title: The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the β-catenin signaling pathway.
abstract: Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (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/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of β-catenin and target genes Cox2, cyclin D1 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 ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 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.
authors.affiliation: Institute of Pathology, Ruhr-University Bochum, D-44789, Germany. johanna.munding@rub.de
authors.forename: Johanna
authors.initials: J
authors.lastname: Munding
authors.forename: Wibke
authors.initials: W
authors.lastname: Ziebarth
authors.forename: Christian P
authors.initials: CP
authors.lastname: Pox
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ladigan
authors.forename: Markus
authors.initials: M
authors.lastname: Reiser
authors.forename: Dietrich
authors.initials: D
authors.lastname: Hüppe
authors.forename: Linda
authors.initials: L
authors.lastname: Brand
authors.forename: Wolff
authors.initials: W
authors.lastname: Schmiegel
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.forename: Anke C
authors.initials: AC
authors.lastname: Reinacher-Schick
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000517:prevention & control; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D019938:Cyclin D1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D019804:Mesalamine / Q000494:pharmacology* / Q000627:therapeutic use; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; D015820:Cadherins; D051820:TCF Transcription Factors; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D019804:Mesalamine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D009955:Ornithine Decarboxylase