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

9 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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