Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion
Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion
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DOI：
10.1038/sj.onc.1208909
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发表时间：
2005-11-24
期刊：
影响因子：
8
通讯作者：
Symons, M
中科院分区：
文献类型：
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作者：
Chan, AY;Coniglio, SJ;Symons, M
小gtpase的Rho家族成员已被证明参与肿瘤的发生和转移。目前，大多数关于Rho蛋白在恶性转化中的功能的可用信息都是基于这些gtpase的显性阴性突变体的使用。然而这些显性阴性突变体的特异性是有限的。在本研究中，我们使用了针对Rac1或Rac3的小干扰RNA来特异性地降低它们的表达。与在其他细胞类型中使用显性阴性Rac1的观察结果一致，我们发现RNA干扰介导的Rac1缺失强烈抑制SNB19胶质母细胞瘤细胞的板足形成、细胞迁移和侵袭。然而，令人惊讶的是，Rac1缺失对SNB19细胞增殖和存活的抑制作用要小得多。有趣的是，尽管Rac3的缺失强烈抑制SNB19细胞的侵袭，但它不影响板足的形成，对细胞的迁移和增殖只有轻微的影响。在BT549乳腺癌细胞中也得到了类似的结果。因此，利用RNA干扰对Rac1和Rac3进行功能分析，揭示了这些gtpase在胶质瘤和乳腺癌细胞侵袭行为中的关键作用。
Members of the Rho family of small GTPases have been shown to be involved in tumorigenesis and metastasis. Currently, most of the available information on the function of Rho proteins in malignant transformation is based on the use of dominant-negative mutants of these GTPases. The specificity of these dominant-negative mutants is limited however. In this study, we used small interfering RNA directed against either Rac1 or Rac3 to reduce their expression specifically. In line with observations using dominant-negative Rac1 in other cell types, we show that RNA interference-mediated depletion of Rac1 strongly inhibits lamellipodia formation, cell migration and invasion in SNB19 glioblastoma cells. Surprisingly however, Rac1 depletion has a much smaller inhibitory effect on SNB19 cell proliferation and survival. Interestingly, whereas depletion of Rac3 strongly inhibits SNB19 cell invasion, it does not affect lamellipodia formation and has only minor effects on cell migration and proliferation. Similar results were obtained in BT549 breast carcinoma cells. Thus, functional analysis of Rac1 and Rac3 using RNA interference reveals a critical role for these GTPases in the invasive behavior of glioma and breast carcinoma cells.