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Combination of Wnt/ß-Catenin Targets S100A4 and DKK1 Improves Prognosis of Human Colorectal Cancer

  1. Author:
    Dahlmann, Mathias [ORCID]
    Monks, Anne
    Harris,Erik
    Kobelt, Dennis
    Osterland, Marc [ORCID]
    Khaireddine, Fadi
    Herrmann, Pia
    Kemmner, Wolfgang
    Burock, Susen
    Walther, Wolfgang
    Shoemaker, Robert H
    Stein, Ulrike [ORCID]

  2. Author Address

    Experimental and Clinical Research Center, a Cooperation between the Charit 233;-Universit 228;tsmedizin Berlin and the Max-Delbr 252;ck-Center for Molecular Medicine in the Helmholtz Association, Lindenberger Weg 80, 13125 Berlin, Germany., Molecular Pharmacology Laboratory, Leidos Biomedical Research, Inc., FNLCR, Frederick, MD 21702, USA., Charit 233; Comprehensive Cancer Center, Charit 233;-Universit 228;tsmedizin Berlin, Corporate Member of Freie Universit 228;t Berlin and Humboldt-Universit 228;t zu Berlin, Invalidenstra 223;e 80, 10117 Berlin, Germany., Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick, Building 440, Frederick, MD 21702, USA., German Cancer Consortium, 69121 Heidelberg, Germany.,
    1. Year: 2021
    2. Date: Dec 22
  2. Journal: Cancers
    1. 14
    2. 1
  4. Type of Article: Article
  1. Abstract:

    Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through ß-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/ß-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 ß-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.

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External Sources

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  2. DOI: 10.3390/cancers14010037
  3. PMID: 35008201
  4. PMCID: PMC8750436
  5. PII : cancers14010037

Library Notes

  1. Open Access Publication
  2. Fiscal Year: FY2021-2022
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