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.