title: Suppressive action of miRNAs to ARP2/3 complex reduces cell migration and proliferation via RAC isoforms in Hirschsprung disease.
abstract: Hirschsprung disease (HSCR) is a congenital disorder caused by the defective function of the embryonic enteric neural crest. The impaired migration of embryonic enteric neural crest plays an important role in the pathogenesis of this disease. Recent studies showed that the ARP2/3 complex and RAC isoforms had effects on actin cytoskeleton remodelling, which contributes to migration. Moreover, some regulatory relationships were identified between ARP2/3 complex and RAC isoforms. Although microRNAs (miRNAs) have been known to modulate target gene expression on the post-transcriptional level, little is known about the regulation among miRNAs, ARP2/3 complex and RAC isoforms. Here, we report that down-regulation of ARP2 and ARP3, two main subunits of ARP2/3 complex, suppressed migration and proliferation in 293T and SH-SY5Y cell lines via the inhibition of RAC1 and RAC2. Meanwhile, as the target genes, ARP2 and ARP3 are reduced by increased miR-24-1* and let-7a*, respectively, in 70 HSCR samples as compared with 74 normal controls. Co-immunoprecipitation showed that aberrant reduction in ARP2 and ARP3 could weaken the function of ARP2/3 complex. Our study demonstrates that the miR-24-1*/let-7a*-ARP2/3 complex-RAC isoforms pathway may represent a novel pathogenic mechanism for HSCR.
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Children's Hospital of Soochow University, Soochow, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Key Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Huo
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, China.|State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Pingfa
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Cell and Molecular Biology, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Hang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|Key Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, Nanjing, China.|Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Children's Hospital of Soochow University, Soochow, China.|Key Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, Nanjing, China.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003710:Demography; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D035683:MicroRNAs; D020033:Protein Isoforms; D012333:RNA, Messenger; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C543845:MIRN24 microRNA, human; C107953:RAC1 protein, human; C487931:mirnlet7 microRNA, human
keywords: ARP2/3 complex; Hirschsprung disease; RAC isoforms; gene regulation; microRNA