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Updated: Jun 8, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via
R T Sitaram1, S Degerman, B Ljungberg
1Department of Medical Biosciences and Pathology, Umeå University, Umeå, Sweden.
Background:
Wilms' tumour 1 (WT1) gene was discovered as a tumour suppressor gene. Later findings have suggested that WT1 also can be oncogenic. This complexity is partly explained by the fact that WT1 has a number of target genes.
Method:
WT1 and its target gene human telomerase reverse transcriptase (hTERT) were analysed in clear cell renal cell carcinoma (ccRCC). In vitro experiments were performed to examine the functional link between WT1 and hTERT by overexpression of WT1 isoforms in the ccRCC cell line, TK-10.
Results:
WT1 demonstrated lower RNA expression in ccRCC compared with renal cortical tissue, whereas hTERT was increased, showing a negative correlation between WT1 and hTERT (P=0.005). These findings were experimentally confirmed in vitro. The WT1 generated effect on hTERT promoter activity seemed complex, as several negative regulators of hTERT transcription, such as SMAD3, JUN (AP-1) and ETS1, were activated by WT1 overexpression. Downregulation of potential positive hTERT regulators, such as cMyc, AP-2α, AP-2γ, IRF1, NFX1 and GM-CSF, were also observed. Chromatin immunoprecipitation analysis verified WT1 binding to the hTERT, cMyc and SMAD3 promoters.
Conclusion:
The collected data strongly indicate multiple pathways for hTERT regulation by WT1 in ccRCC.
Insights
The Wilms' tumour 1 (WT1) gene plays a complex role in clear cell renal cell carcinoma (ccRCC). WT1 negatively regulates human telomerase reverse transcriptase (hTERT) expression in ccRCC through multiple pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Wilms' tumour 1 (WT1) gene, initially identified as a tumor suppressor, exhibits dual oncogenic and tumor-suppressive functions.
- WT1's complex role is attributed to its regulation of numerous target genes.
Purpose of the Study:
- To investigate the relationship between WT1 and its target gene, human telomerase reverse transcriptase (hTERT), in clear cell renal cell carcinoma (ccRCC).
- To elucidate the functional mechanisms underlying WT1's regulation of hTERT in ccRCC.
Main Methods:
- Analysis of WT1 and hTERT expression in ccRCC tissues and renal cortical tissue.
- In vitro experiments involving WT1 isoform overexpression in the ccRCC cell line TK-10.
- Chromatin immunoprecipitation (ChIP) assays to verify WT1 binding to target promoters.
Main Results:
- WT1 RNA expression was lower in ccRCC compared to normal renal tissue, while hTERT expression was elevated, indicating a negative correlation (P=0.005).
- WT1 overexpression in vitro confirmed the inverse relationship between WT1 and hTERT.
- WT1 modulated hTERT promoter activity by activating negative regulators (SMAD3, JUN, ETS1) and downregulating positive regulators (cMyc, AP-2α, AP-2γ, IRF1, NFX1, GM-CSF).
- ChIP analysis confirmed WT1 binding to the hTERT, cMyc, and SMAD3 promoters.
Conclusions:
- WT1 significantly influences hTERT expression in ccRCC through intricate regulatory pathways.
- These findings highlight the complex interplay between WT1 and hTERT in renal cell carcinoma pathogenesis.
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