Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
PLoS One. 2013 Jul 9;8(7):e67990. doi: 10.1371/journal.pone.0067990. Print 2013.
Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis; it has a poor prognosis and shows a predilection for metastasis to the lungs. Brain derived neurotrophic factor (BDNF) is a small-molecule protein from the neurotrophin family of growth factors that is associated with the disease status and outcomes of cancers. However, the effect of BDNF on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma tissues showed significant expression of BDNF, which was higher than that in normal cartilage and primary chondrocytes. We also found that BDNF increased the migration and expression of β5 integrin in human chondrosarcoma cells. In addition, knockdown of BDNF expression markedly inhibited migratory activity. BDNF-mediated migration and β5 integrin up-regulation were attenuated by antibody, inhibitor, or siRNA against the TrkB receptor. Pretreatment of chondrosarcoma cells with PI3K, Akt, and NF-κB inhibitors or mutants also abolished BDNF-promoted migration and integrin expression. The PI3K, Akt, and NF-κB signaling pathway was activated after BDNF treatment. Taken together, our results indicate that BDNF enhances the migration of chondrosarcoma by increasing β5 integrin expression through a signal transduction pathway that involves the TrkB receptor, PI3K, Akt, and NF-κB. BDNF thus represents a promising new target for treating chondrosarcoma metastasis.
软骨肉瘤是一种原发性恶性骨癌，具有很强的局部侵袭和远处转移能力；预后较差，易转移至肺部。脑源性神经营养因子（BDNF）是神经营养因子家族中的一种小分子蛋白生长因子，与癌症的疾病状态和转归有关。然而，BDNF 对人软骨肉瘤细胞迁移活性的影响大多尚不清楚。在这里，我们发现人软骨肉瘤组织中 BDNF 的表达明显升高，高于正常软骨和原代软骨细胞。我们还发现 BDNF 增加了人软骨肉瘤细胞中β5 整合素的迁移和表达。此外，BDNF 表达的敲低显著抑制了迁移活性。BDNF 介导的迁移和β5 整合素的上调被针对 TrkB 受体的抗体、抑制剂或 siRNA 减弱。软骨肉瘤细胞用 PI3K、Akt 和 NF-κB 抑制剂或突变体预处理也消除了 BDNF 促进的迁移和整合素表达。BDNF 处理后激活了 PI3K、Akt 和 NF-κB 信号通路。综上所述，我们的结果表明，BDNF 通过增加β5 整合素的表达来增强软骨肉瘤的迁移，该信号通路涉及 TrkB 受体、PI3K、Akt 和 NF-κB。因此，BDNF 代表了治疗软骨肉瘤转移的一个有前途的新靶点。
