期刊
ONCOTARGET
卷 6, 期 37, 页码 40158-40171出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5522
关键词
TrkB; epithelial-mesenchymal transition (EMT); IL-6/JAK2/STAT3 pathway; PI3K/AKT pathway; metastasis and tumorigenicity
资金
- National Research Foundation of Korea [NRF-2010-0002525, NRF-2012R1A2A2A01002728]
- Korea Healthcare Technology R and D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea [A084024]
- Gachon University Gil Medical Center [FRD 2014-08]
- Ministry of Science, ICT and Future Planning through the National Research Foundation, Korea [NRF-2012M3A9C4048735, NRF-2014M3A9B5073918]
- Korea Health Promotion Institute [A084024] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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