Objective Bladder cancer (BCa) has become a growing concern worldwide, highlighting the importance of early detection and new treatment methods. Recent studies have shown that viruses from the HERV family play a significant role in the development of various cancers and can act as early diagnostic biomarkers. Although hypomethylation of HERV-K has been proven in bladder cancer, no studies have yet explored the role of HERV-K oncogenes such as env, gag, np9, and rec. In this study, for the first time, we investigate the expression of these genes and their relationship with each other, aiming to shed light on their potential role in bladder cancer progression and diagnosis. Methods and Materials We collected a total of 42 samples, comprising 21 bladder transitional cell carcinoma (TCC) samples and 21 adjacent normal tissue samples. Following RNA extraction, the expression levels of HERV-K (HML-2) genes (env, gag, np9, and rec) were evaluated using quantitative real-time PCR (qRT-PCR). For statistical analysis, GraphPad software was employed, utilizing the Kruskal–Wallis test, Mann–Whitney U test, and correlation tests to assess the data. Results We found that env and np9 were significantly upregulated in BCa tissues compared to normal tissues (p < 0.0001 and p = 0.022, respectively). While env showed strong associations with tumor grade (low-grade: p = 0.0006; high-grade: p = 0.0011) and stage (early stage: p = 0.0002; invasive stage: p = 0.0047), np9 exhibited consistent associations across all grades (low-grade: p = 0.017; high-grade: p = 0.042) but was exclusively linked to invasive stages (p = 0.001). Although gag expression did not differ significantly overall, it was elevated in the invasive stages of tumors (p = 0.0021). Interestingly, while rec expression showed an increase in cancerous tissues compared to normal tissues, this change was not statistically significant. However, it exhibited significant correlations with other HERV-K genes in cancerous tissue (r = 0.63, p < 0.0001 with env; r = 0.80, p < 0.0001 with gag; and r = 0.39, p = 0.015 with np9). Age-stratified analysis revealed tumor-specific env (p = 0.0272) and rec (p = 0.0017) variations, whereas normal tissues showed only marginal rec age-dependence (p = 0.0494). Conclusion The results of our study highlight the potential role of HERV-K genes, particularly env and np9, in BCa progression and demonstrate their promising utility as diagnostic biomarkers.

Investigating the expression of HERV-K env, np9, gag, and rec in bladder cancers

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2025年6月21日

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Fariba Rafiei,
Navid Masoumi,
Ebrahim Faghihloo

摘要

Objective

Bladder cancer (BCa) has become a growing concern worldwide, highlighting the importance of early detection and new treatment methods. Recent studies have shown that viruses from the HERV family play a significant role in the development of various cancers and can act as early diagnostic biomarkers. Although hypomethylation of HERV-K has been proven in bladder cancer, no studies have yet explored the role of HERV-K oncogenes such as env, gag, np9, and rec. In this study, for the first time, we investigate the expression of these genes and their relationship with each other, aiming to shed light on their potential role in bladder cancer progression and diagnosis.

Methods and Materials

We collected a total of 42 samples, comprising 21 bladder transitional cell carcinoma (TCC) samples and 21 adjacent normal tissue samples. Following RNA extraction, the expression levels of HERV-K (HML-2) genes (env, gag, np9, and rec) were evaluated using quantitative real-time PCR (qRT-PCR). For statistical analysis, GraphPad software was employed, utilizing the Kruskal–Wallis test, Mann–Whitney U test, and correlation tests to assess the data.

Results

We found that env and np9 were significantly upregulated in BCa tissues compared to normal tissues (p < 0.0001 and p = 0.022, respectively). While env showed strong associations with tumor grade (low-grade: p = 0.0006; high-grade: p = 0.0011) and stage (early stage: p = 0.0002; invasive stage: p = 0.0047), np9 exhibited consistent associations across all grades (low-grade: p = 0.017; high-grade: p = 0.042) but was exclusively linked to invasive stages (p = 0.001). Although gag expression did not differ significantly overall, it was elevated in the invasive stages of tumors (p = 0.0021). Interestingly, while rec expression showed an increase in cancerous tissues compared to normal tissues, this change was not statistically significant. However, it exhibited significant correlations with other HERV-K genes in cancerous tissue (r = 0.63, p < 0.0001 with env; r = 0.80, p < 0.0001 with gag; and r = 0.39, p = 0.015 with np9). Age-stratified analysis revealed tumor-specific env (p = 0.0272) and rec (p = 0.0017) variations, whereas normal tissues showed only marginal rec age-dependence (p = 0.0494).

Conclusion

The results of our study highlight the potential role of HERV-K genes, particularly env and np9, in BCa progression and demonstrate their promising utility as diagnostic biomarkers.