Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2014; 20(45): 17037-17048
Published online Dec 7, 2014. doi: 10.3748/wjg.v20.i45.17037
Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer
Ru Chen, Sheng Pan, Keith Lai, Lisa A Lai, David A Crispin, Mary P Bronner, Teresa A Brentnall
Ru Chen, Sheng Pan, Lisa A Lai, David A Crispin, Teresa A Brentnall, Department of Medicine, University of Washington, Seattle, WA 98195, United States
Keith Lai, Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
Mary P Bronner, Division of Anatomic Pathology, University of Utah, Salt Lake City, UT 84108, United States
Author contributions: Chen R, Pan S and Brentnall TA designed the research; Lai LA and Crispin DA performed the experiments; Chen R, Pan S, Lai K, Bronner MP and Brentnall TA analyzed the data; Chen R, Pan S, Lai LA and Brentnall TA wrote the manuscript; Bronner MP and Brentnall TA contributed equally to this manuscript.
Supported by Grants from National Institutes of Health, No. R21CA164548; and from Crohn’s and Colitis Foundation of America
Correspondence to: Ru Chen, PhD, Department of Medicine, University of Washington, Schmitz Hall, Box 355840, Seattle, WA 98195, United States. ruchen@u.washington.edu
Telephone: +1-206-2214109 Fax: +1-206-6859478
Received: November 28, 2013
Revised: February 21, 2014
Accepted: April 2, 2014
Published online: December 7, 2014
Abstract

AIM: To characterize tumor necrosis factor receptor-associated protein 1 (TRAP1) expression in the progression of ulcerative colitis (UC)-associated colorectal cancer.

METHODS: Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer. Immunohistochemical analysis was used to evaluate TRAP1 expression on tissue microarrays containing colonic tissues from 42 UC progressors (patients with cancer or dysplasia) and 38 non-progressors (dysplasia/cancer free patients). Statistical analyses of the TRAP1 immunohistochemistry staining were performed using GraphPad Prism. Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test. Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.

RESULTS: TRAP1 was up-regulated in the colon tissues from UC progressors, but not in the colon tissues from UC non-progressors. Moreover, up-regulation of TRAP1 preceded the neoplastic changes: it was present in both the dysplastic and non-dysplastic tissues of UC progressors. When TRAP1 staining in rectal tissue was used as a diagnostic marker, it could distinguish progressors from non-progressors with 59% sensitivity and 80% specificity. Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues, which could be related to the increased oxidation present in the colonic mucosa from UC progressors. We then investigated the cellular proteome changes underlying oxidative stress, and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.

CONCLUSION: These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1, which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis. TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.

Keywords: Ulcerative colitis, Colorectal cancer, Inflammation, Oxidative stress, Tumor necrosis factor receptor-associated protein 1

Core tip: Chronic ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer. Our study showed that up-regulation of tumor necrosis factor receptor-associated protein 1 (TRAP1) occurred early in the neoplastic progression of UC associated cancer: it was present in both the dysplastic and non-dysplastic tissues of UC progressors. Our study further showed that the increase of TRAP1 expression in UC progressors positively correlated with the degree of inflammation in the colorectal cancer tissues, which could be related to the increased oxidation present in the colonic mucosa from UC progressors. TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.