Chen Jing, Zhang Chundong, Xu Xiaoyang, Zhu Xinjiang, Dai Dongqiu
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China.
Mol Med Rep. 2015 Aug;12(2):2487-94. doi: 10.3892/mmr.2015.3667. Epub 2015 Apr 23.
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 tissues. 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.
含血小板反应蛋白基序的解聚素和金属蛋白酶1（ADAMTS1）是一种具有抗血管生成活性的金属蛋白酶。先前观察到，原发性胃癌组织中ADAMTS1的mRNA和蛋白水平下调。本研究的目的是检查原发性胃癌组织和胃癌细胞系中ADAMTS1表达降低是否归因于该基因的异常甲基化。此外，还研究了原发性胃癌患者中ADAMTS1甲基化与临床病理特征之间的关联。结果显示，与相应的正常胃组织相比，原发性胃癌组织中ADAMTS1甲基化的频率显著更高。与未甲基化的原发性胃癌组织相比，甲基化的原发性胃癌组织中ADAMTS1的相对mRNA表达水平显著更低。在原发性胃癌中，观察到ADAMTS1甲基化状态与肿瘤浸润深度以及肿瘤、淋巴结、转移分期之间存在显著关联。60%（5个中的3个）的胃癌细胞系中ADAMTS1的mRNA表达显著更低。与未甲基化的胃癌细胞系相比，甲基化的胃癌细胞系中ADAMTS1的相对mRNA表达水平显著更低。此外，用5-氮杂-2'-脱氧胞苷去甲基化剂处理MGC-803、HGC-27和AGS胃癌细胞系后，ADAMTS1的表达显著恢复，并且MGC-803细胞系的去甲基化抑制了细胞侵袭。据我们所知，这些结果首次表明ADAMTS1是一种新型抗肿瘤蛋白酶，并且这种功能在胃癌细胞和胃癌组织中因表观遗传沉默而丧失。因此，ADAMTS1的异常甲基化可能参与胃癌的发生和发展。
