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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]

PMID: 29467412

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Project description:Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.

Dataset Information

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

Publications

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

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