期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 18, 期 12, 页码 2499-2511出版社
WILEY
DOI: 10.1111/jcmm.12325
关键词
DACH1; DNA methylation; gastric cancer; invasion; metastasis; chemosensitive marker; docetaxel
资金
- National Basic Research Program of China (973 Program) [2012CB934002, 2010CB912802]
- National High-tech R&D Program of China (863 Program) [SS2012AA020314, SS2012AA020821, SS2012AA020303]
- National Key Scientific Instrument Special Programme of China [2011YQ03013405]
- National Science Foundation of China [81121004, 81071953, 81161120432, 81072169, 81172422, 81261120395]
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)- 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- signalling pathways both in vitro and in vivo. Epigenetic silencing DACH1 may induce GC cells' resistance to docetaxel.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据