Sun Jianjun, Tang Mingming, Cai Zhigang
Department of Thoracic Surgery, Naval Specialized Medical Center Affiliated to Naval Medical University, Shanghai, China.
J Gastrointest Oncol. 2024 Jun 30;15(3):818-828. doi: 10.21037/jgo-24-302. Epub 2024 Jun 27.
Recurrence and metastasis are the major obstacles affecting the therapeutic efficacy and clinical outcomes for patients with esophageal carcinoma (ESCA). Secreted phosphoprotein 1 (SPP1) is considered as a hub gene in ESCA and is negatively associated with disease-free survival (DFS) in ESCA. However, the exact roles and underlying mechanisms remain elusive. This study aims to examine the roles of SPP1 on ESCA, and elucidate the potential mechanisms.
Bioinformatics were used to analyze the expression of SPP1 in ESCA tissues, and its relations with clinicopathological characteristics and clinical prognosis in patients with ESCA based on The Cancer Genome Atlas (TCGA) dataset. Loss-of-function was conducted to examine the roles of SPP1 on malignant behaviors of ESCA cells by cell counting kit-8 (CCK8), plate clone, wound healing, and transwell assays. Gene set enrichment analysis (GSEA) was conducted to screen the pathways associated with SPP1 in ESCA. Then, the enriched pathway and the underlying mechanism were elucidated by western blotting, cell adhesion, and cell spreading assays. Lastly, Y15 [a specific inhibitor of focal adhesion kinase (FAK)] was used to examine its potential to inhibit tumor growth in ESCA cells.
SPP1 was upregulated in ESCA tissues compared to the adjacent nontumorous tissues, which was closely associated with clinical stage, lymph node metastasis, histological subtype, and p53 mutation. A high expression of SPP1 indicated a poor clinical prognosis in patients with ESCA. The knockdown of SPP1 inhibited cell proliferative, migratory, and invasive capacities in ESCA cells. GSEA indicated that the focal adhesion pathway was closely related with SPP1 in ESCA. Further studies confirmed that the knockdown of SPP1 suppressed cell adhesion ability and reduced the expression of p-FAK and p-Erk in ESCA cells. In addition, Y15 inhibited FAK autophosphorylation and dramatically inhibited cell proliferation, migration, and invasion in ESCA cells.
SPP1 promotes tumor progression in ESCA by activating FAK/Erk pathway, and FAK is a potential therapeutic target to overcome tumor recurrence and metastasis of ESCA.
复发和转移是影响食管癌（ESCA）患者治疗效果和临床结局的主要障碍。分泌磷蛋白1（SPP1）被认为是ESCA中的一个枢纽基因，且与ESCA患者的无病生存期（DFS）呈负相关。然而，其确切作用和潜在机制仍不清楚。本研究旨在探讨SPP1在ESCA中的作用，并阐明其潜在机制。
基于癌症基因组图谱（TCGA）数据集，利用生物信息学分析SPP1在ESCA组织中的表达及其与ESCA患者临床病理特征和临床预后的关系。通过细胞计数试剂盒-8（CCK8）、平板克隆、伤口愈合和Transwell实验进行功能缺失研究，以检测SPP1对ESCA细胞恶性行为的作用。进行基因集富集分析（GSEA）以筛选ESCA中与SPP1相关的通路，并通过蛋白质印迹法、细胞黏附实验及细胞铺展实验阐明富集的通路及其潜在机制。最后，使用Y15[一种粘着斑激酶（FAK）的特异性抑制剂]检测其抑制ESCA细胞肿瘤生长的潜力。
与邻近非肿瘤组织相比，SPP1在ESCA组织中上调，这与临床分期、淋巴结转移、组织学亚型和p53突变密切相关。SPP1高表达表明ESCA患者临床预后较差。敲低SPP1可抑制ESCA细胞的增殖、迁移和侵袭能力。GSEA表明粘着斑通路与ESCA中的SPP1密切相关。进一步研究证实，敲低SPP1可抑制ESCA细胞的黏附能力，并降低p-FAK和p-Erk的表达。此外，Y15抑制FAK自身磷酸化，并显著抑制ESCA细胞的增殖、迁移和侵袭。
SPP1通过激活FAK/Erk通路促进ESCA肿瘤进展，FAK是克服ESCA肿瘤复发和转移的潜在治疗靶点。
