title: Regulation of TRAIL receptor expression by β-catenin in colorectal tumours.
abstract: Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of β-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of β-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of β-catenin in colon carcinoma cells, whereas induction of β-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of β-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of β-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) β-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous β-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant β-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant β-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic β-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased β-catenin expression, independently of TCF-4-signalling.
authors.affiliation: Departments of Medical Oncology and.
authors.forename: M
authors.initials: M
authors.lastname: Jalving
authors.forename: D M
authors.initials: DM
authors.lastname: Heijink
authors.forename: J J
authors.initials: JJ
authors.lastname: Koornstra
authors.forename: W
authors.initials: W
authors.lastname: Boersma-van Ek
authors.forename: N
authors.initials: N
authors.lastname: Zwart
authors.forename: J
authors.initials: J
authors.lastname: Wesseling
authors.forename: W J
authors.initials: WJ
authors.lastname: Sluiter
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: J H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: S
authors.initials: S
authors.lastname: de Jong
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011485:Protein Binding; D021381:Protein Transport; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology; D047368:Tumor Burden; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051176:beta Catenin