{"title":"CACNA2D1 调节结肠癌的进展并影响其微环境。","authors":"Hiroyuki Inoue, Atsushi Shiozaki, Toshiyuki Kosuga, Hiroki Shimizu, Michihiro Kudou, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Yoshiaki Kuriu, Takeshi Kubota, Hitoshi Fujiwara, Yukiko Morinaga, Eiichi Konishi, Eigo Otsuji","doi":"10.1007/s00535-024-02095-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"556-571"},"PeriodicalIF":6.9000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CACNA2D1 regulates the progression and influences the microenvironment of colon cancer.\",\"authors\":\"Hiroyuki Inoue, Atsushi Shiozaki, Toshiyuki Kosuga, Hiroki Shimizu, Michihiro Kudou, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Yoshiaki Kuriu, Takeshi Kubota, Hitoshi Fujiwara, Yukiko Morinaga, Eiichi Konishi, Eigo Otsuji\",\"doi\":\"10.1007/s00535-024-02095-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":16059,\"journal\":{\"name\":\"Journal of Gastroenterology\",\"volume\":\" \",\"pages\":\"556-571\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Gastroenterology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00535-024-02095-x\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-024-02095-x","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：电压门控钙通道辅助亚基α2/δ1（CACNA2D1）是一个编码电压门控钙通道的基因，有报道称它是多种癌症的致癌基因。然而，它在结肠癌（CC）中的作用仍不清楚。本研究旨在探讨 CACNA2D1 的功能及其对 CC 微环境的影响：方法：对 200 例接受治愈性结肠切除术的 CC 患者样本进行免疫组化（IHC）分析。使用 CACNA2D1 siRNA 在人 CC 细胞系 HCT116 和 RKO 中进行敲除实验，然后分析细胞增殖、周期、凋亡和迁移。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。使用芯片分析了细胞的基因表达谱：IHC显示，CACNA2D1高表达是CC患者独立的不良预后因素，而且CACNA2D1的表达与基质相关。删除 CACNA2D1 可减少细胞增殖和迁移；敲除 CACNA2D1 可增加亚 G1 期细胞数量并诱导细胞凋亡。CCD-18Co和HCT116或RKO细胞共培养显示，CACNA2D1通过成纤维细胞调控影响癌症微环境。此外，芯片分析表明，在CACNA2D1缺失的HCT116细胞中，p53信号通路和上皮-间质转化相关通路增强：结论：CACNA2D1通过调控成纤维细胞在CC的进展和微环境中发挥重要作用，可作为疾病进展的生物标记物和CC的治疗靶点。
CACNA2D1 regulates the progression and influences the microenvironment of colon cancer.
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
期刊介绍：
The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
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