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PLoS One. 2013 Dec 30;8(12):e83629. doi: 10.1371/journal.pone.0083629. eCollection 2013.

Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.

Author information

1
Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Laboratory of Cellular Dynamics, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan ; JST, CREST, Chiyoda-ku, Tokyo, Japan ; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
2
Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
3
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
4
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Oita, Japan.
5
Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Laboratory of Cellular Dynamics, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
6
DNA-chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
7
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Oita, Japan.
8
Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Laboratory of Cellular Dynamics, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan ; Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
9
Department of Immunology and Cell Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ; Laboratory of Cellular Dynamics, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan ; JST, CREST, Chiyoda-ku, Tokyo, Japan.
10
Laboratory of Cellular Dynamics, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan ; JST, CREST, Chiyoda-ku, Tokyo, Japan.
11
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Abstract

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.

PMID:
24386239
PMCID:
PMC3875446
DOI:
10.1371/journal.pone.0083629
[Indexed for MEDLINE]
Free PMC Article

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