title: Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway.
abstract: Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real-time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase-activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial-mesenchymal transition markers E-cadherin and N-cadherin, which is important given that epithelial-mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.
authors.affiliation: The Graduate School, Tianjin Medical University, Tianjin, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Graduate School, Tianjin Medical University, Tianjin, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Fu
authors.affiliation: The Graduate School, Tianjin Medical University, Tianjin, China.
authors.forename: Lianling
authors.initials: L
authors.lastname: Li
authors.affiliation: Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Tianjin Neurosurgery Institute, Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory, Tianjin Huanhu Hospital, Tianjin, China.
authors.forename: Jinhuan
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010641:Phenotype; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C473316:ARHGAP15 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020690:GTPase-Activating Proteins; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein
keywords: ARHGAP15; FOXP3; Rac1 activation; epithelial-mesenchymal transition; glioma