Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells
Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells
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DOI：
10.1038/sj.onc.1208177
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发表时间：
2005-02-17
期刊：
影响因子：
8
通讯作者：
Takenawa, T
中科院分区：
文献类型：
--
作者：
Kurisu, S;Suetsugu, S;Takenawa, T
WAVE（WASP家族verprolin-homologous proteins）通过激活Arp 2/3复合物调节肌动蛋白细胞骨架。由于细胞运动受肌动蛋白细胞骨架重排调节，并且是肿瘤侵袭和转移所必需的，因此阻断肌动蛋白聚合可能是防止肿瘤扩散的有效策略。我们发现WAVE，特别是WAVE 2，是黑色素瘤细胞的侵袭和转移所必需的。恶性B16 F10小鼠黑色素瘤细胞表达更多的WAVE 1和WAVE 2蛋白，并显示出比B16亲本细胞更高的Rac活性，B16亲本细胞既不具有侵袭性也不具有转移性。通过RNA干扰（RNAi）沉默WAVE 2对B16 F10细胞的高侵袭性的影响比WAVE 1 RNAi更显著。WAVE 2 RNAi抑制了B16 F10细胞的膜皱褶、细胞运动、细胞外基质侵袭和肺转移。WAVE 2 RNAi对由组成型活性形式的Rac（RacCA）诱导的侵袭也具有深远的影响。此外，RacCA和WAVE 2在B16细胞中的异位表达导致比仅表达RacCA的B16细胞中观察到的侵袭力进一步增加。因此，WAVE 2作为Rae下游的主要效应子来实现侵袭和转移，表明WAVE 2活性的抑制有望预防癌症侵袭和转移。
WAVEs (WASP-family verprolin-homologous proteins) regulate the actin cytoskeleton through activation of Arp2/3 complex. As cell motility is regulated by actin cytoskeleton rearrangement and is required for tumor invasion and metastasis, blocking actin polymerization may be an effective strategy to prevent tumor dissemination. We show that WAVEs, especially WAVE2, are essential for invasion and metastasis of melanoma cells. Malignant B16F10 mouse melanoma cells expressed more WAVE1 and WAVE2 proteins and showed higher Rac activity than B16 parental cells, which are neither invasive nor metastatic. The effect of WAVE2 silencing by RNA interference (RNAi) on the highly invasive nature of B16F10 cells was more dramatic than that of WAVE1 RNAi. Membrane ruffling, cell motility, invasion into the extracellular matrix, and pulmonary metastasis of B16F10 cells were suppressed by WAVE2 RNAi. WAVE2 RNAi also had a profound effect on invasion induced by a constitutively active form of Rac (RacCA). In addition, ectopic expression of both RacCA and WAVE2 in B16 cells resulted in further increase in the invasiveness than that observed in B16 cells expressing only RacCA. Thus, WAVE2 acts as the primary effector downstream of Rae to achieve invasion and metastasis, suggesting that suppression of WAVE2 activity holds a promise for preventing cancer invasion and metastasis.