Abstract
DC-SIGN is previously focused on its physiologic and pathophysiologic roles in immune cells. Little is known about whether DC-SIGN is expressed in malignant epithelial cells and how DC-SIGN participates in tumor progression. Here we showed that DC-SIGN expression was increased in metastatic colorectal cancer (CRC) cell lines and patient tissues. The overall survival in CRC patients with positive DC-SIGN was remarkably reduced. Gain of DC-SIGN function facilitated the CRC metastases both in vitro and in vivo, and this effect was reversed by miR-185. DC-SIGN and Lyn interacted physically, and Lyn maintained the stability of DC-SIGN in cells. DC-SIGN activation recruited Lyn and p85 to form the DC-SIGN-Lyn-p85 complex, which promoted CRC metastasis by increasing PI3K/Akt/β-catenin signaling in tyrosine kinase Lyn-dependent manner. Furthermore, activation of DC-SIGN promoted the transcription of MMP-9 and VEGF by increasing PI3K/Akt/β-catenin signaling, and induced TCF1/LEF1-mediated suppression of miR-185. Our findings reveal the presence of the DC-SIGN-TCF1/LEF1-miR-185 loop in cancer cells with metastatic traits, implying that it may represent a new pathogenic mechanism of CRC metastasis. This character of the loop promises to provide new targets for blocking CRC invasive and metastatic activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Adhesion Molecules / physiology
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Cell Line, Tumor
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / pathology
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Feedback, Physiological
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Gene Expression Regulation, Neoplastic
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Hepatocyte Nuclear Factor 1-alpha / metabolism
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Humans
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism*
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Lectins, C-Type / physiology
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Lymphoid Enhancer-Binding Factor 1 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Phosphatidylinositol 3-Kinases / metabolism
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Prognosis
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Receptors, Cell Surface / physiology
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Signal Transduction
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Vascular Endothelial Growth Factor A / metabolism
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beta Catenin / metabolism
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src-Family Kinases / metabolism
Substances
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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HNF1A protein, human
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Hepatocyte Nuclear Factor 1-alpha
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LEF1 protein, human
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Lectins, C-Type
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Lymphoid Enhancer-Binding Factor 1
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MIRN185 microRNA, human
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MicroRNAs
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Receptors, Cell Surface
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Vascular Endothelial Growth Factor A
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beta Catenin
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lyn protein-tyrosine kinase
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src-Family Kinases
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Proto-Oncogene Proteins c-akt
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Matrix Metalloproteinase 9