PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma.
PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma.
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PI3K 和 MAPK 通路介导神经母细胞瘤中 BDNF/TrkB 增加的转移。
DOI：
10.1007/s13277-016-5433-z
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发表时间：
2016-10-17
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
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作者：
Hua Z;Gu X;Dong Y;Tan F;Liu Z;Thiele CJ;Li Z
据报道，脑源性神经营养因子 (BDNF) 及其酪氨酸激酶受体 TrkB 与神经母细胞瘤 (NB) 患者的不良预后相关。我们之前的研究表明，BDNF 激活 TrkB 通过激活磷酸肌醇 3 激酶 (PI3K)/Akt 途径诱导化疗耐药。在这项研究中，我们研究了 BDNF/TrkB 对 NB 转移的作用。使用四环素调节的表达 TrkB 的 NB 细胞系 (TB3)。进行划痕愈合实验、Boyden小室迁移和侵袭实验来研究TB3细胞的迁移和侵袭。利用SCID-Beige小鼠的肿瘤异种移植模型来检测NB肿瘤的体内转移。使用 PI3K、MAPK、Akt 和 mTOR 抑制剂。采用蛋白质印迹法研究 P-Akt、P-Erk 和 P-mTOR 的表达。我们的结果表明，在表达 TrkB 的 NB 细胞中，BDNF 处理在划痕伤口愈合试验中显着增加间隙闭合（P < 0.01），在 Boyden 小室迁移和侵袭试验中也显着增加迁移细胞（P < 0.01）和入侵细胞（P < 0.01）的数量。在体内，与非 TrkB 表达肿瘤的小鼠相比，TrkB 表达异种移植肿瘤小鼠的 NB 远处转移显着增加 (P < 0.05)。使用任何 PI3K (LY294002)、MAPK (PD98059)、Akt (perifosine) 或 mTOR (雷帕霉素) 抑制剂进行预处理，可阻断 BDNF/TrkB 诱导的 TB3 细胞中细胞迁移和侵袭的增加，并阻断 BDNF/TrkB 诱导的 P-Akt、P-Erk 和 P-mTOR 的表达。这些数据表明BDNF/TrkB通过PI3K/Akt/mTOR和MAPK通路增加NB的转移，BDNF/TrkB及其下游靶点可能是治疗NB转移的潜在靶点。本文的在线版本 (doi:10.1007/s13277-016-5433-z) 包含补充材料，可供授权用户使用。
Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells. A tumor xenograft model using SCID-Beige mice was utilized to detect the metastasis of NB tumors in vivo. Inhibitors of PI3K, MAPK, Akt, and mTOR were used. Western blotting was performed to study the expressions of P-Akt, P-Erk, and P-mTOR. Our results showed that in TrkB-expressing NB cells, BDNF treatment significantly increased gap closing (P < 0.01) in scratch wound healing assay, also significantly enhanced the numbers of migrating cells (P < 0.01) and invading cells (P < 0.01) in the Boyden chamber migration and invasion assays. In vivo, NB distant metastases were significantly increased in mice with TrkB-expressing xenograft tumors compared to those with non-TrkB-expressing tumors (P < 0.05). Pre-treatment with any of the inhibitors for PI3K (LY294002), MAPK (PD98059), Akt (perifosine), or mTOR (rapamycin) blocked the BDNF/TrkB-induced increases of cell migration and invasion in TB3 cells, and also blocked the BDNF/TrkB-induced expressions of P-Akt, P-Erk, and P-mTOR. These data indicated that BDNF/TrkB increased metastasis in NB via PI3K/Akt/mTOR and MAPK pathways, and BDNF/TrkB and the downstream targets may be potential targets for the treatment of NB metastasis. The online version of this article (doi:10.1007/s13277-016-5433-z) contains supplementary material, which is available to authorized users.