Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3
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Bongkun Choi1,5, Eun-Jin Lee1,5, Min-Kyung Shin1,5, Young Soo Park2, Min-Hee Ryu3, Sang-Min Kim1,5, Eun-Young Kim1,5, Hyung Keun Lee4, Eun-Ju Chang1,5
1Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
2Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
3Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
4Department of Ophthalmology and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
5Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Eun-Ju Chang, email: [email protected]
Keywords: BDNF, PTX3, osteoblast, gastric cancer, bone metastasis
Received: May 04, 2016 Accepted: July 11, 2016 Published: July 21, 2016
The brain-derived neurotrophic factor (BDNF) activates its receptor, tropomyosin receptor kinase B (TrkB; also called NTRK2) that has been shown to promote the malignant progression of several cancers. In this study, we investigated the clinical and biological significance of the BDNF/TrkB axis in the progression of human gastric cancer. The increased co-expression of the BDNF/TrkB axis was significantly correlated with bone metastatic properties in advanced gastric cancers. BDNF acting via TrkB receptors increased the levels of long pentraxin 3 (PTX3) that was related to bone metastatic status of gastric cancer by enhancing gastric cancer–osteoblastic niche interactions. In bone metastatic gastric cancer, PTX3 knockdown using small interfering RNA significantly inhibited BDNF-induced interactions of cancer cells with osteoblasts. Moreover, BDNF-derived PTX3 induction supported subsequent osteoclastogenesis, and this effect was significantly reversed by PTX3 silencing. These findings suggest that a functional interaction between BDNF/TrkB and PTX3 enhances the osteolysis of bone metastatic gastric cancer, thereby providing potential prognostic factors for the development of bone metastasis of gastric cancer.
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