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Explore the potential mechanisms between ertugliflozin and kidney cancer through bioinformatics analysis and
Bo Xu1,2,3,4,5,6, Peng Xiang1,2,3,4,6, Xiongwen Yang5
1The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang Hunan, China.
Background:
Current research on sodium-glucose cotransporter 2 (SGLT2) inhibitors and kidney cancer is controversial. Recent studies suggest that ertugliflozin increases the overall cancer risk, especially kidney cancer.
Objective:
This study investigated the potential mechanisms between ertugliflozin and kidney cancer through multidimensional data.
Methods:
We identified core targets between ertugliflozin and clear cell renal cell carcinoma (ccRCC) through network toxicology. Feature genes were obtained through analysis of the TCGA database, and additional analysis was conducted on SLC5A2. Finally, a two-sample Mendelian randomization (MR) approach (mainly inverse variance weighted) was used to assess the association between feature genes, SGLT2 inhibition, and ccRCC or renal cell carcinoma (RCC).
Results:
Through network toxicology, 15 core targets between ertugliflozin and ccRCC were identified. Cox regression analysis, ROC curve plotting, and survival analysis were conducted, and then two feature genes, SRC and ESR2, were obtained. Additionally, the expression of SLC5A2 was lower in tumor tissues compared to normal tissues. MR analysis results showed that SRC was not associated with RCC/ccRCC risk, while ESR2 may be associated with a higher risk of ccRCC (P = 0.03). SGLT2 inhibition potentially led to a higher risk of renal cell carcinoma [odds ratio (OR) 3.05; 95% confidence interval 1.03-9.04; P = 0.04]. When using UK Biobank Genome-Wide Association Study data, SGLT2 inhibition was associated with a higher risk of ccRCC (OR 83.70; 95%CI 3.60-1946.03; P < 0.01). Experiments verified that ertugliflozin acted on ESR2 rather than SRC.
Conclusion:
Ertugliflozin may affect kidney cancer by targeting ESR2. SGLT2 inhibition may also be a contributing factor to renal cancer, and further investigation is required.
Insights
Ertugliflozin may increase kidney cancer risk by targeting ESR2. Sodium-glucose cotransporter 2 (SGLT2) inhibition is also linked to renal cancer, warranting further study.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Controversy exists regarding sodium-glucose cotransporter 2 (SGLT2) inhibitors and kidney cancer risk.
- Recent studies suggest ertugliflozin may elevate overall and kidney cancer incidence.
Purpose of the Study:
- To investigate potential mechanisms linking ertugliflozin and kidney cancer using multidimensional data.
- To explore the association between SGLT2 inhibition and renal cell carcinoma (RCC).
Main Methods:
- Network toxicology identified core targets between ertugliflozin and clear cell renal cell carcinoma (ccRCC).
- TCGA database analysis and SLC5A2 analysis identified feature genes.
- Two-sample Mendelian randomization (MR) assessed associations between feature genes, SGLT2 inhibition, and RCC/ccRCC.
Main Results:
- Fifteen core targets were identified; SRC and ESR2 were selected as feature genes.
- ESR2 showed a potential association with increased ccRCC risk (P=0.03).
- SGLT2 inhibition was associated with higher RCC risk (OR 3.05, P=0.04) and ccRCC risk in UK Biobank data (OR 83.70, P<0.01). Ertugliflozin acted on ESR2.
Conclusions:
- Ertugliflozin may influence kidney cancer by targeting ESR2.
- SGLT2 inhibition might contribute to renal cancer development.
- Further research is necessary to elucidate these relationships.
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