The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1
The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1
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DOI：
10.1172/jci42975
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Yang, Pan-Chyr
中科院分区：
文献类型：
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作者：
Pan, Szu-Hua;Chao, Yu-Chih;Yang, Pan-Chyr
转移是癌症患者死亡的主要原因。这是一个复杂的多步骤过程，如果我们要开发新的方法来管理肿瘤转移，就需要更好地理解。肿瘤细胞对局部间质的侵袭被抑制素反应介导蛋白-1（CRMP-1）。最近，我们鉴定了CRMP-1（LCRMP-1）的长亚型，其表达与非小细胞肺癌（NSCLC）患者的癌细胞侵袭性和不良临床结局相关。在此，我们报道了LCRMP-1在非侵袭性人类细胞系中的过表达通过稳定肌动蛋白增强丝状伪足形成、癌细胞迁移和侵袭。这种作用需要LCRMP-1的高度保守的N-末端区域以及WASP家族的verprolin同源蛋白-1/肌动蛋白成核途径（WAVE-1/actin nucleation pathway）。此外，LCRMP-1似乎作用于Cdc 42的下游，Cdc 42是已知参与肌动蛋白重排的Rho家族蛋白。此外，LCRMP-1与CRMP-1相关，CRMP-1通过中断LCRMP-1和WAVE-1的关联来下调癌细胞转移。最后，我们发现LCRMP-1的高表达和CRMP-1的低表达与NSCLC患者的淋巴结转移和不良生存相关。总之，我们发现LCRMP-1和CRMP-1在调节癌细胞侵袭和转移方面具有相反的功能，并提出该途径可能作为潜在的抗癌靶点。
Metastasis is a predominant cause of death in patients with cancer. It is a complex multistep process that needs to be better understood if we are to develop new approaches to managing tumor metastasis. Tumor cell invasion of the local stroma is suppressed by collapsin response mediator protein-1 (CRMP-1). Recently, we identified a long isoform of CRMP-1 (LCRMP-1), expression of which correlates with cancer cell invasiveness and poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). Here, we report that LCRMP-1 overexpression in noninvasive human cell lines enhanced filopodia formation, cancer cell migration, and invasion via stabilization of actin. This effect required a highly conserved N-terminal region of LCRMP-1 as well as the WASP family verprolin-homologous protein-1/actin nucleation pathway (WAVE-1/actin nucleation pathway). Furthermore, LCRMP-1 appeared to act downstream of Cdc42, a Rho family protein known to be involved in actin rearrangement. In addition, LCRMP-1 associated with CRMP-1, which downregulated cancer cell metastasis by interrupting the association of LCRMP-1 and WAVE-1. Finally, we found that high-level expression of LCRMP-1 and low-level expression of CRMP-1 were associated with lymph node metastasis and poor survival in patients with NSCLC. In sum, we show that LCRMP-1 and CRMP-1 have opposing functions in regulating cancer cell invasion and metastasis and propose that this pathway may serve as a potential anticancer target.