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Loss of disabled-2 expression is an early event in esophageal squamous tumorigenesis
Kumar Anupam1, Chatopadhyay Tusharkant, Siddhartha Datta Gupta
1Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
Aim:
Disabled-2 (DAB2) is a candidate tumor-suppressor gene identified in ovarian cancer that negatively influences mitogenic signal transduction of growth factors and blocks ras activity. In a recent study, we observed down-regulation of DAB2 transcripts in ESCCs using cDNA microarrays. In the present study, we aimed to determine the clinical significance of loss of DAB2 protein in esophageal tumorigenesis, hypothesizing that DAB2 promoter hypermethylation-mediated gene silencing may account for loss of the protein.
Methods:
DAB2 expression was analyzed by immunohistochemistry in 50 primary esophageal squamous cell carcinomas (ESCCs), 30 distinct hyperplasia, 15 dysplasia and 10 non-malignant esophageal tissues. To determine whether promoter hypermethylation contributes to loss of DAB2 expression in ESCCs, methylation status of DAB2 promoter was analyzed in DAB2 immuno-negative tumors using methylation-specific PCR.
Results:
Loss of DAB2 protein was observed in 5/30 (17%) hyperplasia, 10/15 (67%) dysplasia and 34/50 (68%) ESCCs. Significant loss of DAB2 protein was observed from esophageal normal mucosa to hyperplasia, dysplasia and invasive cancer (P(trend) < 0.001). Promoter hypermethylation of DAB2 was observed in 2 of 10 (20%) DAB2 immuno-negative ESCCs.
Conclusion:
Loss of DAB2 protein expression occurs in early pre-neoplastic stages of development of esophageal cancer and is sustained down the tumorigenic pathway. Infrequent DAB2 promoter methylation in ESCCs suggests that epigenetic gene silencing is only one of the mechanisms causing loss of DAB2 expression in ESCCs.
Insights
Loss of Disabled-2 (DAB2) protein occurs early in esophageal cancer development and persists through tumorigenesis. While promoter hypermethylation is implicated, it
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Disabled-2 (DAB2) is a candidate tumor suppressor gene.
- DAB2 negatively influences growth factor signaling and blocks ras activity.
- Previous studies observed reduced DAB2 transcripts in esophageal squamous cell carcinoma (ESCC).
Purpose of the Study:
- To investigate the clinical significance of DAB2 protein loss in esophageal tumorigenesis.
- To determine if DAB2 promoter hypermethylation causes gene silencing and protein loss in ESCC.
- To analyze the role of DAB2 in the progression of esophageal cancer.
Main Methods:
- Immunohistochemistry used to assess DAB2 protein expression in 50 ESCCs, 30 hyperplasias, 15 dysplasias, and 10 normal esophageal tissues.
- Methylation-specific PCR performed on DAB2-negative tumors to analyze DAB2 promoter methylation status.
- Statistical analysis to determine the trend of DAB2 loss across different stages of esophageal tissue.
Main Results:
- DAB2 protein loss was observed in 17% of hyperplasia, 67% of dysplasia, and 68% of ESCCs.
- A significant decrease in DAB2 protein expression was noted from normal mucosa to invasive cancer (P < 0.001).
- DAB2 promoter hypermethylation was detected in 20% of DAB2-immuno-negative ESCCs.
Conclusions:
- Loss of DAB2 protein expression is an early event in esophageal tumorigenesis and is maintained throughout cancer progression.
- Epigenetic silencing via promoter methylation is one, but not the sole, mechanism for DAB2 loss in ESCC.
- DAB2 protein downregulation is a significant event in the development of esophageal squamous cell carcinoma.
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