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Effect of APOBEC3A functional polymorphism on renal cell carcinoma is influenced by tumor necrosis factor-α and
Xiaojie Tan1, Shaoling Zheng2, Wenbin Liu1
1Department of Epidemiology, Second Military Medical University Shanghai 200433, China.
Abstract:
Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) 3 cytidine deaminases are the prominent drivers of somatic mutations in cancers. However, the effect of APOBEC3s functional polymorphisms on the development of renal cell carcinoma (RCC) remains unknown. Five genetic polymorphisms affecting the expression of APOBEC3A (A3A), APOBEC3B, and APOBEC4 and uracil DNA glycosylase (UNG) were genotyped in 728 RCC patients and 1500 healthy controls. The effects of tumor necrosis factor-α (TNFα) and interleukin-6 on the activity of the A3A promoter with rs12157810-A or -C in four RCC cell lines (786-O, A498, Caki2, ACHN) and two colorectal cancer cell lines (HCT116, SW620) were evaluated using dual-luciferase assays. Transcriptional repressors to the A3A promoter were identified by chromatin immunoprecipitation-quantitative PCR. The proapoptotic effect of A3A on RCC cells was evaluated using cytometry. The prognostic values of A3A and ETS1 were evaluated by the Cox regression analysis. The expressions of A3A and ETS1 were evaluated in clear cell RCC (ccRCC) specimens with different polymorphic genotypes using quantitative RT-PCR and immunohistochemistry. Of those functional polymorphisms, CC genotype at rs12157810 in the A3A promoter was significantly associated with a decreased risk of ccRCC, compared to the AA genotype (odds ratio adjusted for age and gender, 0.41, 95% confidence interval [CI], 0.28-0.57). Other polymorphic genotypes were not associated with the risk of RCC. The activity of the A3A promoter with rs12157810-C was significantly higher than that with rs12157810-A in the four RCC cell lines and two colorectal cancer cell lines. The activity of the A3A promoter with rs12157810-C was greatly up-regulated by TNFα and predominantly inhibited by a transcriptional repressor ETS1. The binding of ETS1 to the A3A promoter with rs12157810-C was looser than that with rs12157810-A. Ectopic expression of A3A significantly promoted apoptosis in ccRCC cells, rather than in colorectal cancer cells. Higher ETS1 expression predicted a favorable prognosis in ccRCC, with a hazard ratio of 0.58 (95% CI, 0.43-0.78). Rs121567810-C up-regulates the A3A promoter activity, possibly due to higher response to TNFα and looser transcriptional repression by ETS1. Up-regulation of A3A increases apoptosis, thus decreasing ccRCC risk in those carrying rs121567810-C.
Insights
A specific genetic variation in the APOBEC3A promoter (rs12157810-C) is linked to a reduced risk of clear cell renal cell carcinoma (ccRCC). This variation enhances APOBEC3A expression, promoting apoptosis and lowering ccRCC incidence.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) 3 cytidine deaminases are key drivers of somatic mutations in various cancers.
- The influence of functional polymorphisms in APOBEC3s on renal cell carcinoma (RCC) development remains largely unexplored.
Purpose of the Study:
- To investigate the association between functional polymorphisms in APOBEC3A (A3A), APOBEC3B, APOBEC4, and uracil DNA glycosylase (UNG) and RCC risk.
- To elucidate the molecular mechanisms underlying the effect of the A3A promoter polymorphism rs12157810 on A3A activity, gene expression, and ccRCC prognosis.
Main Methods:
- Genotyping of five functional polymorphisms in 728 RCC patients and 1500 controls.
- Dual-luciferase assays to assess A3A promoter activity influenced by TNFα and ETS1 in cancer cell lines.
- Chromatin immunoprecipitation-quantitative PCR to identify transcriptional repressors of the A3A promoter.
- Flow cytometry to evaluate the pro-apoptotic effect of A3A.
- Cox regression and immunohistochemistry to assess prognostic values and expression levels of A3A and ETS1 in ccRCC specimens.
Main Results:
- The CC genotype at rs12157810 in the A3A promoter was significantly associated with decreased ccRCC risk (OR, 0.41; 95% CI, 0.28-0.57) compared to the AA genotype.
- The A3A promoter activity was higher with the rs12157810-C allele, showing increased response to TNFα and reduced repression by ETS1.
- Ectopic A3A expression significantly induced apoptosis in ccRCC cells.
- Higher ETS1 expression correlated with a favorable prognosis in ccRCC (HR, 0.58; 95% CI, 0.43-0.78).
Conclusions:
- The rs12157810-C polymorphism enhances A3A promoter activity, potentially through increased TNFα responsiveness and decreased ETS1 binding, leading to elevated A3A expression.
- Increased A3A expression promotes apoptosis, thereby reducing the risk of clear cell renal cell carcinoma in individuals with the rs12157810-C genotype.
- ETS1 serves as a prognostic biomarker for ccRCC, with higher expression indicating a better outcome.
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