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Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization

ABSTRACT: Metastasis is an important factor affecting the prognosis and survival of bladder cancer (BLCA) patients. Our previous study found that the mevalonate pathway is associated with the migratory ability of BLCA cells, but the exact mechanism is unclear. Here, we found that BLCA patients with mevalonate pathway activation had a poorer prognosis. Inhibition of the mevalonate pathway (FDPS knockdown, simvastatin or zoledronic acid) significantly reduced the migratory ability of BLCA cells. Therefore, we tested the changes of key genes after knocking down the key enzymes of the mevalonate pathway, FDPS and SQLE1, and the transcription factor YY1 in bladder cancer cells using RNA sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252007 | GEO | 2024/09/08

REPOSITORIES: GEO

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Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment

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Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization

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