MUCIN GENES AND COLONIC CELL TRANSFORMATION

Project: Research project

Project Details

Description

To develop better strategies for differentiation therapy for colonic
cancer, mechanisms which generate lineages of differentiation and their
relationship to mechanisms of transformation must be understood. In
colonic cancer, mucinous tumors provide a superb clinical entity in
which to investigate this question: though uncommon, the incidence is
still greater than 15,000 new cases per year. Further, the tumor is
characterized by the vast overexpression of a product similar to that
which characterizes the lineages of normal goblet cell differentiation,
and yet the prognosis foe patients with these tumors is poor. Thus,
understanding the mucin and the mechanisms of deregulation of its
synthesis in such tumors, and the link to increased aggressiveness and
poor prognosis, will provide significant insight into the relationship
of differentiation mechanisms to tumorigenesis and tumor behavior.

We have demonstrated that mucinous tumors differ fundamentally from
common moderately to well-differentiated colon tumors: they exhibit a
small but frequent amplification of the c-myc gene and enormously
overexpress a gene for a colonic mucin, a sequence which we have
demonstrated can be regulated by TPA and forskolin in culture. They also
have a lower frequency of 17P (the p53 gene) deletions (Kern et al,
1989). In this project, we will complete cloning, mapping and sequencing
of a mucin core peptide and a link peptide gene; will determine whether
these genes are structurally altered in mucinous tumors and tumor cell
lines, and if so, define this structural alteration and identify other
genes involved; and proceed to identify cis and possibly other
regulatory sequences involved in mucin gene expression, and potential
differences in these sequences in mucinous colonic tumors and cell lines
as compared to normal tissue and non-mucin producing colonic cell lines
and tumors. Having accomplished this, we will then be in a position to
continue to dissect regulatory elements which lead to the vast
constitutive overexpression of at least the core peptide gene in
mucinous tumors.
StatusFinished
Effective start/end date2/12/921/31/93

Funding

  • National Cancer Institute

ASJC

  • Gastroenterology
  • Genetics
  • Molecular Biology
  • Cancer Research
  • Pathology and Forensic Medicine

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