Regulation of TRAIL receptor expression by β-catenin in colorectal tumours

M. Jalving, D. M. Heijink, J. J. Koornstra, W. Boersma-van Ek, N. Zwart, Johannes Wesseling, W. J. Sluiter, E.G.E. de Vries, J. H. Kleibeuker, S. de Jong*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    15 Citations (Scopus)

    Abstract

    Expression of the pro-apoptotic TRAIL receptors is regulated, at least in part, by beta-catenin. We show that beta-catenin co-localizes with DR4/5 in human and mouse colorectal tumours and that downregulation of beta-catenin in cell line models reduces TRAIL receptor expression and TRAIL sensitivity.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 beta-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of beta-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of beta-catenin in colon carcinoma cells, whereas induction of beta-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of beta-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 beta-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) beta-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous beta-catenin staining only (mean: 50 and 70%, respectively, P <0.01 for both). Furthermore, aberrant beta-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant beta-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic beta-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 beta-catenin expression, independently of TCF-4-signalling.

    Original languageEnglish
    Pages (from-to)1092-1099
    Number of pages8
    JournalCARCINOGENESIS
    Volume35
    Issue number5
    DOIs
    Publication statusPublished - May-2014

    Keywords

    • Adenoma
    • Adolescent
    • Adult
    • Aged
    • Aged, 80 and over
    • Carcinoma
    • Cell Line, Tumor
    • Child
    • Colorectal Neoplasms
    • Down-Regulation
    • Female
    • Gene Expression Regulation, Neoplastic
    • Humans
    • Male
    • Middle Aged
    • Neoplasm Grading
    • Neoplasm Staging
    • Protein Binding
    • Protein Transport
    • Receptors, TNF-Related Apoptosis-Inducing Ligand
    • TNF-Related Apoptosis-Inducing Ligand
    • Tumor Burden
    • Young Adult
    • beta Catenin

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