The influence of 5-Aminosalicylic acid on the progression of colorectal adenomas via the ß-catenin signaling pathway
Menée à partir de cellules épithéliales cancéreuses du côlon et de 227 polypes colorectaux prélevés sur 56 patients traités pendant 3 ans avec l'acide 5-aminosalicylique, cette étude évalue l'effet de l'acide 5-aminosalicylique sur la voie de signalisation Wnt/béta-caténine dans la chimioprévention d'un adénome du côlon et suggère l'utilisation de cette molécule pour prévenir un carcinome colorectal sporadique
Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-ASA (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients.The current study analyses the effect of 5-ASA on Wnt/β-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a β-catenin/TCF-reporter assay and by western blotting in cultured colon cancer cells. FFPE material from 227 polyps removed from a subgroup of 56 patients who participated in a randomized placebo-controlled three-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclinD1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low risk and a high risk group according to the number of adenomas at initial colonoscopy.ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in b-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localisation in patients’ adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclinD1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment.Our study shows a significant in vitro and long term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.
http://carcin.oxfordjournals.org/content/early/2011/12/22/carcin.bgr306.abstract