Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma.
Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma.
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TrkB 上调促进子宫内膜癌的上皮间质转化和失巢凋亡抵抗
DOI：
10.1371/journal.pone.0070616
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wan X
中科院分区：
文献类型：
--
作者：
Bao W;Qiu H;Yang T;Luo X;Zhang H;Wan X
子宫内膜癌（EC）的转移机制尚不清楚。最近的数据支持细胞表面受体酪氨酸激酶TrkB在几种人类肿瘤进展中的作用。在这里，我们提出的证据TrkB在人类EC中的直接作用。免疫组化分析显示TrkB及其分泌的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高表达与EC的淋巴结转移（p<0.05）和淋巴管间隙受累（p<0.05）相关。通过稳定的shRNA介导的敲低来消耗TrkB降低了癌细胞系在体外的迁移和侵袭能力，并导致悬浮细胞中的失巢凋亡。相反，外源性表达TrkB增加细胞的迁移和侵袭，并促进悬浮培养中的抗失巢凋亡。此外，TrkB的过度表达或BDNF的刺激导致改变上皮向间充质转化（EMT）的分子介质的表达。RNA干扰（RNAi）介导的下游调节因子Twist的耗竭阻断了TrkB诱导的EMT样转化。体内模型的使用显示TrkB耗尽的EC细胞中腹膜播散减少。此外，TrkB耗尽的EC细胞在体内经历了间充质至上皮的转变和失巢凋亡。我们的数据支持TrkB在促进EMT和抗失巢凋亡中的新功能。因此，TrkB可能构成人类EC的潜在治疗靶点。
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.
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DOI：
10.1158/1078-0432.ccr-08-1815
发表时间：
2009-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brodeur GM;Minturn JE;Ho R;Simpson AM;Iyer R;Varela CR;Light JE;Kolla V;Evans AE
通讯作者：
Evans AE
影响因子：
11.2
作者：
Geiger, Thomas R.;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.
影响因子：
11.2
作者：
Nakamura, K;Martin, KC;Thiele, CJ
通讯作者：
Thiele, CJ
影响因子：
4.8
作者：
Huang, Yang Z.;McNamara, James O.
通讯作者：
McNamara, James O.
影响因子：
3.7
作者：
Makino K;Kawamura K;Sato W;Kawamura N;Fujimoto T;Terada Y
通讯作者：
Terada Y