ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Pramod Bonde
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bonde, P.
Right arrow Articles by Wei, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bonde, P.
Right arrow Articles by Wei, C.
Related Collections
Right arrow Esophagus - cancer

Ann Thorac Surg 2007;83:433-440
© 2007 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Duodenal Reflux Leads to Down Regulation of DNA Mismatch Repair Pathway in an Animal Model of Esophageal Cancer

Pramod Bonde, MD, MSa, Daqing Gao, PhDa, Lei Chen, PhDa, Tomoharu Miyashita, MDb, Elizabeth Montgomery, MD, PhDb, John W. Harmon, MDc, Chiming Wei, MD, PhDa,*

a Cardiothoracic-Renal Molecular Research Program, Johns Hopkins University School of Medicine, Baltimore, Maryland
b Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
c Department of Surgery, Johns Hopkins Bayview Medical Center, Baltimore, Maryland

Accepted for publication June 28, 2006.

* Address correspondence to Dr Wei, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Blalock 1206, Baltimore, MD 21205 (Email: cmwei{at}jhmi.edu).

Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.

BACKGROUND: Gastroduodenal reflux is implicated in esophageal carcinogenesis. This effect is mediated by reactive oxygen species. We hypothesized that this is mediated by DNA mismatch lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG), which is repaired by the Mut Y homologue (MYH). We tested the effect of reflux, either alone or in combination with the human dietary mutagen methyl-n-amyl nitrosamine (MNAN), on DNA damage in adenocarcinoma and squamous cell cancer of the esophagus in a rat model.

METHODS: Reflux was promoted in male Sprague-Dawley rats by duodenoesophageal anastomosis (8 weeks) without gastric bypass. MNAN treatment (25 mg/kg per week intraperitoneally for four doses) commenced at 10 weeks age. Ten animals served as controls. Quantification of 8-oxoG was performed by using immunohistochemistry, and MYH was analyzed by Western blot. Apoptosis was assessed by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL), cytochrome C, and caspase.

RESULTS: Tumors (adenocarcinoma) developed in 15 (50%) of 30 animals with reflux alone; this increased to 26 (86.6%) of 30 when reflux was combined with MNAN treatment, with tumor histology consistent with adenosquamous and squamous cell cancer. DNA damage, as reflected by positive 8-oxoG staining in reflux groups, was significantly increased compared with control (p < 0.01), and this was maximal in tissues with malignant transformation. Protein levels of the DNA repair enzyme MYH were significantly less in tissues subjected to reflux compared with controls (p < 0.05). TUNEL, cytochrome C, and caspase positivity confirmed increased apoptosis in cancer lesions.

CONCLUSIONS: Gastroduodenal reflux leads to increased DNA damage and downregulation of the DNA mismatch repair pathway. This pathway has an important role in esophageal carcinogenesis in rats.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS
Copyright © 2007 by The Society of Thoracic Surgeons.