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ENPP1 promotes immune suppression, drug resistance, and adverse outcomes in bladder cancer: Potential for targeted
Chengyu You1, Qixiang Fang1, Xi Xiao1
1Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu 730000, China; Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, Gansu 730030, China.
Background:
ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) plays a critical role in multiple cancers; however, its role in bladder cancer (BC) remains largely unexplored. This study investigates the impact of ENPP1 on tumor progression, apoptosis, and the immune microenvironment through bioinformatics and experimental validation.
Materials And Methods:
ENPP1 expression and clinical significance were analyzed using TCGA-BLCA, GEO datasets, and a local clinical cohort of 36 BC patients. Immune infiltration and functional enrichment were assessed using ESTIMATE, CIBERSORT, and clusterProfiler. Single-cell RNA sequencing (scRNA-seq) data examined ENPP1 expression in BC tissues. Stable ENPP1-overexpressing (UMUC3) and ENPP1-knockdown (J82) cell lines were established. Functional assays, including proliferation, migration, and apoptosis marker analysis, were performed.
Results:
RT-qPCR, Western blotting, and immunohistochemistry confirmed differential ENPP1 expression between BC tissues and adjacent normal tissues. High ENPP1 expression was associated with worse overall survival (OS), advanced T and N stages, and poor pathological grades. Functional assays demonstrated that ENPP1 overexpression enhanced proliferation, migration, and apoptosis resistance, while knockdown suppressed these processes. Mechanistically, ENPP1 overexpression reduced pro-apoptotic markers BAX and Caspase-3 while increasing anti-apoptotic Bcl-2. Immune infiltration analysis revealed a positive correlation between ENPP1 expression and M2 macrophage infiltration, alongside decreased CD8+ T cell infiltration. scRNA-seq identified high ENPP1 expression in cancer-associated fibroblasts and epithelial cells. Drug sensitivity analysis linked elevated ENPP1 expression to resistance against chemotherapies like gemcitabine and cytarabine.
Conclusion:
ENPP1 drives tumor progression, modulates immune infiltration, and contributes to chemotherapy resistance in BC, underscoring its potential as a therapeutic target.
Insights
Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) promotes bladder cancer progression, immune evasion, and chemotherapy resistance. Targeting ENPP1 may offer a new therapeutic strategy for bladder cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Immunology
Background:
- Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) is implicated in various cancers, but its role in bladder cancer (BC) is understudied.
- This research investigates ENPP1's function in BC progression, apoptosis, and the tumor immune microenvironment.
Purpose of the Study:
- To elucidate the role of ENPP1 in bladder cancer development and progression.
- To explore ENPP1's impact on tumor cell apoptosis and the tumor immune microenvironment.
- To assess ENPP1's influence on chemotherapy resistance in bladder cancer.
Main Methods:
- Bioinformatic analysis of TCGA-BLCA and GEO datasets, alongside a local cohort of 36 BC patients.
- Assessment of immune infiltration using ESTIMATE and CIBERSORT, and functional enrichment analysis.
- In vitro functional assays using stable ENPP1-overexpressing and knockdown bladder cancer cell lines.
Main Results:
- High ENPP1 expression correlates with poorer overall survival, advanced tumor stage, and higher pathological grade in BC.
- ENPP1 overexpression enhances BC cell proliferation, migration, and apoptosis resistance, while knockdown suppresses these effects.
- ENPP1 modulates the immune microenvironment by increasing M2 macrophage infiltration and decreasing CD8+ T cell infiltration, and is linked to gemcitabine and cytarabine resistance.
Conclusions:
- ENPP1 significantly drives bladder cancer progression and influences the tumor immune microenvironment.
- ENPP1 contributes to chemoresistance in bladder cancer, suggesting its potential as a therapeutic target.
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