title: Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer.
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.
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.
authors.forename: Won Sung
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Surgery, Kangnam Severance Hospital, Yonsei University, Kangnam, Seoul 146-92, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Jeong
authors.affiliation: CHA Cancer Institute, CHA University, Seongnam-si, Kyunggi-do 463-400, Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.|Gachon Medical Research Institute, Gil Medical Center, Gachon University, Incheon 405-760, Korea.
authors.forename: Wook
authors.initials: W
authors.lastname: Jin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D020813:Receptor, trkB; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; D051879:Twist-Related Protein 1; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt
keywords: IL-6/JAK2/STAT3 pathway; PI3K/AKT pathway; TrkB; epithelial-mesenchymal transition (EMT); metastasis and tumorigenicity