PMID- 28423707 OWN - NLM STAT- MEDLINE DCOM- 20180326 LR - 20181113 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 8 IP - 22 DP - 2017 May 30 TI - Tropomyosin-related kinase B mediated signaling contributes to the induction of malignant phenotype of gallbladder cancer. PG - 36211-36224 LID - 10.18632/oncotarget.16063 [doi] AB - This study aims to demonstrate the clinical and biological significance of Brain derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) signaling in gallbladder cancer (GBC) through a series of in vitro and in vivo experiments. TrkB expression was detected in 63 (91.3%) out of 69 surgically resected primary GBC specimens by immunohistochemistry. TrkB expression in the invasive front correlated with T factor (p=0.0391) and clinical staging (p=0.0391). Overall survival was lower in patients with high TrkB expression in the invasive front than in those with low TrkB expression (p=0.0363). In vitro experiment, we used five TrkB-expressing GBC cell lines with or without K-ras mutation. TrkB-mediated signaling increased proliferation and the invasiveness by inducing epithelial mesenchymal transition, and activating matrix metalloproteinases-2 (MMP-2) and MMP-9. Inhibition of TrkB-mediated signaling also decreased hypoxia-inducible factor-1alpha, vascular endothelial growth factor A (VEGF-A), VEGF-C, and VEGF-D expression. In vivo experiment, inhibition of TrkB-mediated signaling suppressed tumorigenicity and tumor growth in GBC. These findings demonstrate that TrkB-mediated signaling contributes to the induction of malignant phenotypes (proliferation, invasiveness, angiogenesis, lymphangiogenesis, and tumorigenesis) in GBC, and could be a promising therapeutic target regardless of K-ras mutation status. FAU - Kawamoto, Makoto AU - Kawamoto M AD - Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Onishi, Hideya AU - Onishi H AD - Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Ozono, Keigo AU - Ozono K AD - Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Yamasaki, Akio AU - Yamasaki A AD - Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Imaizumi, Akira AU - Imaizumi A AD - Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. AD - Shukoukai Inc., Tokyo, Japan. FAU - Kamakura, Sachiko AU - Kamakura S AD - Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Nakano, Kenji AU - Nakano K AD - Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. FAU - Oda, Yoshinao AU - Oda Y AD - Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Sumimoto, Hideki AU - Sumimoto H AD - Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Nakamura, Masafumi AU - Nakamura M AD - Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. LA - eng PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Membrane Glycoproteins) RN - 0 (RNA, Small Interfering) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) RN - EC 3.4.24.- (Matrix Metalloproteinases) SB - IM MH - Aged MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Line, Tumor MH - Cell Movement MH - Cell Proliferation MH - Epithelial-Mesenchymal Transition MH - Female MH - Gallbladder Neoplasms/*genetics/mortality MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Male MH - Matrix Metalloproteinases/metabolism MH - Membrane Glycoproteins/*genetics/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Neoplasm Staging MH - RNA, Small Interfering/genetics MH - Receptor, trkB/*genetics/metabolism MH - Signal Transduction MH - Survival Analysis MH - Tumor Burden MH - Vascular Endothelial Growth Factor A/metabolism PMC - PMC5482650 OTO - NOTNLM OT - BDNF OT - HIF-1alpha OT - TrkB OT - biliary tract cancer OT - gallbladder cancer COIS- CONFLICTS OF INTEREST The authors declare no potential conflicts of interest. EDAT- 2017/04/21 06:00 MHDA- 2018/03/27 06:00 PMCR- 2017/05/30 CRDT- 2017/04/21 06:00 PHST- 2016/11/25 00:00 [received] PHST- 2017/02/07 00:00 [accepted] PHST- 2017/04/21 06:00 [pubmed] PHST- 2018/03/27 06:00 [medline] PHST- 2017/04/21 06:00 [entrez] PHST- 2017/05/30 00:00 [pmc-release] AID - 16063 [pii] AID - 10.18632/oncotarget.16063 [doi] PST - ppublish SO - Oncotarget. 2017 May 30;8(22):36211-36224. doi: 10.18632/oncotarget.16063.