CD73 contributes to the pathogenesis of fusion- negative rhabdomyosarcoma through the purinergic signaling pathway
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(2024)
摘要
Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and adolescents. Fusion- negative RMS (FN- RMS) accounts for more than 80% of all RMS cases. The long- term event- free survival rate for patients with high- grade FN- RMS is below 30%, highlighting the need for improved therapeutic strategies. CD73 is a 5 ' ectonucleotidase that hydrolyzes AMP to adenosine and regulates the purinergic signaling pathway. We found that CD73 is elevated in FN- RMS tumors that express high levels of TWIST2. While high expression of CD73 contributes to the pathogenesis of multiple cancers, its role in FN- RMS has not been investigated. We found that CD73 knockdown decreased FN- RMS cell growth while up- regulating the myogenic differentiation program. Moreover, mutation of the catalytic residues of CD73 rendered the protein enzymatically inactive and abolished its ability to stimulate FN- RMS growth. Overexpression of wildtype CD73, but not the catalytically inactive mutant, in CD73 knockdown FN- RMS cells restored their growth capacity. Likewise, treatment with an adenosine receptor A2A- B agonist partially rescued FN- RMS cell proliferation and bypassed the CD73 knockdown defective growth phenotype. These results demonstrate that the catalytic activity of CD73 contributes to the pathogenic growth of FN- RMS through the activation of the purinergic signaling pathway. Therefore, targeting CD73 and the purinergic signaling pathway represents a potential therapeutic approach for FN- RMS patients.
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关键词
sarcoma,cell signaling,pediatric cancer,Cell biology
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