TrkBT1 induces liver metastasis of pancreatic cancer cells by sequestering Rho GDP dissociation inhibitor and promoting RhoA activation.
TrkBT1 induces liver metastasis of pancreatic cancer cells by sequestering Rho GDP dissociation inhibitor and promoting RhoA activation.
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DOI：
10.1158/0008-5472.can-08-4002
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Chiao PJ
中科院分区：
文献类型：
--
作者：
Li Z;Chang Z;Chiao LJ;Kang Y;Xia Q;Zhu C;Fleming JB;Evans DB;Chiao PJ
在胰腺癌中，K-ras基因突变和NF-κB活化等多种基因和分子改变已被证实。然而，胰腺癌转移的机制仍有待确定。虽然我们先前发现原肌球蛋白相关激酶B（Trk B）与胰腺癌肝转移的发生显著相关，但其在胰腺癌转移中的作用仍不清楚。在本研究中，我们发现，过表达的TrkB是一种选择性剪接的TrkB（TrkBT 1）的转录变体，具有独特的COOH-末端12-氨基酸序列，主要定位于细胞质中。我们的研究结果表明，在胰腺癌原位异种移植小鼠模型中，在非转移性胰腺癌细胞中过表达Flag-taged TrkBT 1而非Flag-taged TrkBT 1 COOH末端缺失突变体（Flag-TrkBT 1 ΔC）可增强细胞增殖，促进软琼脂集落形成，刺激肿瘤细胞侵袭，并诱导肝转移。TrkBT 1与Rho GDP解离抑制剂（GDI）在体内有相互作用，而Flag-TrkBT 1 ΔC则无相互作用。此外，Flag-TrkBT 1过表达和RhoGDI短发夹RNA敲低RhoGDI表达促进RhoA活化，但Flag-TrkBT 1 ΔC过表达没有。因此，我们的研究结果表明，TrkBT 1过表达诱导胰腺癌的肝转移，并揭示了一个独特的信号转导机制，TrkBT 1螯合GDI和激活RhoA信号。
Many genetic and molecular alterations, such as K-ras mutation and NF-κB activation, have been identified in pancreatic cancer. However, the mechanisms by which pancreatic cancer metastasizes still remain to be determined. Although we previously showed that the tropomyosin-related kinase B (TrkB) was significantly correlated with the development of liver metastasis, its function in pancreatic cancer metastasis remained unresolved. In the present study, we showed that overexpressed TrkB is an alternatively spliced transcript variant of TrkB (TrkBT1) with a unique COOH-terminal 12–amino acid sequence and is mainly localized in the cytoplasm. Our results showed that overexpression of Flag-tagged TrkBT1 but not a Flag-tagged TrkBT1 COOH-terminal deletion mutant (Flag-TrkBT1ΔC) in nonmetastatic pancreatic cancer cells enhanced cell proliferation, promoted formation of colonies in soft agar, stimulated tumor cell invasion, and induced liver metastasis in an orthotopic xenograft mouse model of pancreatic cancer. TrkBT1 interacted with Rho GDP dissociation inhibitor (GDI) in vivo, but Flag-TrkBT1ΔC did not. Furthermore, overexpression of Flag-TrkBT1 and knockdown of RhoGDI expression by RhoGDI short hairpin RNAs promoted RhoA activation, but Flag-TrkBT1ΔC overexpression did not. Therefore, our results showed that TrkBT1 overexpression induces liver metastasis of pancreatic cancer and uncovered a unique signaling mechanism by which TrkBT1 sequesters GDI and activates RhoA signaling.