Modulation of gene expression as a biomarker in colon.

Computer-driven scanning and image processing methodology has demonstrated that genetic inheritance of risk for colorectal cancer in familial polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) families is associated with highly pleiotropic effects on patterns of gene expression in the flat colonic mucosa. The mitochondrial (mt) gene encoding subunit 3 of cytochrome oxidase (COXIII) is one of a panel of cloned sequences which characterize genetic risk. Expression of COXIII decreased in progression of, and risk for, colonic tumors in vivo. Further, metabolizable, unbranched, short-chain fatty acids (SCFAs) elevated expression of mtCOXIII, as well as mtCOXI, in HT29 cells and also elevated mtCOX enzymatic activity. However, expression of nuclear encoded COX subunits were unaffected. These changes may be related to documented alterations in mitochondria structure and function in transformed colonic epithelial cells. SCFAs produced when colonic microflora causes fermentation of fiber are the principle energy source for normal colonic epithelial cells; SCFAs also induce a more differentiated phenotype both in vitro and in vivo. Therefore, a mechanistic link may exist between molecular events in inherited risk and a dietary factor (fiber) which may modulate such risk. In a preliminary intervention trial in collaboration with M. Lipkin, high risk HNPCC patients received daily supplements of 1500 mg CaCO3 per day, which may be protective for development of colorectal tumors. Elevations in COXIII expression were seen in 7 of 12 patients within the first 7 months, followed by complex changes in expression of this sequence.