PIGU overexpression and regulation of cellular biological functions in bladder cancer

Abstract

BACKGROUND

PIGU has been proposed as a potential oncogene in bladder cancer (BLCA); however, experimental evidence regarding PIGU expression in BLCA remains lacking, necessitating further investigation into its functions and underlying mechanisms.

AIM

To explore the expression of PIGU in BLCA and to understand its function and underlying mechanisms.

METHODS

This study assessed PIGU protein expression in BLCA tissues via immunohistochemistry. We integrated 14 high-throughput datasets from TCGA, GEO, and Array Express to evaluate PIGU’s mRNA expression levels and diagnostic efficacy. siRNA-knockdown cell lines were established using the PIGU-overexpressing HT-1376 BLCA cell line. Proliferation capacity was assessed via CCK-8 assays, while apoptosis and cell cycle distribution were evaluated using flow cytometry. PIGU’s potential mechanism in BLCA were explored through differential gene enrichment analysis, protein interaction network analysis, and immune infiltration analysis.

RESULTS

PIGU expression was significantly upregulated in 121 BLCA and 32 non-BLCA samples at the protein level (10.65 ± 2.14 vs 5.56 ± 2.68, P < 0.0001) and in 1065 BLCA and 170 non-BLCA samples at the mRNA level (standardized mean difference = 0.74, 95% confidence interval: 0.07-1.41). Elevated PIGU expression correlated with poorer prognosis in BLCA patients, making it an independent prognostic factor. PIGU knockdown inhibited BLCA cell proliferation (P < 0.05), increased apoptosis, and caused cell cycle arrest at the G1 phase. PIGU-regulated genes are enriched in cell cycle pathways, with PCNA and MCM2 serving as hub genes. High PIGU expression was associated with reduced immune cell infiltration and higher tumor purity, potentially promoting immune evasion through VTCN1 activation and ICOS inhibition.

CONCLUSION

PIGU is upregulated in BLCA and has prognostic value. It promotes tumor progression by regulating the cell cycle and immune microenvironment, showing potential as an effective therapeutic target for BLCA.

Keywords: PIGU; Bladder cancer; Immunohistochemistry; Cell cycle; Apoptosis; Prognosis; Immune infiltration

Core Tip: This study indicated that PIGU expression is markedly increased in bladder cancer at both the mRNA and protein levels and that this elevation serves as an independent predictor of unfavorable clinical outcomes. In vitro experiments further revealed that PIGU knockdown suppresses cell proliferation and induces apoptosis accompanied by G1-phase arrest, while mechanistic analyses indicated that PIGU facilitates tumor progression by regulating key cell cycle-related genes and modulating the immune microenvironment. These results indicate that PIGU could function not only as an independent prognostic indicator but also as a promising candidate for therapeutic targets.