Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
Department of Orthopaedics, People's Hospital of Tongzhou Bay Demonstration Zone, Nantong, Jiangsu, China.
Funct Integr Genomics. 2024 Apr 18;24(3):77. doi: 10.1007/s10142-024-01345-8.
Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies.
This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC.
We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity.
SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine.
SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.
胃癌（GC）仍然是全球癌症死亡的主要原因。突触结合蛋白 4（SYT4），一种钙感应突触小泡蛋白，已被牵连到多种恶性肿瘤的发生中。
本研究旨在描述 SYT4 在调节 GC 临床结果和生物学行为中的作用。
我们使用生物信息学分析和免疫组织化学评估了 GC 标本中的 SYT4 表达。功能测定包括 CCK8 增殖试验、流式细胞术检测的细胞凋亡试验、共聚焦钙成像和异种移植模型。Western blot 揭示了 MAPK 途径的参与。此外，我们研究了钙通道阻滞剂氨氯地平对细胞动力学和 MAPK 途径活性的影响。
SYT4 在 GC 组织中表达升高，并且升高的 SYT4 与不良预后显著相关。单因素和多因素分析均证实 SYT4 是 GC 的独立预后指标。功能上，SYT4 通过促进细胞增殖、抑制细胞凋亡和增强细胞内钙内流，主要通过 MAPK 途径激活，促进肿瘤发生。氨氯地平预处理减弱了 SYT4 驱动的细胞生长并增强了细胞凋亡，这在体内异种移植评估中得到了证实。这些作用归因于氨氯地平对 MAPK 途径的抑制。
SYT4 通过钙依赖性 MAPK 机制成为 GC 中潜在的预后生物标志物和致癌介质。氨氯地平对 SYT4 驱动的 GC 具有显著的抗肿瘤作用，预示着其治疗潜力。本研究强调了靶向 GC 治疗策略中钙信号的重要性。
