Abstract 1129: Mitochondrial dysfunction precedes tumor progression in ulcerative colitis, but it is restored in advanced dysplasia and cancer

Abstract

Abstract Ulcerative colitis (UC) is an inflammatory disease of the colon that predisposes to colorectal cancer. Dysplasia and cancer arise in pre-cancerous fields of inflammed epithelium, which harbor molecular alterations in spite of histologically normal appearance. We previously demonstrated that these molecular alterations include telomere shortening and the loss of cytochrome C oxidase (COX, Complex IV, subunit I), which is a marker of mitochondrial dysfunction. COX loss was more frequent in UC progressors (patients with dysplasia or cancer) than in UC non progressors (patients without dysplasia). Interestingly, COX expression reappeared in dysplasia and cancer, suggesting that the recovery of mitochondrial function is essential for further tumor progression. We are confirming and extending these preliminary results by: (1) analyzing the expression of additional electron transport chain proteins (complexes II, III, IV subunit II, and IV subunit Va), mitochondrial fusion proteins (Opa1 and Mfn1), and PGC1α, the master regulator of mitochondrial biogenesis; (2) investigating the potential association between mitochondrial abnormalities and telomere shortening; (3) quantifying mitochondrial copy number in areas of COX loss; and (4) validating the original COX results in a second, larger set of UC patients. The expression of mitochondrial proteins was analyzed by immunohistochemistry from serial sections of UC colon. Lightly-fixed paraffin-embedded colon biopsies were used for telomere FISH and laser capture microdissection with subsequent mitochondrial copy number quantification by Q-PCR. A tissue microarray including all grade biopsies from 38 UC non progressors and 37 UC progressors was immunostained with COX to validate the original COX results. The serial staining of the four mitochondrial respiratory proteins showed a striking correlation amongst them and with the original COX pattern: loss early in progression and focal gain in later dysplasia. Interestingly, Opa1, Mfn1, and PGC1α also showed very similar expression patterns. Telomere shortening, however, was not associated with COX loss. Preliminary quantification of mitochondrial copy number indicated that the areas with COX loss had normal amounts of mitochondrial DNA. The analysis of a larger number of biopsies in tissue microarrays confirmed previous findings. In conclusion, our results indicate that a severe loss of mitochondrial components, including all complexes of the respiratory transport chain, occur early in UC progression. That loss is likely to be of epigenetic origin, as it is reversible in later progression. Downregulation of mitochondria biogenesis by PGC1α might be the underlying mechanism, but it is not secondary to telomere shortening and it does not appear to be accompanied by mitochondrial DNA loss. Further experiments are warranted to unveil these intriguing results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1129. doi:1538-7445.AM2012-1129