Pro-tumorigenic role of protocadherin 17 and its prognostic significance in Ewing sarcoma

Ewing sarcoma (ES) is an aggressive bone tumor in children and adolescents, and metastatic dissemination remains the major cause of treatment failure. Protocadherin 17 (PCDH17), a member of the cadherin superfamily, has been reported to exert context-dependent roles in solid tumors, but its significance in ES is unclear. Here, we analyzed Gene Expression Omnibus (GEO) datasets to evaluate PCDH17 expression, its association with overall survival and event-free survival, and the enrichment of biological pathways related to PCDH17 levels, and further examined PCDH17 expression in ES cell lines. The biological functions of PCDH17 were investigated using short hairpin RNA-mediated knockdown in A673 and RD-ES cells, followed by Cell counting kit-8 (CCK-8), colony formation, wound healing and transwell invasion assay, as well as western blotting (WB) and immunofluorescence (IF). PCDH17 was markedly upregulated in ES tissues and cell lines compared with normal counterparts, and high expression correlated with shorter survival. Gene set enrichment analysis (GSEA) indicated that high PCDH17 expression is associated with transcriptional programs driving cell cycle progression and oncogenic growth. Functionally, silencing PCDH17 significantly impairs proliferation, colony formation, migration and invasion of ES cells, and attenuates mesenchymal marker expression as well as associated morphological features. Collectively, our data indicate that PCDH17 is upregulated in ES and associated with worse survival, and that PCDH17 depletion suppresses malignant phenotypes in vitro. Together, these results nominate PCDH17 as a candidate prognostic biomarker and potential therapeutic target, which merits further validation.