Fan Tan-Chi, Yeo Hui Ling, Hung Tsai-Hsien, Chang Nai-Chuan, Tang Yun-Hsin, Yu John, Chen Shih-Hsiang, Yu Alice L
Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan; Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch, and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
J Biol Chem. 2025 Apr;301(4):108368. doi: 10.1016/j.jbc.2025.108368. Epub 2025 Feb 28.
Metastasis is a major cause of cancer-related morbidity and mortality. The overexpression of the sialyltransferase ST3GAL1 in breast cancer correlates with metastasis. However, the molecular mechanisms underlying the effect of ST3GAL1 on cell movement are poorly understood. We identified neuropilin-1/NRP1 as a substrate for ST3GAL1. Gene expression analysis revealed that recurrence-free survival (p = 0.0046) and distant metastasis-free survival (p = 0.0003) were significantly shorter in the ST3GAL1NRP1 cohort than in the both-low subgroup. We demonstrated that the ST3GAL1-mediated sialylation of NRP1 results in increased binding affinity toward EGFR at the molecular level. At the cellular level, ST3GAL1 silencing impaired cell migration and wound healing ability, which was linked to reduced activities of CAPN2 as a consequence of diminished EGF/EGFR signaling. These data establish a function for the ST3GAL1-mediated sialylation of NRP1, leading to increased EGF/EGFR downstream signaling and enhanced tumor cell motility. Furthermore, ST3GAL1 silencing augmented the sensitivity to cetuximab-mediated cell lysis. Our findings provide novel insight into the mechanisms underlying the function of ST3GAL1 in promoting tumor cell migration through the EGFR/NRP1 pathway. Our results suggest that ST3GAL1 may represent a valuable target for strategies aimed at inhibiting tumor migration.
转移是癌症相关发病和死亡的主要原因。唾液酸转移酶ST3GAL1在乳腺癌中的过表达与转移相关。然而，ST3GAL1对细胞运动影响的分子机制尚不清楚。我们确定神经纤毛蛋白-1/NRP1是ST3GAL1的一个底物。基因表达分析显示，与双低亚组相比，ST3GAL1高表达/NRP1高表达队列的无复发生存期（p = 0.0046）和无远处转移生存期（p = 0.0003）显著缩短。我们证明，ST3GAL1介导的NRP1唾液酸化在分子水平上导致对表皮生长因子受体（EGFR）的结合亲和力增加。在细胞水平上，ST3GAL1沉默损害细胞迁移和伤口愈合能力，这与表皮生长因子（EGF）/EGFR信号减弱导致的钙蛋白酶2（CAPN2）活性降低有关。这些数据确定了ST3GAL1介导的NRP1唾液酸化的功能，导致EGF/EGFR下游信号增加和肿瘤细胞运动增强。此外，ST3GAL1沉默增强了对西妥昔单抗介导的细胞裂解的敏感性。我们的研究结果为ST3GAL1通过EGFR/NRP1途径促进肿瘤细胞迁移的功能机制提供了新的见解。我们的结果表明，ST3GAL1可能是旨在抑制肿瘤迁移策略的一个有价值的靶点。
