP-3 promoter, but this effect was reversed by the treatment of DNA methyltransferase inhibitor (5-Aza-CdR) and NF-κB inhibitor (PS1145), suggesting that a marked increase in TIMP-3 expression was caused by inhibition of promoter hypermethylation via decreased DNMT1 expression through the NF-κB pathway. In an in vivo carcinogen induced lung tumor model, tumor growth was inhibited in IL-32γ overexpressed mice with elevated TIMP-3 expression and hypomethylation accompanied with reduced NF-κB activity. Moreover, in the lung cancer patient tissue, the expression of IL-32 and TIMP-3 was dramatically decreased at a grade-dependent manner compared to normal lung tissue. In summary, IL-32γ may increase TIMP-3 expression via hypomethylation through inactivation of NF-κB activity, and thereby reduce lung tumor growth.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-0375-6