Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.
Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.
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DOI：
10.1371/journal.pone.0083629
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ishii M
中科院分区：
文献类型：
--
作者：
Kagawa Y;Matsumoto S;Kamioka Y;Mimori K;Naito Y;Ishii T;Okuzaki D;Nishida N;Maeda S;Naito A;Kikuta J;Nishikawa K;Nishimura J;Haraguchi N;Takemasa I;Mizushima T;Ikeda M;Yamamoto H;Sekimoto M;Ishii H;Doki Y;Matsuda M;Kikuchi A;Mori M;Ishii M
癌细胞动力学的时空控制背后的机制及其与细胞增殖的可能关联尚未得到很好的建立。通过利用活体成像技术，我们发现癌细胞的运动性和侵袭性与细胞周期密切相关。在体内接种的人结肠癌细胞的荧光泛素化的细胞周期指示剂（Fucci）表现出一个意想不到的现象：S/G2/M细胞比G1细胞更具运动性和侵袭性。微阵列分析表明，Arhgap 11 a，一个未表征的Rho GTP酶激活蛋白（RhoGAP），在细胞周期依赖性的方式表达。ARHGAP 11 A在癌细胞中的表达抑制了RhoA依赖性机制，如应力纤维形成和粘着斑，这使得细胞更容易迁移。我们还证明了ARHGAP 11 A对RhoA的抑制诱导了Rac 1相对活性的增强，导致了侵袭性的增加。基于RNAi的Arhgap 11 a抑制减少了癌症的侵袭和体内扩散。此外，对人类样本的分析显示，结肠癌中Arhgap 11 a的显著上调与临床侵袭状态相关。目前的研究表明，ARHGAP 11 A是一种细胞周期依赖性RhoGAP，是癌细胞迁移的关键调节因子，因此是浸润性癌症中有希望的治疗靶点。
The mechanism behind the spatiotemporal control of cancer cell dynamics and its possible association with cell proliferation has not been well established. By exploiting the intravital imaging technique, we found that cancer cell motility and invasive properties were closely associated with the cell cycle. In vivo inoculation of human colon cancer cells bearing fluorescence ubiquitination-based cell cycle indicator (Fucci) demonstrated an unexpected phenomenon: S/G2/M cells were more motile and invasive than G1 cells. Microarray analyses showed that Arhgap11a, an uncharacterized Rho GTPase-activating protein (RhoGAP), was expressed in a cell-cycle-dependent fashion. Expression of ARHGAP11A in cancer cells suppressed RhoA-dependent mechanisms, such as stress fiber formation and focal adhesion, which made the cells more prone to migrate. We also demonstrated that RhoA suppression by ARHGAP11A induced augmentation of relative Rac1 activity, leading to an increase in the invasive properties. RNAi-based inhibition of Arhgap11a reduced the invasion and in vivo expansion of cancers. Additionally, analysis of human specimens showed the significant up-regulation of Arhgap11a in colon cancers, which was correlated with clinical invasion status. The present study suggests that ARHGAP11A, a cell cycle-dependent RhoGAP, is a critical regulator of cancer cell mobility and is thus a promising therapeutic target in invasive cancers.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
KOVESDI, I;REICHEL, R;NEVINS, JR
通讯作者：
NEVINS, JR
影响因子：
16.6
作者：
Kostourou V;Lechertier T;Reynolds LE;Lees DM;Baker M;Jones DT;Tavora B;Ramjaun AR;Birdsey GM;Robinson SD;Parsons M;Randi AM;Hart IR;Hodivala-Dilke K
通讯作者：
Hodivala-Dilke K
影响因子：
3.7
作者：
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通讯作者：
Ronaghi, Mostafa
影响因子：
9.2
作者：
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通讯作者：
Miki, Hiroaki