Abstract
Aberrantly activated Wnt signaling causes cellular transformation that can lead to human colorectal cancer. Wnt signaling is mediated by Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) DNA-binding factors. Here we investigate whether altered LEF/TCF expression is conserved in human colorectal tumor sample and may potentially be correlated with indicators of cancer progression. We carried out a meta-analysis of carefully selected publicly available gene expression data sets with paired tumor biopsy and adjacent matched normal tissues from colorectal cancer patients. Our meta-analysis confirms that among the four human LEF/TCF genes, LEF1 and TCF7 are preferentially expressed in tumor biopsies, while TCF7L2 and TCF7L1 in normal control tissue. We also confirm positive correlation of LEF1 and TCF7 expression with hallmarks of active Wnt signaling (i.e., AXIN2 and LGR5). We are able to correlate differential LEF/TCF gene expression with distinct transcriptomes associated with cell adhesion, extracellular matrix organization, and Wnt receptor feedback regulation. We demonstrate here in human colorectal tumor sample correlation of altered LEF/TCF gene expression with quantitatively and qualitatively different transcriptomes, suggesting LEF/TCF-specific transcriptional regulation of Wnt target genes relevant for cancer progression and survival. This bioinformatics analysis provides a foundation for future more detailed, functional, and molecular analyses aimed at dissecting such functional differences.
Highlights
Wnt signaling functions in normal development and stem-cell-mediated homeostasis; and in the etiology of disease, such as cancer [1,2]
We carefully reviewed publicly available transcriptomics datasets of human colorectal cancer samples
Our meta-analysis reveals that AXIN2 (Figure 2E) is consistently expressed at a higher level in tumor relative to normal tissue, and so is LGR5 (Figure 2H), indicating as expected increased
Summary
Wnt signaling functions in normal development and stem-cell-mediated homeostasis; and in the etiology of disease, such as cancer [1,2]. The best understood Wnt signaling mechanism is a nuclear β-catenin-mediated signal transduction pathway regulating transcriptional gene expression [3]. Wnt pathway-promoted nuclear β-catenin proteins regulate transcription indirectly by binding to and altering multi-protein complexes associated with sequence-specific DNA binding factors, predominantly of the Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) protein family [4,5]. Humans have four genes encoding LEF/TCF proteins, similar to other mammals and most vertebrates [6,7]. With little or without nuclear β-catenin protein, LEF/TCF proteins mostly mediate transcriptional. With increased nuclear β-catenin levels, LEF/TCF proteins generally mediate transcriptional activation [8]
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