Tropomyosin-related kinase B mediated signaling contributes to the induction of malignant phenotype of gallbladder cancer
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Makoto Kawamoto1, Hideya Onishi1, Keigo Ozono2, Akio Yamasaki1, Akira Imaizumi1,3, Sachiko Kamakura4, Kenji Nakano5, Yoshinao Oda2, Hideki Sumimoto4 and Masafumi Nakamura6
1Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3Shukoukai Inc., Tokyo, Japan
4Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
5Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan
6Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Hideya Onishi, email: firstname.lastname@example.org
Keywords: TrkB, BDNF, gallbladder cancer, biliary tract cancer, HIF-1α
Received: November 25, 2016 Accepted: February 07, 2017 Published: March 10, 2017
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-1α, 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.
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