title: Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.
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.
authors.affiliation: 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.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kagawa
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kamioka
authors.affiliation: Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Oita, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.affiliation: 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.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Naito
authors.affiliation: 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.
authors.forename: Taeko
authors.initials: T
authors.lastname: Ishii
authors.affiliation: DNA-chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: 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.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: 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.
authors.forename: Sakae
authors.initials: S
authors.lastname: Maeda
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Naito
authors.affiliation: 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.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: Laboratory of Cellular Dynamics, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan ; JST, CREST, Chiyoda-ku, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Haraguchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Sekimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: 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.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D020690:GTPase-Activating Proteins; C085379:rho GTPase-activating protein