Selective decrease in the DNA base excision repair pathway in squamous cell cancer of the esophagus.
OBJECTIVE
Oxidative damage can lead to a highly mutagenic 8-oxoguanine lesion, which mispairs with adenosine residues, leading to G:C-->T:A transversions. In mammalian cells 8-oxoguanine glycosylase initiates the DNA base excision repair pathway to repair the 8-oxoguanine 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 the DNA damage and repair pathways in esophageal cancer by expression of 8-oxoguanine glycosylase in reflux-induced and mutagen (methyl-n-amyl nitrosamine)-induced DNA damage and apoptosis in esophageal tumors.


METHODS
Gastroduodenal reflux was surgically created in male Sprague Dawley rats (n = 120). Half of the animals received methyl-n-amyl nitrosamine. Animals not undergoing operations served as control animals (n = 10). The experiment concluded 30 weeks postoperatively. Immunohistochemistry for 8-oxoguanine and 8-oxoguanine glycosylase was assessed by 2 independent observers. Protein expression was assessed by using the Western blot method.


RESULTS
There was significantly more DNA damage in both adenocarcinoma (n = 15) and squamous cell carcinoma (n = 19), as exemplified by positive 8-oxoguanine expression compared with that seen in control animals (P < .05). 8-Oxoguanine glycosylase was several folds upregulated in adenocarcinoma (P < .05), but there was significantly decreased expression in squamous cell carcinoma (P < .01). The apoptosis was assessed as caspase-dependent and caspase-independent pathways, and both were active and correlated well with 8-oxoguanine expression.


CONCLUSIONS
These results demonstrate the selective decrease in the DNA base excision repair pathway in combined reflux and methyl-n-amyl nitrosamine-induced squamous cell cancer of the esophagus.
Bonde
Pramod
P
Cardiothoracic-Renal Research Program, Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA.
Gao
Daqing
D
Chen
Lei
L
Duncan
Mark
M
Miyashita
Tomoharu
T
Montgomery
Elizabeth
E
Harmon
John W
JW
Wei
Chiming
C
D000230:Adenocarcinoma / Q000235:genetics; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001471:Barrett Esophagus / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004941:Esophagitis / Q000150:complications / Q000235:genetics / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000235:genetics / Q000473:pathology; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009602:Nitrosamines; D010212:Papilloma / Q000150:complications / Q000235:genetics / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D051033:Apoptosis Inducing Factor; D002273:Carcinogens; D009602:Nitrosamines; D006151:Guanosine; C025033:N-amyl-N-methylnitrosamine; C046215:8-hydroxyguanosine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D053148:Caspase 3