Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PLoS One. 2013 Jul 30;8(7):e70616. doi: 10.1371/journal.pone.0070616. Print 2013.
Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC.
子宫内膜癌（EC）转移的调控机制尚未完全明确。最近的数据表明，细胞表面酪氨酸激酶受体 TrkB 在几种人类肿瘤的进展中起作用。在这里，我们提出了 TrkB 直接参与人 EC 的证据。免疫组织化学分析显示，TrkB 及其分泌配体脑源性神经营养因子（BDNF）在 EC 中的表达高于正常子宫内膜。TrkB 水平高与 EC 的淋巴结转移（p<0.05）和淋巴管侵犯（p<0.05）相关。通过稳定的 shRNA 介导的敲低降低了癌细胞系的体外迁移和侵袭能力，并导致悬浮细胞发生凋亡。相反，外源性表达 TrkB 增加了细胞迁移和侵袭，并促进了悬浮培养中的凋亡抵抗。此外，TrkB 的过表达或 BDNF 的刺激导致上皮-间质转化（EMT）的分子介质表达发生改变。下游调节剂 Twist 的 RNA 干扰（RNAi）介导的耗尽阻断了 TrkB 诱导的 EMT 样转化。体内模型的使用显示，TrkB 耗尽的 EC 细胞腹膜播散减少。此外，TrkB 耗尽的 EC 细胞在体内经历间充质-上皮转化和凋亡。我们的数据支持 TrkB 在促进 EMT 和凋亡抵抗中的新功能。因此，TrkB 可能成为人类 EC 的潜在治疗靶点。
