Colon cancer is the second leading cause of cancer deaths in the U.S. There are about 57,000 deaths from colorectal cancer per year in the U.S. and about half a million deaths worldwide. Since the cure rate for metastatic colon cancer is less than 50%, early diagnosis and the identification of patients at high risk for colon cancer is of paramount importance. The identification of biomarkers that are both specific and sensitive is crucially needed to target individuals for either more frequent colonoscopies, recommendations for lifestyle changes and/or chemopreventive strategies. Our preliminary data indicates that we may have identified cytochrome c oxidase subunit I (CcOl) as such a biomarker. We found a generalized loss of CcOl expression in many of the colonic crypts of patients with colon cancer in a pilot study. In addition, we observed a dramatic crypt-restricted loss (CRL) of CcOl immunostaining, which has not been previously described. The cause of this CRL of CcOl expression is not known, but may be caused by specific mutations in mitochondrial DMA (mtDNA). Therefore, our long-term objective is to develop the loss of CcOl protein expression [assessed using either 1) the frequency of CRL by immunohistochemistry or 2) the reverse phase protein array (RPPA) quantitative assay] as an early, sensitive and specific hypothesis-driven biomarker of cancer risk on an individual basis. This proposal has the following 3 specific aims:1) To determine if an assessment of decreased CcOl protein expression could be developed as a sensitive and specific biomarker of colon cancer risk; 2) To determine if the decreased protein expression and """"""""crypt-restricted loss"""""""" of CcOl is associated with mitochondrial mutations in the CcOl gene using the combined techniques of laser capture microdissection, PCR and temporal temperature gradient gel electrophoresis (TTGE); 3) To determine if deoxycholate induces mtDNA damage and mutations in CcOl in vitro using cultured colon epithelial cell lines. Various molecular and cellular techniques will be used in these studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Cancer Biomarkers Study Section (CBSS)
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Wagner, Paul D
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University of Arizona
Anatomy/Cell Biology
Schools of Medicine
United States
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Bernstein, Harris; Bernstein, Carol; Payne, Claire M et al. (2009) Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol 15:3329-40
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Bernstein, Harris; Holubec, Hana; Bernstein, Carol et al. (2007) Deoxycholate-induced colitis is markedly attenuated in Nos2 knockout mice in association with modulation of gene expression profiles. Dig Dis Sci 52:628-42
Payne, C M; Weber, C; Crowley-Skillicorn, C et al. (2007) Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis 28:215-22
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