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

ABSTRACT: 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-32? mice lung tissues. In this study, we investigated whether IL-32? 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-32? cDNA plasmid. A marked increase in TIMP-3 expression was caused by promoter methylation. Mechanistic studies indicated that TIMP-3 overexpression reduced NF-?B activity, which led to cell growth inhibition in IL-32? transfected lung cancer cells. We also showed that IL-32? inhibits expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1). Moreover, IL-32? 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-?B 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-?B pathway. In an in vivo carcinogen induced lung tumor model, tumor growth was inhibited in IL-32? overexpressed mice with elevated TIMP-3 expression and hypomethylation accompanied with reduced NF-?B 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-32? may increase TIMP-3 expression via hypomethylation through inactivation of NF-?B activity, and thereby reduce lung tumor growth.

SUBMITTER: Yun J 

PROVIDER: S-EPMC5833366 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature