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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

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

Yun Jaesuk J   Park Mi Hee MH   Son Dong Ju DJ   Nam Kyung Tak KT   Moon Dae Bong DB   Ju Jung Heun JH   Hwang Ok Kyung OK   Choi Jeong Soon JS   Kim Tae Hoon TH   Jung Young Suk YS   Hwang Dae Yeon DY   Han Sang Bae SB   Yoon Do-Young DY   Hong Jin Tae JT  

Cell death & disease 20180221 3


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 plasm  ...[more]

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