ENPP1 promotes immune suppression, drug resistance, and adverse outcomes in bladder cancer: Potential for targeted therapy

IF 1.4 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics Pub Date : 2025-03-04 DOI:10.1016/j.cancergen.2025.03.001

Chengyu You , Qixiang Fang , Xi Xiao , Yang Liu , Weiguang Yang , Liangliang Qing , Qingchao Li , Rongxin Li , Yanan Wang , Zhilong Dong

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引用次数: 0

Abstract

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.

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来源期刊

Cancer Genetics ONCOLOGY-GENETICS & HEREDITY

CiteScore

3.20

自引率

5.30%

发文量

167

审稿时长

27 days

期刊介绍： The aim of Cancer Genetics is to publish high quality scientific papers on the cellular, genetic and molecular aspects of cancer, including cancer predisposition and clinical diagnostic applications. Specific areas of interest include descriptions of new chromosomal, molecular or epigenetic alterations in benign and malignant diseases; novel laboratory approaches for identification and characterization of chromosomal rearrangements or genomic alterations in cancer cells; correlation of genetic changes with pathology and clinical presentation; and the molecular genetics of cancer predisposition. To reach a basic science and clinical multidisciplinary audience, we welcome original full-length articles, reviews, meeting summaries, brief reports, and letters to the editor.