Early modulation of gene expression used as a biomarker for chemoprevention in a preclinical model of colon carcinogenesis.
By using the rat azoxymethane (AOM)-induced colon carcinogenesis model, which mirrors many clinical features of human colorectal cancer, we examined whether genetic changes occurring early in colonic mucosa are predictive of treatment efficacy. In the present study the administration of the chemopreventive agent lupulone over the course of 7 weeks postinitiation reduced the number of preneoplastic lesions in the colonic mucosa by 50%. At the molecular level we observed the downregulation of genes involved in the inflammatory response, including IL-1β and TNF-α, and of matrix metalloproteinase-7 gene and protein expression. We also observed a substantial upregulation of components of the innate immune system, α-defensin-5 and lipocalin 2. Lupulone induced the expression of apoptosis-related genes and caused a reversal of the B-cell lymphoma/leukemia 2 (Bcl-2; antiapoptotic) to Bcl-2 associated X protein (Bax; proapoptotic) transcript and protein ratios (Bcl-2/Bax > 1 in AOM controls and Bcl-2/Bax < 1 in lupulone-treated AOM rats). Here, we identify several target genes that could be considered early biomarkers of colon carcinogenesis and indicative of drug efficacy.
University of Strasbourg, Unit EA4438, Laboratory of Nutritional Cancer Prevention, IRCAD-EITS, Strasbourg, France.
Souad
S
Bousserouel
Virginie
V
Lamy
Francine
F
Gossé
Annelise
A
Lobstein
Jacques
J
Marescaux
Francis
F
Raul
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007249:Inflammation / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000494:pharmacology
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D013729:Terpenes; C008299:lupulon