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Cell Death Dis. 2018 Feb 21;9(3):306. doi: 10.1038/s41419-018-0375-6.

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

Author information

1
College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea.
2
Department of Pharmacy, Wonkwang University, #460 Iksan-daero, Iksan-si, Jeonbuk, 54538, Republic of Korea.
3
Department of Biomaterial Science, Pusan National University, Miryang, Kyungnam, 50463, Republic of Korea.
4
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul, 05029, Republic of Korea. ydy4218@konkuk.ac.kr.
5
College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea. jinthong@chungbuk.ac.kr.

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-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.

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