PIN1 suppresses bladder cancer progression by inducing cellular senescence and activating the interferon response...

Bladder cancer (BCa) represents the most frequently malignancies of the urinary system with high recurrence rates and heterogeneous outcomes. While peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is recognized as an oncogene in multiple cancers, its expression pattern, biological function, and the molecular basis of bladder tumorigenesis is still poorly understood.

We performed comprehensive single-cell RNA sequencing (scRNA-seq) analysis to characterize the cellular heterogeneity of BCa tumor microenvironment and identify malignant epithelial cells. Through integrative bioinformatics approaches combining differential expression analysis, survival correlation, and cellular senescence association, PIN1 was identified as a key downregulated gene. We systematically validated PIN1 expression in clinical specimens and cell lines using immunohistochemistry, Western blot, and qRT-PCR. Functional consequences of PIN1 manipulation were assessed through in vitro assays measuring proliferation, apoptosis, migration, invasion, and cellular senescence. A xenograft mouse model was established to evaluate tumor growth and senescence induction in vivo. RNA sequencing and pathway enrichment analysis were conducted to explore the molecular mechanisms.

PIN1 was significantly downregulated in malignant epithelial cells of BCa tissues compared to normal counterparts. Low PIN1 expression correlated strongly with poor overall survival (HR = 0.693, p = 0.0265) and progression-free survival (HR = 0.698, p = 0.0471). Elevated PIN1 expression markedly reduced the proliferative, clonogenic, migratory, and invasive capacities of bladder cancer cells, while concurrently driving apoptosis and senescence. Conversely, PIN1 depletion intensified malignant behavior. In vivo studies further showed that PIN1 up-regulation restrained tumor expansion and elevated senescence-associated β-galactosidase activity. Mechanistically, PIN1 overexpression activated the interferon response pathway, upregulating key components including IFNAR1, IRF7, and IRF9. Rescue experiments confirmed that blockade of the interferon pathway partially reversed PIN1-induced growth suppression and senescence, indicating that interferon signaling is a critical downstream mediator of PIN1's tumor-suppressive effects.

Our study reveals PIN1 as a previously unrecognized bladder-cancer tumor suppressor that halts progression by provoking senescence and re-awakening interferon signaling. This work rewrites the molecular landscape of the disease and positions PIN1 as both a prognostic indicator and a druggable node for future therapies.