Experimental and Clinical Research Center, Charité-Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany.
Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
Cells. 2022 Mar 21;11(6):1056. doi: 10.3390/cells11061056.
Deregulated Wnt-signaling is a key mechanism driving metastasis in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S). The oncogene was identified as a Wnt-signaling target gene and is known to promote metastasis. In this project, we illuminate the role of S100A4 for metastases development and disease prognosis of AGE/S. Five gastric cancer cell lines were assessed for S100A4 expression. Two cell lines with endogenous high S100A4 expression were used for functional phenotyping including analysis of proliferation and migration after stable knock-down. The prognostic value of S100A4 was evaluated by analyzing the S100A4 expression of tissue microarrays with samples of 277 patients with AGE/S. knock-down induced lower migration in FLO1 and NCI-N87 cells. Treatment with niclosamide in these cells led to partial inhibition of S100A4 and to reduced migration. Patients with high S100A4 expression showed lower 5-year overall and disease-specific survival. In addition, a larger share of patients in the S100A4 high expressing group suffered from metachronous metastasis. This study identifies S100A4 as a negative prognostic marker for patients with AGE/S. The strong correlation between S100A4 expression, metastases development and patient survival might open opportunities to use S100A4 to improve the prognosis of these patients and as a therapeutic target for intervention in this tumor entity.
Wnt 信号通路失调是驱动胃食管结合部和胃腺癌（AGE/S）转移的关键机制。癌基因 被鉴定为 Wnt 信号通路的靶基因，已知其可促进转移。在本项目中，我们阐明了 S100A4 对 AGE/S 转移发展和疾病预后的作用。评估了五株胃癌细胞系的 S100A4 表达。使用两个内源性高 S100A4 表达的细胞系进行功能表型分析，包括稳定敲低后增殖和迁移分析。通过分析 277 例 AGE/S 患者组织微阵列的 S100A4 表达，评估了 S100A4 的预后价值。在 FLO1 和 NCI-N87 细胞中敲低 S100A4 可诱导较低的迁移。在这些细胞中用尼立达唑治疗可部分抑制 S100A4 的表达，并减少迁移。S100A4 高表达的患者 5 年总生存率和疾病特异性生存率较低。此外，S100A4 高表达组中更多的患者发生异时性转移。本研究将 S100A4 鉴定为 AGE/S 患者的预后不良标志物。S100A4 表达、转移发展和患者生存之间的强相关性为利用 S100A4 改善这些患者的预后以及作为该肿瘤实体干预的治疗靶点提供了机会。
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