We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells, leading to reduced expression of downstream targets (SHP, IBABP) involved in BA homeostasis while increasing the expression of factors (COX-2, c-MYC) that contribute to inflammation and colon cancer.
Patients having either APC missense mutations or b-catenin nuclear accumulation had less frequent COX-2 overexpression (24% vs. 76%, p = 0.043) and more frequent lymph node involvement (75% vs. 38%, p = 0.023).
Positive cytoplasmic HuR immunostaining correlated with high COX-2 immunoreactivity in colon mucosa of FAP patients (p < 0.01) and in sporadic colorectal carcinomas.(p = 0.016)
Increased cyclooxygenase-2 expression in duodenal compared with colonic tissues in familial adenomatous polyposis and relationship to the -765G -> C COX-2 polymorphism.
Effects on NF kappa B and apoptosis were observed irrespective of COX-2 expression, or mutation status in APC, beta-catenin, p53 and DNA MMR genes, underscoring the generality of the aspirin effect on NF kappa B in CRC cells.
Additionally, treatment with COX-2-selective inhibitors reduces polyp burden in animal models of intestinal neoplasia and in humans with familial adenomatous polyposis (FAP).
The clinical use of these agents is limited to patients with familial adenomatous polyposis (FAP), which may benefit from chemopreventive treatment with sulindac or the selective COX-2 inhibitor celecoxib.
Specifically, chemoprevention trials are currently ongoing to evaluate the efficacy of COX-2 inhibitors in the prevention of colorectal cancer in HNPCC and familial adenomatous polyposis patients.
A genetic study using compound mutant mice of COX-2(-)/(-), and Apc(Delta716) which is a model for human familial adenomatous polyposis (FAP), directly demonstrated that induction of COX-2 is critical for intestinal polyp formation.
Over the past decade, in vitro, preclinical, and clinical data have supported the hypothesis that cyclooxygenase (COX)-2 plays a central role in oncogenesis and that treatment with COX-2 inhibitors offers an effective chemoprevention strategy, as exemplified by the activity of celecoxib (Celebrex) in familial adenomatous polyposis.
On the other hand, while COX 1 expression in mononuclear cells was prominent in normal and FAP mucosa, densitometric analysis showed immunoreactive prostaglandin endoperoxide synthase levels were further increased in FAP, due to a greater than fourfold elevation of COX 2 expression among mononuclear cells and epithelia.
Furthermore, PKCbeta, MMP-7, ODC, and COX-2 as well as all RXRs displayed altered expression in apparently healthy FAP mucosa as opposed to that of healthy individuals.