SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma

摘要: Synovial sarcoma is a high-grade soft tissue malignancy characterized by specific reciprocal translocation t(X;18), which leads to the fusion of SS18 (SYT) gene one three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein suggested act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease often lethal and development novel targeted strategies required. Several expression-profiling studies identified distinct expression signatures, implying consistent role Wnt/β-catenin signaling in synovial tumorigenesis. Here we investigate functional relevance pathway activation vitro vivo. Immunohistochemical analyses nuclear β-catenin Wnt downstream targets revealed canonical significant subset 30 primary specimens. Functional aspects including dependence Tcf/β-catenin complex activity on proteins were analyzed. Efficient SS18-SSX-dependent was confirmed TOPflash reporter luciferase assays immunoblotting. In five human cell lines, inhibition protein-protein interaction significantly blocked cascade, accompanied effective downregulation (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 Survivin) suppression viability associated with induction apoptosis. SYO-1 xenografts, administration small molecule inhibitors reduced tumor growth, diminished AXIN2 levels. summary, SS18-SSX-induced appears be crucial biological importance tumorigenesis progression, representing potential molecular target for strategies.