Functions and Clinical Significance of CACNA2D1 in Gastric Cancer
Functions and Clinical Significance of CACNA2D1 in Gastric Cancer
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DOI：
10.1245/s10434-022-11752-5
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发表时间：
2022-04-20
影响因子：
3.7
通讯作者：
Otsuji, Eigo
中科院分区：
文献类型：
--
作者：
Inoue, Hiroyuki;Shiozaki, Atsushi;Otsuji, Eigo
电压门控钙通道是由几个亚基组成的复合物，其中编码α 2 δ亚基的基因之一CACNA2D1的功能尚不清楚。本研究旨在探讨CACNA2D1的作用，并评价CACNA2D1阻滞剂氨氯地平治疗胃癌的疗效。方法采用CACNA2D1小干扰RNA （siRNA）对人胃癌细胞系MKN7和HGC27进行敲低实验，观察细胞增殖、细胞周期、凋亡、迁移和侵袭的变化。使用微阵列分析检测细胞的基因表达谱。对196例接受根治性胃切除术的胃癌患者进行了免疫组化（IHC）分析。此外，采用异种移植模型研究了氨氯地平的抗肿瘤作用。结果cacna2d1缺失后，细胞增殖、迁移、侵袭均受到抑制，并诱导细胞凋亡。芯片分析结果显示，在cacna2d1缺失的细胞中，凋亡信号通路通过p53、BAX和caspase 3增强。一项多变量分析发现，免疫组化（IHC）证实，CACNA2D1高表达水平是胃癌患者预后不良的独立因素。此外，联合氨氯地平和顺铂治疗的异种移植裸鼠模型皮下肿瘤体积明显小于单用顺铂治疗的裸鼠模型。结论CACNA2D1调节细胞凋亡信号通路，有可能作为肿瘤生长的生物标志物和胃癌的治疗靶点。
Background Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the alpha 2 delta subunit, remains unclear. The aim of our study was to investigate the role of CACNA2D1 and evaluate the efficacy of amlodipine, a blocker of CACNA2D1, in the treatment of gastric cancer (GC). Methods Knockdown experiments were performed on the human GC cell lines MKN7 and HGC27 using CACNA2D1 small interfering RNA (siRNA), and changes in cell proliferation, the cell cycle, apoptosis, migration, and invasion were assessed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical (IHC) analysis was conducted on samples obtained from 196 GC patients who underwent curative gastrectomy. In addition, the antitumor effects of amlodipine were investigated using a xenograft model. Results Cell proliferation, migration, and invasion were suppressed in CACNA2D1-depleted cells, and apoptosis was induced. The results of the microarray analysis showed that the apoptosis signaling pathway was enhanced via p53, BAX, and caspase 3 in CACNA2D1-depleted cells. A multivariate analysis identified high CACNA2D1 expression levels, confirmed by IHC, as an independent poor prognostic factor in GC patients. Moreover, subcutaneous tumor volumes were significantly smaller in a xenograft nude mouse model treated with a combination of amlodipine and cisplatin than in a model treated with cisplatin alone. Conclusions The present study indicates that CACNA2D1 regulates the apoptosis signaling pathway and may have potential as a biomarker for cancer growth and as a therapeutic target for GC.