title: Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer.
abstract: Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer.
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-840, Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Gangnam Severance Hospital, Yonsei University Medical College, 712 Eonjuro, Gangnam-Gu, Seoul, 135-720, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Medicinal Chemistry, CMG Pharma, 335, CHA Bio Complex, Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Korea.
authors.forename: Jeongbeob
authors.initials: J
authors.lastname: Seo
authors.affiliation: TheragenEtex Bio Institute, TheragenEtex Co., Suwon, Gyeonggi-do 16229, Republic of Korea.
authors.forename: Hae-Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Nano-Bio Medicine Research Center, Advanced Institutes of Convergence Technology, and Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Kyunggi-do 16229, Republic of Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-840, Korea.|Gachon Medical Research Institute, Gil Medical Center, Incheon, 405-760, Korea.
authors.forename: Wook
authors.initials: W
authors.lastname: Jin