Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness.
Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness.
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DOI：
10.1158/0008-5472.can-08-1463
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Zhang YE
中科院分区：
文献类型：
--
作者：
Jin C;Yang YA;Anver MR;Morris N;Wang X;Zhang YE
泛素/蛋白酶体系统(UPS)介导的受控蛋白质降解在调节广泛的细胞反应中起着至关重要的作用。UPS的调节失调往往伴随着肿瘤的发生和发展。在这里，我们报告了Smad泛素化调节因子2(Smad泛素化调节因子2)，一个含有E3泛素连接酶的Hect结构域，在某些乳腺癌组织和细胞中上调。我们发现，在转移性乳腺癌细胞中，用特定的短干扰RNA降低SMurf2的表达可以诱导细胞圆化和肌动蛋白细胞骨架的重组，这与运动性和侵袭性较差的表型有关。SMurf2的过表达促进了裸鼠模型的转移，并增加了乳腺癌细胞的迁移和侵袭。此外，SMurf2的E3连接酶缺陷突变体SMurf2CG的表达抑制了上述转移行为。这些结果确立了SMurf2在乳腺癌进展中的重要作用，并表明SMurf2是一种新的乳腺癌细胞迁移和侵袭调节因子。
Controlled protein degradation mediated by ubiquitin/proteasome system (UPS) plays a crucial role in modulating a broad range of cellular responses. Dysregulation of the UPS often accompanies tumorigenesis and progression. Here, we report that Smad ubiquitination regulatory factor 2 (Smurf2), a HECT-domain containing E3 ubiquitin ligase, is up-regulated in certain breast cancer tissues and cells. We show that reduction of Smurf2 expression with specific short interfering RNA in metastatic breast cancer cells induces cell rounding and reorganization of the actin cytoskeleton, which are associated with a less motile and invasive phenotype. Overexpression of Smurf2 promotes metastasis in a nude mouse model and increases migration and invasion of breast cancer cells. Moreover, expression of Smurf2CG, an E3 ligase–defective mutant of Smurf2, suppresses the above metastatic behaviors. These results establish an important role for Smurf2 in breast cancer progression and indicate that Smurf2 is a novel regulator of breast cancer cell migration and invasion.