Inoue Hiroyuki, Shiozaki Atsushi, Kosuga Toshiyuki, Shimizu Hiroki, Kudou Michihiro, Ohashi Takuma, Arita Tomohiro, Konishi Hirotaka, Komatsu Shuhei, Kubota Takeshi, Fujiwara Hitoshi, Okamoto Kazuma, Kishimoto Mitsuo, Konishi Eiichi, Otsuji Eigo
Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Surgical Pathology, Kyoto City Hospital, Kyoto, Japan.
Ann Surg Oncol. 2022 Apr 20. doi: 10.1245/s10434-022-11752-5.
Voltage-gated calcium channels form as a complex of several subunits, among which the function of CACNA2D1, one of the genes encoding the α2δ 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).
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.
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.
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.
电压门控钙通道由几个亚基组成复合物，其中编码α2δ亚基的基因之一CACNA2D1的功能尚不清楚。我们研究的目的是探讨CACNA2D1的作用，并评估氨氯地平（一种CACNA2D1阻滞剂）在治疗胃癌（GC）中的疗效。
使用CACNA2D1小干扰RNA（siRNA）对人GC细胞系MKN7和HGC27进行敲低实验，并评估细胞增殖、细胞周期、凋亡、迁移和侵袭的变化。使用微阵列分析检查细胞的基因表达谱。对196例行根治性胃切除术的GC患者的样本进行免疫组织化学（IHC）分析。此外，使用异种移植模型研究氨氯地平的抗肿瘤作用。
在CACNA2D1缺失的细胞中，细胞增殖、迁移和侵袭受到抑制，并诱导了凋亡。微阵列分析结果表明，在CACNA2D1缺失的细胞中，凋亡信号通路通过p53、BAX和半胱天冬酶3得到增强。多变量分析确定，经IHC证实的高CACNA2D1表达水平是GC患者独立的不良预后因素。此外，在氨氯地平和顺铂联合治疗的异种移植裸鼠模型中，皮下肿瘤体积明显小于单独用顺铂治疗的模型。
本研究表明，CACNA2D1调节凋亡信号通路，可能具有作为癌症生长生物标志物和GC治疗靶点的潜力。
