DIET AND MOLECULAR GENETICS OF COLONIC CANCER

Project: Research project

Project Details

Description

Novel computer driven scanning and image processing methodology
demonstrated that genetic inheritance of risk for colorectal cancer in
familial polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC)
families is associated with highly pleiotropic affects on patterns of gene
expression in the flat colonic mucosa. Among a panel of cloned sequences
identified which characterize genetic risk, one is the mitochondrial (mt)
encoded gene for the third subunit of mt cytochrome oxidase (COXIII).
Expression was decreased in both progression of, and genetic risk for,
colonic tumors in vivo, and metabolizable, unbranched, short-chain fatty
acids (SCFAs) elevated these depressed levels of mtCOXIII expression, as
well as mtCOXI, in colonic carcinoma cells in culture and also elevated
mtCOX enzymatic activity, while leaving unaffected nuclear encoded
subunits of COX. These changes may underlie the documented alterations in
mitochondria structure and function in transformed colonic epithelial
cells. Since SCFAs produced by fermentation of fiber by colonic
microflora are the principle energy source for colonic epithelial cells,
and since SCFAs also induce colonic epithelial cell differentiation both
in vitro and in vivo, this suggests a mechanistic link between the
molecular events in inherited risk and a dietary factor (fiber) which may
modulate risk.

To understand this relationship between diet and genetic risk, we will: l)
determine SCFA affects on expression of genes on the mtDNA H and L strands
in colonic carcinoma, adenoma and normal epithelial cells; 2) utilize a
unique Utah kindred K353, in which gene carriers have variable penetrance
of a mutation at the FAP locus on chromosome 5q21, to determine the
relationship between the number of tumors which form and mt gene
expression, and the impact of fiber intake in these patients on these two
parameters; 3) determine mechanisms by which SCFAs elevate mt gene
expression, including: the rate constants for mtRNA synthesis and
degredation; structural alterations in the H and L strand bipartite
promotors in tumors and tissue at risk; alterations in function and
covalent modification of the major mt transcription factor mtTF1; and
alterations in the mtTF1 nuclear encoded sequence in colonic tumors.
StatusFinished
Effective start/end date7/21/935/31/94

Funding

  • National Cancer Institute

ASJC

  • Genetics(clinical)
  • Gastroenterology
  • Genetics
  • Cancer Research
  • Histology

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