Abstract
In metastatic breast cancers, the acquisition of metastatic ability, which leads to clinically incurable disease and poor survival, has been associated with acquisition of epithelial-mesenchymal transition (EMT) program and self-renewing trait (CSCs) via activation of PI3K/AKT and IL6/JAK2/STAT3 signaling pathways. We found that TrkB is a key regulator of PI3K/AKT and JAK/STAT signal pathway-mediated tumor metastasis and EMT program. Here, we demonstrated that TrkB activates AKT by directly binding to c-Src, leading to increased proliferation. Also, TrkB increases Twist-1 and Twist-2 expression through activation of JAK2/STAT3 by inducing c-Src-JAK2 complex formation. Furthermore, TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3-mediated JAK2 degradation, resulting in increased total JAK2 and STAT3 levels, which subsequently leads to JAK2/STAT3 activation and Twist-1 upregulation. Additionally, activation of the JAK2/STAT3 pathway via induction of IL-6 secretion by TrkB enables induction of activation of the EMT program via induction of STAT3 nuclear translocation. These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program and self-renewing trait in breast cancer.
Keywords:
IL-6/JAK2/STAT3 pathway; PI3K/AKT pathway; TrkB; epithelial-mesenchymal transition (EMT); metastasis and tumorigenicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / therapy
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Cell Line
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Cell Line, Tumor
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Dogs
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Gene Expression Regulation, Neoplastic / drug effects
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HEK293 Cells
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism*
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Madin Darby Canine Kidney Cells
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Metastasis
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA Interference
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RNAi Therapeutics / methods
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Receptor, trkB
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Twist-Related Protein 1 / genetics
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Twist-Related Protein 1 / metabolism
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Xenograft Model Antitumor Assays / methods
Substances
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Interleukin-6
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Membrane Glycoproteins
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STAT3 Transcription Factor
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Twist-Related Protein 1
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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Receptor, trkB
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tropomyosin-related kinase-B, human
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JAK2 protein, human
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Janus Kinase 2
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Proto-Oncogene Proteins c-akt