胃癌中 NDRG2 的 DNA 甲基化及其临床意义。
DNA methylation of NDRG2 in gastric cancer and its clinical significance.
机构信息
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
出版信息
Dig Dis Sci. 2013 Mar;58(3):715-23. doi: 10.1007/s10620-012-2393-z. Epub 2012 Sep 26.
BACKGROUND
Gastric cancer is one of the most common digestive malignancies worldwide. N-myc downstream-regulated gene 2 (NDRG2) is a differentiation-related gene that is considered to be a metastasis suppressor gene. In this study, we examined the expression and DNA methylation of NDRG2 in gastric cancer cell lines and tissues, as well as its clinical significance.
METHODS
Six gastric cancer cell lines and 42 paired normal and gastric cancer tissue samples were used to assess NDRG2 mRNA expression using RT-PCR. NDRG2 DNA methylation status was evaluated by methylation-specific PCR (MSP) in gastric cancer cell lines and tissues. The suppression of NDRG2 in BGC823 cells by siRNA transfection was utilized to detect the role of NDRG2 in gastric cancer progression.
RESULTS
NDRG2 mRNA was down-regulated in gastric cancer cell lines and tissues, and its expression was just related to lymph node metastasis (p = 0.032). MSP showed methylation of NDRG2 in 54.0 % (47/87) of primary gastric cancer specimens and in 20.0 % (16/80) of corresponding nonmalignant gastric tissues. NDRG2 methylation was related to depth of tumor invasion, Borrmann classification and TNM stage (p < 0.05). Upon treatment with 5-aza-2'-deoxycytidine and trichostatin A, NDRG2 expression was upregulated in HGC27 cells, and demethylation of the highly metastatic cell line, MKN45, inhibited cell invasion. Furthermore, the suppression of NDRG2 by siRNA transfection enhanced BGC823 cells invasion.
CONCLUSIONS
Our results suggest that the aberrant methylation of NDRG2 may be mainly responsible for its downregulation in gastric cancer, and may play an important role in the metastasis of gastric cancer.
背景
胃癌是全球最常见的消化系统恶性肿瘤之一。N- MYC 下游调节基因 2（NDRG2）是一种分化相关基因，被认为是一种转移抑制基因。本研究检测了 NDRG2 在胃癌细胞系和组织中的表达和 DNA 甲基化情况及其临床意义。
方法
采用 RT-PCR 检测 6 株胃癌细胞系和 42 对配对的正常胃组织和胃癌组织中 NDRG2mRNA 的表达，用甲基化特异性 PCR（MSP）检测胃癌细胞系和组织中 NDRG2 的 DNA 甲基化状态，并用 siRNA 转染 BGC823 细胞抑制 NDRG2 的表达，检测 NDRG2 对胃癌进展的作用。
结果
NDRG2mRNA 在胃癌细胞系和组织中表达下调，其表达与淋巴结转移有关（p=0.032）。MSP 显示 87 例胃癌组织标本中有 54.0%（47/87）存在 NDRG2 甲基化，80 例相应的非癌性胃组织中有 20.0%（16/80）存在甲基化。NDRG2 甲基化与肿瘤浸润深度、Borrman 分型和 TNM 分期有关（p<0.05）。用 5-氮杂-2′-脱氧胞苷和曲古抑菌素 A 处理 HGC27 细胞后，NDRG2 表达上调，高转移细胞系 MKN45 去甲基化抑制细胞侵袭。此外，siRNA 转染抑制 NDRG2 表达增强 BGC823 细胞的侵袭能力。
结论
我们的研究结果表明，NDRG2 的异常甲基化可能是导致胃癌中 NDRG2 下调的主要原因，可能在胃癌转移中发挥重要作用。
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