Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer
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Min Soo Kim1, Won Sung Lee1, Joon Jeong2, Seong-Jin Kim3, Wook Jin1,4
1Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea
2Department of Surgery, Kangnam Severance Hospital, Yonsei University, Kangnam, Seoul 146-92, Korea
3CHA Cancer Institute, CHA University, Seongnam-si, Kyunggi-do 463-400, Korea
4Gachon Medical Research Institute, Gil Medical Center, Gachon University, Incheon 405-760, Korea
Seong-Jin Kim, e-mail: firstname.lastname@example.org
Wook Jin, e-mail: email@example.com
Keywords: TrkB, epithelial-mesenchymal transition (EMT), IL-6/JAK2/STAT3 pathway, PI3K/AKT pathway, metastasis and tumorigenicity
Received: June 27, 2015 Accepted: October 08, 2015 Published: October 20, 2015
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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