Yan Wenji, Wu Kongming, Herman James G, Brock Malcolm V, Zhou Yusen, Lu Youyong, Zhang Zhiqian, Yang Yunsheng, Guo Mingzhou
Institute of Digestive Diseases, Chinese PLA General Hospital, Beijing, China.
J Cell Mol Med. 2014 Dec;18(12):2499-511. doi: 10.1111/jcmm.12325. Epub 2014 Jun 9.
Gastric cancer (GC) is the fourth most common malignancy in males and the fifth most common malignancy in females worldwide. DACH1 is frequently methylated in hepatic and colorectal cancer. To further understand the regulation and mechanism of DACH1 in GC, eight GC cell lines, eight cases of normal gastric mucosa, 98 cases of primary GC and 50 cases of adjacent non-tumour tissues were examined. Methylation-specific PCR, western blot, transwell assay and xenograft mice were used in this study. Loss of DACH1 expression correlated with promoter region methylation in GC cells, and re-expression was induced by 5-Aza-2'-deoxyazacytidine. DACH1 is methylated in 63.3% (62/98) of primary GC and 38% (19/50) of adjacent non-tumour tissues, while no methylation was found in normal gastric mucosa. Methylation of DACH1 correlated with reduced expression of DACH1 (P < 0.01), late tumour stage (stage III/IV) (P < 0.01) and lymph node metastasis (P < 0.05). DACH1 expression inhibited epithelial-mesenchymal transition and metastasis by inhibiting transforming growth factor (TGF)-β signalling and suppressed GC cell proliferation through inducing G2/M phase arrest. The tumour size is smaller in DACH1-expressed BGC823 cell xenograft mice than in unexpressed group (P < 0.01). Restoration of DACH1 expression also sensitized GC cells to docetaxel. These studies suggest that DACH1 is frequently methylated in human GC and expression of DACH1 was controlled by promoter region methylation. DACH1 suppresses GC proliferation, invasion and metastasis by inhibiting TGF-β signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.
胃癌（GC）是全球男性中第四大常见恶性肿瘤，女性中第五大常见恶性肿瘤。DACH1在肝癌和结直肠癌中经常发生甲基化。为了进一步了解DACH1在胃癌中的调控及机制，我们检测了8种胃癌细胞系、8例正常胃黏膜、98例原发性胃癌及50例癌旁非肿瘤组织。本研究采用甲基化特异性PCR、蛋白质免疫印迹法、Transwell实验及异种移植小鼠实验。DACH1表达缺失与胃癌细胞启动子区域甲基化相关，5-氮杂-2'-脱氧胞苷可诱导其重新表达。63.3%（62/98）的原发性胃癌及38%（19/50）的癌旁非肿瘤组织中DACH1发生甲基化，而正常胃黏膜中未发现甲基化。DACH1甲基化与DACH1表达降低（P<0.01）、肿瘤晚期（III/IV期）（P<0.01）及淋巴结转移（P<0.05）相关。DACH1表达通过抑制转化生长因子（TGF）-β信号通路抑制上皮-间质转化及转移，并通过诱导G2/M期阻滞抑制胃癌细胞增殖。DACH1表达的BGC823细胞异种移植小鼠的肿瘤体积比未表达组小（P<0.01）。DACH1表达的恢复也使胃癌细胞对多西他赛敏感。这些研究表明，DACH1在人类胃癌中经常发生甲基化，其表达受启动子区域甲基化控制。DACH1在体外和体内均通过抑制TGF-β信号通路抑制胃癌增殖、侵袭和转移。DACH1的表观遗传沉默可能诱导胃癌细胞对多西他赛耐药。
