Abstract
BACKGROUND: Bladder cancer (BC) remains the leading global mortality and poor prognosis in genitourinary malignancies, especially in patients with metastasis. RESULTS: In this study, we demonstrate that loss of polarity protein partitioning defective 3 (Par3, encoded by PARD3) is correlated with stronger metastatic capability and a poorer prognosis in BC. Par3 deletion in high grade BC cells accelerates their invasion and metastasis in vitro and in vivo. Mechanistically, Par3 could directly interact with protein phosphatase 1 regulatory subunit 12 C (Ppp1r12c). Either Par3 or Ppp1r12c over-expression rescues the invasion and metastasis caused by Par3 deficiency in vitro. Moreover, the actin filament-related processions are enriched in the downstream biological function, resulting from the activation of ERK 1/2 and p38 signaling pathways, indicated by proteomics analysis from BC cells and tissue, as well as data mining results from BC public database. CONCLUSION: Together, our study reveals that Par3 deficiency promotes BC metastasis. Par3 directly interacts with Ppp1r12c (390-782aa), activating the Par3/Ppp1r12c/ERK/p38 axis. Par3 could act as a prognostic biomarker and potential therapeutic target for BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13062-026-00727-1.