Recently, Professor Wang Xinghuan's team from Zhongnan Hospital of Wuhan University held a seminar at the International Society of Pharmacogenomics (the International Society of Pharmacogenomics). The Pharmacogenomics Journal, the official journal of ISP, published a paper entitled "Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics”[1]. A comprehensive analysis of Mendelian randomization, animal models, and transcriptomics showed that inhibitors of HMB-COA reductase (HMGCR), especially simvastatin, can reduce the risk of bladder cancer and reveal the potential mechanism by which simvastatin inhibits bladder cancer. The study provides new evidence for the role of simvastatin in the treatment or adjuvant therapy of bladder cancer.
Mendelian randomization is a new epidemiological research method. Since the random allocation of genes precedes disease, Mendelian randomization can be used to infer the effect of exposure on disease. Mendelian randomization uses the random allocation of genes to simulate randomization in randomized controlled trials, which has high evidence power and can be a good supplement when the actual situation does not allow to carry out randomized controlled studies or the cost of carrying out randomized controlled studies is too high.
Based on the UK biobank and FinnGen databases, this study first verified the correlation between 23 common drugs and the risk of bladder cancer by two-sample Mendelian randomization, and the results showed that HMGCR inhibitors could significantly reduce the risk of bladder cancer. Since there are many types of HMGCR inhibitors on the market, four of the most commonly used HMGCR inhibitors (atorvastatin, pravastatin, Rosuvastatin, simvastatin) were selected for analysis, and it was found that simvastatin could most significantly reduce the risk of bladder cancer. It was subsequently verified by subcutaneous tumor bearing model in nude mice, and it was found that simvastatin could inhibit the growth of bladder cancer cells and epithelial mesenchymal transformation process in mice. In addition, bladder cancer sequencing data sets in TCGA and GEO databases and clinical bladder cancer samples have confirmed that HMGCR is highly expressed in bladder cancer, and bladder cancer patients with high expression of HMGCR have worse prognosis. Transcriptome sequencing analysis revealed that simvastatin can affect DNA replication, cell cycle, TNF-α/NF-κB and other signaling pathways closely related to tumor proliferation and metastasis. Finally, based on two-sample Mendelian randomization, two types of lipids that may affect the incidence of bladder cancer were screened, namely lipoprotein particles and VLDL cholesterol.
In summary, this study screened common drug types significantly associated with the risk of bladder cancer, and combined with animal models and transcriptomic sequencing analysis, verified the tumor inhibitory effect of simvastatin in bladder cancer, and initially explored the possible mechanism of simvastatin's role, suggesting that simvastatin may become a potential drug for the prevention and treatment of bladder cancer. The first author of the paper is Wei Houyi, a doctoral candidate in urology at Zhongnan Hospital of Wuhan University. The research was supported by the National Natural Science Foundation of China and the special fund for Basic scientific research operation of central universities.
References:
[1] Wei, H., Li, Z., Qian, K. et al. Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics. Pharmacogenomics J 24, 24 (2024).https://doi.org/10.1038/s41397-024-00346-x
Links:
https://www.nature.com/articles/s41397-024-00346-x#citeas