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An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 2, 2013
RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors
Wun-Jae Kim1, Eun-Jung Kim, Pildu Jeong
1Department of Urology , College of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju, South Korea. wjkim@chungbuk.ac.kr
Abstract:
RUNX3 is inactivated at high frequency in many tumors. However, in most cases, inactivation is caused by silencing of the gene due to promoter hypermethylation. Because epigenetic silencing is known to affect many major tumor suppressor genes in cancer cells, it is not clear whether RUNX3 is primarily responsible for the induction of carcinogenesis in these cases, except for the gastric cancer cases that we reported previously. We investigated genetic and epigenetic alterations of RUNX3 in 124 bladder tumor cases and seven bladder tumor-derived cell lines. Here we show that RUNX3 is inactivated by aberrant DNA methylation in 73% (90 of 124) of primary bladder tumor specimens and 86% (six of seven) of bladder tumor cell lines. In contrast, the promoter regions of 20 normal bladder mucosae were unmethylated. Importantly, one patient bore missense mutations, each of which resulted in amino acid substitutions in the highly conserved Runt domain. The mutations abolished the DNA-binding ability of RUNX3. A second patient had a single nucleotide deletion within the Runt domain coding region that resulted in truncation of the protein. RUNX3 methylation was a significant risk factor for bladder tumor development, superficial bladder tumor recurrence, and subsequent tumor progression. These results strongly suggest that inactivation of RUNX3 may contribute to bladder tumor development and that promoter methylation and silencing of RUNX3 could be useful prognostic markers for both bladder tumor recurrence and progression.
Insights
RUNX3 (Runt-related transcription factor 3) inactivation, primarily through promoter hypermethylation, is frequent in bladder tumors. This epigenetic silencing significantly contributes to bladder cancer development and progression, serving as a potential prognostic marker.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- RUNX3 (Runt-related transcription factor 3) is a known tumor suppressor gene frequently inactivated in various cancers.
- Epigenetic silencing via promoter hypermethylation is a common mechanism for tumor suppressor gene inactivation in cancer cells.
- Previous research highlighted RUNX3's role in gastric cancer, but its specific involvement in bladder carcinogenesis remained unclear.
Purpose of the Study:
- To investigate the frequency and mechanisms of RUNX3 genetic and epigenetic alterations in bladder tumors.
- To determine the correlation between RUNX3 inactivation and bladder tumor development, recurrence, and progression.
- To evaluate RUNX3 promoter methylation as a potential prognostic biomarker for bladder cancer.
Main Methods:
- Analysis of genetic and epigenetic alterations (DNA methylation, mutations) of the RUNX3 gene in 124 primary bladder tumors and 7 bladder tumor-derived cell lines.
- Comparison of RUNX3 methylation status between tumor specimens and 20 normal bladder mucosa samples.
- Assessment of the functional impact of identified RUNX3 mutations on DNA-binding ability.
Main Results:
- RUNX3 was aberrantly methylated and silenced in 73% of primary bladder tumors and 86% of cell lines, with normal tissues showing no methylation.
- Missense mutations and a single nucleotide deletion within the Runt domain were identified in two patients, abolishing RUNX3's DNA-binding function.
- RUNX3 methylation was significantly associated with increased risk of bladder tumor development, recurrence, and progression.
Conclusions:
- RUNX3 inactivation, predominantly through promoter hypermethylation, plays a critical role in bladder tumor development.
- RUNX3 alterations, particularly promoter methylation, are significant risk factors for bladder tumor recurrence and progression.
- RUNX3 promoter methylation serves as a promising prognostic marker for bladder cancer patients.
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