SAPCD2 Drives Bladder Cancer Progression by Stabilizing TANK and Engaging a CREB-PLAGL2 Feedback Loop to Sustain MAPK Signaling.

Background: Bladder cancer (BCa) is a prevalent and aggressive malignancy characterized by high recurrence and metastasis rates. Despite advances in treatment, the prognosis for patients with advanced BCa remains poor. This study aimed to investigate the role of SAPCD2 in BCa progression and its potential as a therapeutic target. Methods: We performed a series of in vitro and in vivo experiments to assess the expression and function of SAPCD2 in BCa. The correlation between SAPCD2 expression and clinicopathological features was analyzed using tissue samples from BCa patients. Functional assays, including cell proliferation, migration, invasion, and metastasis tests, were conducted to evaluate the biological impact of SAPCD2. Mechanistic studies focused on the MAPK signaling pathway, TANK stabilization, and the interaction between SAPCD2 and the PLAGL2-CREB feedback loop. Results: Our results showed that SAPCD2 was significantly upregulated in BCa tissues and correlated with advanced clinicopathological features and poor prognosis. Overexpression of SAPCD2 promoted cell proliferation, migration, invasion, and metastasis, while its silencing led to the opposite effects. Mechanistically, SAPCD2 activated the MAPK signaling pathway by stabilizing TANK and preventing its degradation by SYVN1. Furthermore, we identified a positive feedback loop in which SAPCD2 enhanced PLAGL2 expression through CREB phosphorylation, further amplifying SAPCD2 expression and MAPK signaling. Conclusions: This study indicated that SAPCD2 could serve as a critical driver of BCa malignancy, emphasizing its role in sustaining oncogenic signaling through the SAPCD2-TANK-MAPK axis and the PLAGL2-SAPCD2-CREB feedback loop. Targeting this pathway may offer novel therapeutic strategies for treating aggressive BCa.