title: RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis.
abstract: Survival of colorectal cancer patients is strongly dependent on development of distant metastases. S100A4 is a prognostic biomarker and inducer for colorectal cancer metastasis. Besides exerting intracellular functions, S100A4 is secreted extracellularly. The receptor for advanced glycation end products (RAGE) is one of its interaction partners. The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer has not been elucidated so far. Here we demonstrate the RAGE-dependent increase in migratory and invasive capabilities of colorectal cancer cells via binding to extracellular S100A4. We show the direct interaction of S100A4 and RAGE, leading to hyperactivated MAPK/ERK and hypoxia signaling. The S100A4-RAGE axis increased cell migration (P<0.005) and invasion (P<0.005), which was counteracted with recombinant soluble RAGE and RAGE-specific antibodies. In colorectal cancer patients, not distantly metastasized at surgery, high RAGE expression in primary tumors correlated with metachronous metastasis, reduced overall (P=0.022) and metastasis-free survival (P=0.021). In summary, interaction of S100A4-RAGE mediates S100A4-induced colorectal cancer cell motility. RAGE by itself represents a biomarker for prognosis of colorectal cancer. Thus, therapeutic approaches targeting RAGE or intervening in S100A4-RAGE-dependent signaling early in tumor progression might represent alternative strategies restricting S100A4-induced colorectal cancer metastasis.
authors: Experimental and Clinical Research Center, Charité University Medicine Berlin and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors: Mathias
authors: M
authors: Dahlmann
authors: Anna
authors: A
authors: Okhrimenko
authors: Patrick
authors: P
authors: Marcinkowski
authors: Marc
authors: M
authors: Osterland
authors: Pia
authors: P
authors: Herrmann
authors: Janice
authors: J
authors: Smith
authors: Claus W
authors: CW
authors: Heizmann
authors: Peter M
authors: PM
authors: Schlag
authors: Ulrike
authors: U
authors: Stein
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: C000593871:AGER protein, human; D014408:Biomarkers, Tumor; D000067759:Receptor for Advanced Glycation End Products; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human