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F12. Selective Decrease in the DNA Base Excision Repair Pathway in Squamous Cell Cancer of the Esophagus.
Pramod N Bonde, Daquing Gao, Lei Chen, Apoorv Broor, Guy Marti, Mark Ferguson, Mark Duncan, John W Harmon, Chiming Wei; Baltimore, MD
Objective:
Oxidative damage can lead to highly mutagenic 8-Oxoguanine (8-oxoG) lesion, which mispairs with adenosine residues, leading to G:C→T:A transversions. In mammalian cells, 8-oxoguanine glycosylase (OGG1) initiates the DNA Base Excision repair (BER) pathway to repair 8-oxoG lesion. To date there is no information regarding oxidative DNA damage and repair pathways in esophageal cancer. Therefore we designed the current study to demonstrate for the first time the DNA damage and repair pathways in esophageal cancer by expression of OGG1 in reflux and mutagen [methyl-n-amyl nitrosamine, (MNAN)] induced DNA damage and apoptosis in esophageal tumors.
Methods:
Jejuno-esophageal and dudeno-esophageal reflux was surgically created in male Sprague Dawley rats. A half of the animals received MNAN. Non-operated animals served as controls. Experiment concluded 30 weeks post-operatively. Immunohistochemistry for 8-oxoG and OGG1 were assessed by two independent observers. TUNEL assay was used to assess apoptosis.
Results:
There was significantly more DNA damage in both adenocarcinoma (n=15) and squamous cell carcinoma (n=9) as exemplified by positive 8-oxoG compared to control (p<0.05). OGG1 was several folds up regulated in adenocarcinoma (p<0.05). But there was significantly decreased expression in squamous cell carcinoma (p<0.01). The TUNEL showed increased apoptosis in both cancers.
Conclusions:
These results demonstrate the selective decrease in the DNA Base Excision Repair pathway in combined reflux and MNAN induced squamous cell cancer of the esophagus. This can be an attractive target for a gene based therapy in these tumors.
Table 1
|
Control(n=10) |
Adenocarcinoma(n=15) |
Squmous Cell Cancer (n=9) |
| 8-oxoG (% positive nuclei) |
0.5±0.1 |
46±5* |
48±8* |
| OGG1 (0 to 5 scale, 0=absent, 5=maximum) |
2.2±0.6 |
4.6±0.3* |
0.2±0.1*# |
| TUNEL(% positive nuclei) |
0.2±0.1 |
42±6* |
53±8* |
| Mean ±SE, *p<0.05 vs. control; # p<0.01 vs. adenocarcinoma |
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