Methylation of the calcium channel-related gene, CACNA2D3, is frequent and a poor prognostic factor in gastric cancer
Methylation of the calcium channel-related gene, CACNA2D3, is frequent and a poor prognostic factor in gastric cancer
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DOI：
10.1053/j.gastro.2008.05.041
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发表时间：
2008-08-01
期刊：
影响因子：
29.4
通讯作者：
Akiyama, Yoshimitsu
中科院分区：
文献类型：
--
作者：
Wanajo, Aira;Sasaki, Akane;Akiyama, Yoshimitsu
背景和目标：钙通道电压依赖性α 2 δ亚基由4个基因组成，CACNA 2D 1至CACNA 2D 4，其中CACNA 2D 2和CACNA 2D 3分别位于3p21.3和3p21.1。在此，我们研究了α 2 δ亚基基因改变与胃癌发生的关系.研究方法：采用逆转录聚合酶链反应（RT-PCR）和甲基化特异性PCR（methylation-specific PCR）检测胃癌组织中α 2 δ亚基基因的表达和甲基化状态。通过细胞增殖和粘附试验检查CACNA 2D 3表达的影响，并预测靶基因的改变。结果：CACNA 2D 1和CACNA 2D 3基因在胃癌细胞中的异常甲基化与其表达状态基本一致。CACNA 2D 1/3甲基化分别在10例（12.5%）和24例（30%）胃癌中检出，但在32例胃癌中未发现CACNA 2D 2甲基化。弥漫型胃癌中CACNA 2D 3甲基化的发生率高于肠型胃癌（16/38 [42.1%] vs 8/42 [19.0%]; P = 0.025）。在53例晚期GC患者中，显示CACNA 2D 3甲基化的癌症患者的生存时间明显短于未显示这种甲基化的患者（P = .003）。外源性CACNA 2D 3表达强烈抑制HEK-293 T和NUGC 4细胞的细胞生长和粘附，并上调p21和p27表达。在CACNA 2D 3阳性细胞系中观察到CACNA 2D 3小干扰RNA处理的相反效应，表明CACNA 2D 3可能具有肿瘤抑制功能。结论：CACNA 2D 3基因启动子区异常甲基化导致的CACNA 2D 3表达缺失可能与胃癌的发生有关，CACNA 2D 3甲基化是晚期胃癌患者的一个有用的预后指标。
Background & Aims: The calcium channel voltage-dependent alpha 2 delta subunit consists of 4 genes, CACNA2D1 to CACNA2D4, of which CACNA2D2 and CACNA2D3 are located on 3p21.3 and 3p21.1, respectively. Here, we examined the relation between alpha 2 delta subunit gene alterations and gastric carcinogenesis. Methods: The expression and methylation status of the alpha 2 delta subunit genes were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR in gastric cancers (GCs). The effects of CACNA2D3 expression were examined by cell proliferation and adhesion assays, and they predicted target gene, alterations. Results: Aberrant methylation of CACNA2D1 and CACNA2D3 mostly corresponded to their expression status in GC cell lines. CACNA2D1/3 methylation was detected in 10 (12.5%) and 24 (30%) of the 80 GC cases, respectively, but no CACNA2D2 methylation was seen in 32 cases. CACNA2D3 methylation was more frequently found in diffuse type than in intestinal type (16/38 [42.1%] vs 8/42 [19.0%]; P = .025) GCs. Among the 53 patients with advanced GCs, patients with cancers showing CACNA2D3 methylation had a significantly shorter survival time than patients without this methylation (P = .003). Exogenous CACNA2D3 expression strongly inhibited cell growth and adhesion and upregulated p21 and p27 expression in HEK-293T and NUGC4 cells. Inverse effects were seen by CACNA2D3 small interfering RNA treatment in the CACNA2D3-positive cell lines, indicating that CACNA2D3 may have tumor suppressive functions. Conclusions: Loss of CACNA2D3 expression through aberrant promoter hypermethylation may contribute to gastric carcinogenesis, and CACNA2D3 methylation is a useful prognostic marker for patients with advanced GC.