Abstract
Simple SummaryAberrant Wnt/β-catenin signaling contributes to the development, progression, and metastasis of CRC, by altering target gene expression connected to cancer cell proliferation and motility. S100A4 is a Wnt/β-catenin target gene, which strongly enhances migration and invasion of CRC cells and thus CRC metastasis. Here, we report the transcriptional cross-regulation of S100A4 and the Wnt antagonist DKK1, in which the expression of S100A4 down-regulates DKK1 expression, sustaining activated Wnt signaling. S100A4 is an established prognostic biomarker for CRC patient survival, and the combination of S100A4 and DKK1 can be used to improve the prognosis of overall and metastasis-free survival.Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types. We aimed to identify S100A4-dependent expression alterations to better understand CRC progression and metastasis for improved patient survival. S100A4-induced transcriptome arrays, confirmatory studies in isogenic CRC cell lines with defined β-catenin genotypes, and functional metastasis studies were performed. S100A4-regulated transcriptome examination revealed the transcriptional cross-regulation of metastasis-inducing S100A4 with Wnt pathway antagonist Dickkopf-1 (DKK1). S100A4 overexpression down-regulated DKK1, S100A4 knock-down increased DKK1. Recombinant DKK1 reduced S100A4 expression and S100A4-mediated cell migration. In xenografted mice, systemic S100A4-shRNA application increased intratumoral DKK1. The inverse correlation of S100A4 and DKK1 was confirmed in five independent publicly available CRC expression datasets. Combinatorial analysis of S100A4 and DKK1 in two additional independent CRC patient cohorts improved prognosis of overall and metastasis-free survival. The newly discovered transcriptional cross-regulation of Wnt target S100A4 and Wnt antagonist DKK1 is predominated by an S100A4-induced Wnt signaling feedback loop, increasing cell motility and metastasis risk. S100A4 and DKK1 combination improves the identification of CRC patients at high risk.
Highlights
Colorectal cancer (CRC) is a major cause of cancer death worldwide and in Western countries [1]
We observed an that sustain the pro-metastatic action of S100A4 [5], much less is known about changes in inverse expression pattern of DKK1 in those cells
S100A4 under constitutive active Wnt signaling restored the expression of DKK1 in vitro and in vivo
Summary
Colorectal cancer (CRC) is a major cause of cancer death worldwide and in Western countries [1]. APC truncation distinctly reduces the degradation of β-catenin, which subsequently accumulates in the nucleus and triggers Wnt/β-catenin target gene expression even without upstream activation of the signaling pathway [7,8]. Aberrantly activated Wnt/β-catenin signaling is mediated by gain-of-function mutations in β-catenin itself, which occur in almost 50% of CRC tumors without APC mutations [9]. The majority of gain-of-function mutations (amino acid substitutions or in-frame deletions) within β-catenin occur in exon 3 at a regulatory region (aa32-aa45) for protein phosphorylation and binding of the E3 ubiquitin-protein ligase β-TrCP, which triggers the subsequent proteasomal degradation of β-catenin, resulting in a stabilization of mutated β-catenin in these cells [10]
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