Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, Kyoto, 602-8566, Japan.
Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
J Gastroenterol. 2024 Jul;59(7):556-571. doi: 10.1007/s00535-024-02095-x. Epub 2024 Mar 27.
Calcium voltage-gated channel auxiliary subunit alpha 2/delta 1 (CACNA2D1), a gene encoding a voltage-gated calcium channel, has been reported as an oncogene in several cancers. However, its role in colon cancer (CC) remains unclear. This study aimed to investigate the function of CACNA2D1 and its effect on the microenvironment in CC.
Immunohistochemistry (IHC) analysis was performed on samples collected from 200 patients with CC who underwent curative colectomy. Knockdown experiments were performed using CACNA2D1 siRNA in the human CC cell lines HCT116 and RKO, and cell proliferation, cycle, apoptosis, and migration were then analyzed. The fibroblast cell line CCD-18Co was co-cultured with CC cell lines to determine the effect of CACNA2D1 on fibroblasts and the relationship between CACNA2D1 and the cancer microenvironment. Gene expression profiles of cells were analyzed using microarray analysis.
IHC revealed that high CACNA2D1 expression was an independent poor prognostic factor in patients with CC and that CACNA2D1 expression and the stroma are correlated. CACNA2D1 depletion decreased cell proliferation and migration; CACNA2D1 knockdown increased the number of cells in the sub-G1 phase and induced apoptosis. CCD-18Co and HCT116 or RKO cell co-culture revealed that CACNA2D1 affects the cancer microenvironment via fibroblast regulation. Furthermore, microarray analysis showed that the p53 signaling pathway and epithelial-mesenchymal transition-associated pathways were enhanced in CACNA2D1-depleted HCT116 cells.
CACNA2D1 plays an important role in the progression and the microenvironment of CC by regulating fibroblasts and may act as a biomarker for disease progression and a therapeutic target for CC.
钙电压门控通道辅助亚基 alpha 2/delta 1（CACNA2D1）是编码电压门控钙通道的基因，已在几种癌症中被报道为癌基因。然而，其在结肠癌（CC）中的作用尚不清楚。本研究旨在探讨 CACNA2D1 的功能及其对 CC 微环境的影响。
对 200 例接受根治性结肠切除术的 CC 患者的样本进行免疫组织化学（IHC）分析。使用 CACNA2D1 siRNA 在人 CC 细胞系 HCT116 和 RKO 中进行敲低实验，然后分析细胞增殖、周期、凋亡和迁移。将成纤维细胞系 CCD-18Co 与 CC 细胞系共培养，以确定 CACNA2D1 对成纤维细胞的影响以及 CACNA2D1 与癌症微环境之间的关系。使用微阵列分析分析细胞的基因表达谱。
IHC 显示，CACNA2D1 高表达是 CC 患者的独立不良预后因素，且 CACNA2D1 表达与基质相关。CACNA2D1 耗竭降低了细胞增殖和迁移；CACNA2D1 敲低增加了 sub-G1 期细胞数量并诱导了凋亡。CCD-18Co 与 HCT116 或 RKO 细胞共培养显示，CACNA2D1 通过调节成纤维细胞影响癌症微环境。此外，微阵列分析显示，在 CACNA2D1 耗尽的 HCT116 细胞中，p53 信号通路和上皮-间质转化相关途径增强。
CACNA2D1 通过调节成纤维细胞在 CC 的进展和微环境中发挥重要作用，可能作为疾病进展的生物标志物和 CC 的治疗靶点。
