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J Thorac Cardiovasc Surg 2007;133:74-81
© 2007 The American Association for Thoracic Surgery

General Thoracic Surgery

Selective decrease in the DNA base excision repair pathway in squamous cell cancer of the esophagus

Pramod Bonde, MD, MS, FRCSa,*, Daqing Gao, PhDa,*, Lei Chen, PhDa, Mark Duncan, MDb, Tomoharu Miyashita, MDc, Elizabeth Montgomery, MDc, John W. Harmon, MD, FACSb, Chiming Wei, MD, PhD, FACC, FAHAa,*

a Cardiothoracic-Renal Research Program, Johns Hopkins University School of Medicine, Baltimore, Md
b Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
c Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.

Received for publication April 10, 2005; revisions received May 22, 2006; accepted for publication June 7, 2006.

* Address for reprints: Chiming Wei, MD, PhD, FACC, FAHA, 600 N Wolfe St/Blalock 1206, Johns Hopkins University School of Medicine, Baltimore, MD 21205. (Email: cmwei{at}jhmi.edu).

OBJECTIVES: 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.

CONCLUSION: 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.

Abbreviations and Acronyms AIF = apoptosis inducible factor; BER = base excision repair; DAB = diaminobenzamide tetrahydrochloride; GERD = gastroesophageal reflux disease; MNAN = methyl-n-amyl nitrosamine; OGG1 = 8-oxoguanine DNA glycosylase; 8-oxoG = 8-oxo-7,8-dihydro-2' deoxyguanosine; PARP = poly (adenosine diphosphate–ribose) polymerases; PBS = phosphate-buffered saline; ROS = reactive oxygen species; TUNEL = terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling


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J. Thorac. Cardiovasc. Surg. 2007 133: 81. [Extract] [Full Text] [PDF]





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