Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Respiratory Medicine, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushu, Japan.
Lung Cancer. 2018 Jun;120:98-107. doi: 10.1016/j.lungcan.2018.04.005. Epub 2018 Apr 5.
TrkB is a receptor for brain-derived neurotrophic factor (BDNF) and is highly expressed in various cancers, with BDNF-TrkB signaling having been implicated in tumor progression and metastasis. The role of the BDNF-TrkB system in small cell lung cancer (SCLC), a neuroendocrine cancer, has remained unclear, however. We examined BDNF and TrkB expression in SCLC patients as well as the function of BDNF-TrkB signaling in SCLC cell lines.
BDNF and TrkB expression in tumor specimens of 58 SCLC patients and 20 non-small cell lung cancer (NSCLC) patients was examined by immunohistochemistry and was scored on the basis of the distribution and intensity of staining. TrkB-overexpressing SCLC (SBC5) cells were established by retrovirus transduction and were examined for the effects of BDNF on intracellular signaling, cell proliferation, and cell migration in vitro.
The staining score for TrkB in NSCLC and SCLC specimens was 2.80 ± 0.19 and 3.60 ± 0.15, respectively, whereas that for BDNF was 1.95 ± 0.32 and 2.76 ± 0.14, respectively. High levels of both TrkB and BDNF expression in SCLC tumors were significantly associated with poor overall survival in multivariate analysis (hazard ratio = 1.821, P = 0.036). BDNF activated AKT and ERK signaling pathways in and promoted the migration of SBC5 cells, and these effects were attenuated by the pan-Trk inhibitor GNF-5837. GNF-5837 also inhibited the proliferation of SBC5 cells in the presence of BDNF.
Coexpression of BDNF and TrkB was associated with poor prognosis in SCLC patients, and BDNF promoted the migration of TrkB-overexpressing SCLC cells. TrkB is thus a potential therapeutic target for SCLC.
TrkB 是脑源性神经营养因子（BDNF）的受体，在各种癌症中高度表达，BDNF-TrkB 信号已被牵连到肿瘤进展和转移中。然而，BDNF-TrkB 系统在小细胞肺癌（SCLC）中的作用仍然不清楚，SCLC 是一种神经内分泌癌。我们检查了 58 例 SCLC 患者和 20 例非小细胞肺癌（NSCLC）患者的肿瘤标本中的 BDNF 和 TrkB 表达，并根据染色的分布和强度对其进行评分。通过逆转录病毒转导建立了 TrkB 过表达的 SCLC（SBC5）细胞，并在体外研究了 BDNF 对细胞内信号、细胞增殖和细胞迁移的影响。
NSCLC 和 SCLC 标本中 TrkB 的染色评分分别为 2.80±0.19 和 3.60±0.15，BDNF 的染色评分分别为 1.95±0.32 和 2.76±0.14。多变量分析显示，SCLC 肿瘤中高水平的 TrkB 和 BDNF 表达与总生存不良显著相关（危险比=1.821，P=0.036）。BDNF 在 SBC5 细胞中激活 AKT 和 ERK 信号通路，并促进其迁移，而 pan-Trk 抑制剂 GNF-5837 可减弱这些作用。在存在 BDNF 的情况下，GNF-5837 还抑制了 SBC5 细胞的增殖。
BDNF 和 TrkB 的共表达与 SCLC 患者的不良预后相关，BDNF 促进了 TrkB 过表达的 SCLC 细胞的迁移。因此，TrkB 是 SCLC 的一个潜在治疗靶点。
