下调和上调
MAPK/ERK通路
基因敲除
精氨酸
癌症研究
激酶
细胞生物学
骨肉瘤
精氨酸酶
细胞外
细胞迁移
磷酸化
生物
化学
细胞
细胞培养
生物化学
氨基酸
基因
遗传学
作者
Peng Wang,Yihui Song,Hongyu Li,Jiahao Zhuang,Xin Shen,Yunfei Wen,Rujia Mi,Yixuan Lu,Biao Yang,Mengjun Ma,Huiyong Shen
出处
期刊:Cancer Letters
[Elsevier]
日期:2023-11-01
卷期号:576: 216412-216412
被引量:7
标识
DOI:10.1016/j.canlet.2023.216412
摘要
The function of signal regulatory protein alpha (SIRPA) has been well studied in macrophages and dendritic cells, but relatively less in tumors. Notably, SIRPA is upregulated in osteosarcoma tissues, particularly in metastatic tissues, and is associated with unfavorable clinical outcomes. Knockdown of SIRPA impaired OS cell migration by decreasing specificity protein 1 (SP1) stability and arginine uptake. Importantly, SIRPA phosphorylated SP1 at threonine 278 (Thr278) through extracellular signal-regulated kinase (ERK) activation to protect SP1 from proteasomal degradation. In addition, SP1 increased solute carrier family 7 member 3 (SLC7A3) expression by binding to the SLC7A3 promoter and increased the capability of arginine uptake, thereby facilitating OS cell migration. More interestingly, arginine promoted the stability of SP1 in an ERK-independent manner and thus formed the "SP1 stabilization circle". Combined treatment with the anti-SIRPA antibody and arginase, which blocked the circle, impaired tumor metastasis in mice bearing xenografts formed from SIRPA-overexpressing cells. In summary, our study demonstrates that the upregulation of SIRPA promotes OS metastasis via the "SP1 stabilization circle" and SLC7A3-mediated arginine uptake, which might serve as a target for OS treatment.
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