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Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer

 Min Soo Kim l Won Sung Lee  ;  Joon Jeong  ;  Seong-Jin Kim  ;  Wook Jin 
 ONCOTARGET , Vol.6(37) : 40158-40171, 2015 
Journal Title
Issue Date
Animals ; Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism* ; Breast Neoplasms/therapy ; Cell Line ; Cell Line, Tumor ; Dogs ; Gene Expression Regulation, Neoplastic/drug effects ; HEK293 Cells ; Humans ; Interleukin-6/genetics ; Interleukin-6/metabolism* ; Interleukin-6/pharmacology ; Janus Kinase 2/genetics ; Janus Kinase 2/metabolism* ; Madin Darby Canine Kidney Cells ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism* ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism* ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism* ; RNA Interference ; RNAi Therapeutics/methods ; Receptor, trkB ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism* ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Twist-Related Protein 1/genetics ; Twist-Related Protein 1/metabolism ; Xenograft Model Antitumor Assays/methods
IL-6/JAK2/STAT3 pathway ; PI3K/AKT pathway ; TrkB ; epithelial-mesenchymal transition (EMT) ; metastasis and tumorigenicity
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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
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