Abstract
The acquisition of inappropriate migratory feature is crucial for tumor metastasis. It has been suggested that CD147 and Annexin A2 are involved in regulating tumor cell movement, while the regulatory mechanisms are far from clear. In this study, we demonstrated that CD147 physically interacted with the N-terminal domain of Annexin A2 and decreased Annexin A2 phosphorylation on tyrosine 23. In vitro kinase assay showed that the I domain of CD147 was indispensable for CD147-mediated downregulation of Annexin A2 phosphorylation by Src. Furthermore, we determined that p-Annexin A2 promoted the expression of dedicator of cytokinesis 3 (DOCK3) and DOCK3 blocked β-catenin nuclear translocation, resulting in inhibition of β-catenin signaling. In addition, DOCK3 inhibited lamellipodium dynamics and tumor cell movement. Also, we found that β-catenin signaling increased WAVE2 expression. Therefore, DOCK3 was characterized as a negative regulator of WAVE2 expression via inhibiting β-catenin signaling. Our study provides the first evidence that CD147 promotes tumor cell movement and metastasis via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling axis.
Keywords:
Annexin A2; CD147; DOCK3; WAVE2; cell movement.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Annexin A2 / antagonists & inhibitors
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Annexin A2 / genetics
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Annexin A2 / metabolism*
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Apoptosis
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Basigin / chemistry
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Basigin / genetics
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Basigin / metabolism*
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Blotting, Western
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / secondary*
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Cell Movement*
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Cell Proliferation
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Fluorescent Antibody Technique
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Gene Expression Regulation, Neoplastic
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Guanine Nucleotide Exchange Factors / antagonists & inhibitors
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Phosphorylation
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Surface Plasmon Resonance
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Tumor Cells, Cultured
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Wiskott-Aldrich Syndrome Protein Family / antagonists & inhibitors
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Wiskott-Aldrich Syndrome Protein Family / genetics
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Wiskott-Aldrich Syndrome Protein Family / metabolism*
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Xenograft Model Antitumor Assays
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beta Catenin / antagonists & inhibitors
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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ANXA2 protein, human
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Annexin A2
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BSG protein, human
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CTNNB1 protein, human
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DOCK3 protein, human
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Guanine Nucleotide Exchange Factors
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Nerve Tissue Proteins
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RNA, Messenger
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RNA, Small Interfering
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WASF2 protein, human
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Wiskott-Aldrich Syndrome Protein Family
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beta Catenin
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Basigin