Downregulation of A disintegrin and metallopeptidase with thrombospondin motif type 1 by DNA hypermethylation in human gastric cancer

Chen,Jing; Zhang,Chundong; Xu,Xiaoyang; Zhu,Xinjiang; Dai,Dongqiu

doi:10.3892/mmr.2015.3667

Downregulation of A disintegrin and metallopeptidase with thrombospondin motif type 1 by DNA hypermethylation in human gastric cancer

Authors:
- Jing Chen
- Chundong Zhang
- Xiaoyang Xu
- Xinjiang Zhu
- Dongqiu Dai
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Affiliations: Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
Published online on: April 23, 2015 https://doi.org/10.3892/mmr.2015.3667
Pages: 2487-2494
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

A disintegrin and metallopeptidase with thrombospondin motif type 1 (ADAMTS1) is a metalloproteinase with antiangiogenic activity. It was previously observed that the mRNA and protein levels of ADAMTS1 are downregulated in primary gastric tumors. The aim of the present study was to examine whether the reduction in the expression of ADAMTS1 is due to aberrant methylation of the gene in primary gastric tumor tissues and gastric cancer cell lines. In addition, the association between ADAMTS1 methylation and clinicopathological features in were investigated in patients with primary gastric cancer. The results revealed that the frequency of ADAMTS1 methylation in primary gastric tumor tissues was significantly higher, compared with the corresponding normal gastric tissues. The relative mRNA expression levels of ADAMTS1 were significantly lower in the methylated primary gastric tumor tissues, compared with the unmethylated primary gastric tumor tissuess. A significant association was observed between the ADAMTS1 methylation status and the depth of tumor invasion and tumor, node, metastasis stage in primary gastric cancer. The mRNA expression of ADAMTS1 was significantly lower in 60% (3 of 5) of the gastric cancer cell lines. The relative mRNA expression levels of ADAMTS1 were significantly lower in the methylated gastric cancer cell lines, compared with the unmethylated gastric cancer cell lines. Furthermore, the expression of ADAMTS1 was significantly restored following treatment with the 5‑Aza‑2'‑deoxycytidine demethylating agent in the MGC‑803, HGC‑27 and AGS gastric cancer cell lines, and the demethylation of the MGC‑803 cell line inhibited cell invasion. Together, these results suggested for the first time, to the best of our knowledge, ADAMTS1 as a novel antitumor protease, and this function was lost following epigenetic silencing in the gastric cancer cells and gastric tumor tissues. Therefore, the aberrant methylation of ADAMTS1 may be involved in the development and progression of gastric cancer.

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