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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
Frequent inactivation of RUNX3 in endometrial carcinoma
Tatsuo Yoshizaki1, Takayuki Enomoto, Masami Fujita
1Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, Suita, Osaka, Japan.
Objective:
Our objective was to determine whether RUNX3 tumor suppressor is inactivated in endometrial carcinoma.
Methods:
We have investigated 24 endometrial carcinomas, 3 endometrial carcinoma cell lines, and 9 normal endometria for genetic and epigenetic alterations of RUNX3. Reverse-transcription PCR (RT-PCR), methylation-specific PCR (MS-PCR) analysis, and loss of heterozygosity (LOH) analysis were performed. We also tested RUNX3 protein expression by immunohistochemistry.
Results:
Using RT-PCR technique, we observed a significant loss of RUNX3 mRNA expression in nine of 24 endometrial carcinomas (38%) and in all 3-cell lines (100%). In contrast, all nine of the normal endometria showed an abundant expression of RUNX3 mRNA. Methylation-specific PCR (MS-PCR) analysis of the CpG islands of RUNX3 showed the promoter region to be hypermethylated in 18 of 21 analyzed carcinomas (86%), whereas only two of nine normal endometria (22%) were methylated (p<0.01). By using two polymorphic microsatellite markers, D1S199 and D1S1676, we detected 1p36 LOH in 7 of 21 carcinomas (33%). We observed a significant relationship between the loss of RUNX3 mRNA expression and this regional LOH (p<0.01). Immunohistochemical staining showed that RUNX3 protein expression was lost in 12 of 21 endometrial carcinomas (57%). We observed a significantly more frequent loss of RUNX3 protein expression in the histologically higher-grade tumors (Grade 3) than in Grade 1 or 2 tumors (p<0.01).
Conclusion:
These findings indicate that RUNX3 inactivation may play an important role in carcinogenesis of the endometrium, especially in high-grade endometrial carcinoma.
Insights
RUNX3 tumor suppressor inactivation, through genetic and epigenetic changes, is common in endometrial carcinoma. This loss of RUNX3 is particularly prevalent in high-grade tumors, suggesting its role in endometrial cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RUNX3 is a known tumor suppressor gene.
- Its role in endometrial carcinoma is not well understood.
Purpose of the Study:
- To investigate the inactivation of the RUNX3 tumor suppressor in endometrial carcinoma.
- To identify the mechanisms of RUNX3 inactivation, including genetic and epigenetic alterations.
Main Methods:
- Analysis of RUNX3 in 24 endometrial carcinomas, 3 cell lines, and 9 normal endometria.
- Utilized reverse-transcription PCR (RT-PCR) for mRNA expression, methylation-specific PCR (MS-PCR) for promoter methylation, and loss of heterozygosity (LOH) analysis.
- Immunohistochemistry was used to assess RUNX3 protein expression.
Main Results:
- Loss of RUNX3 mRNA expression was observed in 38% of carcinomas and 100% of cell lines.
- Hypermethylation of the RUNX3 promoter was found in 86% of carcinomas.
- Loss of RUNX3 protein expression occurred in 57% of carcinomas, significantly higher in high-grade tumors.
Conclusions:
- RUNX3 inactivation, via genetic and epigenetic alterations, is a significant event in endometrial carcinogenesis.
- RUNX3 inactivation appears to be particularly important in the development of high-grade endometrial carcinoma.
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