Abstract 4562: Alteration of mitochondrial proteome in neoplastic progression of ulcerative colitis
Authors: Pan Sheng , Brentnall Teresa A. , Crispin David A. , Bronner Mary P. , Lai Lisa A. , May Damon , McIntosh Martin , Rabinovitch Peter S. , Chen Ru 
Published: February 2011

Abstract
Patients with extensive ulcerative colitis (UC) have an increased risk of colon cancer. Current colonoscopic surveillance of these patients is expensive, time consuming, and invasive. An objective biomarker of dysplasia would aid the clinical management of cancer risk in UC patients. The purpose of this study is to investigate alterations in mitochondrial proteome during UC neoplastic progression to: 1) better understand the underlying mechanisms of neoplastic progression in UC; and 2) employ this knowledge for improved, more cost effective surveillance for UC cancer. Stable isotope labeling and tandem mass spectrometry were used to identify differential mitochondrial proteins associated with UC neoplastic progression. We identified 23, 31 and 32 mitochondrial proteins dysregulated in the colonic epithelium of UC non-progressors (UC patients who do not progress to dysplasia), and the non-dysplastic and dysplastic epithelium of UC progressors (UC patients who have dysplasia/cancer), respectively by at least 1.5-fold change. Nine of the mitochondrial proteins displayed gradually increasing dysregulation from UC non-progressor mucosa to UC progressor non-dysplastic mucosa and finally the worst changes were present in the dysplasia itself. One of the dysregulated mitochondrial proteins, carbamoyl-phosphate synthase 1 (CPS1) was further studied by immunohistochemistry (IHC) analysis. The expression level of CPS1 was significantly higher in UC progressors (in both dysplastic N=9 and non-dysplastic biopsies N=10) than non-progressors (N=29, P&lt;0.003). If the IHC score of 1+ or higher was used as a cutoff, CPS1 could achieve 90% sensitivity and 59% specificity in distinguishing a rectal UC progressor non-dysplastic biopsy from a rectal UC non-progressor biopsy. To further evaluate the mechanism for mitochondrial protein changes in UC, a disease of chronic inflammation, we investigated protein oxidation and carbonylation of the mitochondria during UC neoplastic progression. Carbonyl-modified proteins in UC dysplastic biopsies were enriched using hydrazide-based chemistry and identified by proteomics analysis. We identified 19 carbonylated mitochondrial proteins in UC dysplasia. Several heat shock proteins were among these oxidized mitochondrial proteins. Oxidation of mitochondrial proteins can cause dysfunction of mitochondria, which may in turn contribute to neoplastic progression. In summary, we discovered that mitochondrial proteins are dysregulated in UC neoplastic progression and this is likely caused by chronic oxidation. The mitochondrial proteins become dysregulated early in tumorigenesis, with the changes present in non-dysplastic mucosa of patients with dysplasia. One of these proteins, CPS1, is significantly overexpressed in the normal appearing mucosa of UC progressors and may serve as a biomarker of dysplasia elsewhere in the colon.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4562.