Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer
- Authors
- Kim, Min Soo; Lee, Won Sung; Jeong, Joon; Kim, Seong-Jin; Jin, Wook
- Issue Date
- 24-Nov-2015
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- TrkB; epithelial-mesenchymal transition (EMT); IL-6/JAK2/STAT3 pathway; PI3K/AKT pathway; metastasis and tumorigenicity
- Citation
- ONCOTARGET, v.6, no.37, pp.40158 - 40171
- Journal Title
- ONCOTARGET
- Volume
- 6
- Number
- 37
- Start Page
- 40158
- End Page
- 40171
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/9923
- DOI
- 10.18632/oncotarget.5522
- ISSN
- 1949-2553
- 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.
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