title: MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts.
abstract: OBJECTIVE
  Keloids are fibrous overgrowths induced by cutaneous injury. MicroRNAs (miRNAs) have recently emerged as post-transcriptional gene repressors and participants in a diverse array of pathophysiological processes leading to skin disease. The purpose of the current study was to explore the precise functions of miR-181a in human keloid development and the underlying mechanisms.
  
  
  METHODS
  A miRNA microarray analysis was performed to compare expression profiles between keloid and normal skin tissues. Quantitative real-time PCR was conducted to estimate miR-181a expression. Cell proliferation was determined using the cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays, and cell cycle and apoptosis were detected with flow cytometry. Direct targets of miR-181a were identified using the luciferase reporter assay.
  
  
  RESULTS
  miR-181a was significantly upregulated in human keloid tissues and fibroblasts, compared with their control counterparts. Overexpression of miR-181a enhanced keloid fibroblast DNA synthesis and proliferation and inhibited apoptosis, whereas miR-181a suppression triggered the opposite effects. Moreover, miR-181a suppressed the expression of PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) through direct interactions with its 3'UTR region and subsequently enhanced AKT activation. Overexpression of PHLPP2 without its 3'UTR attenuated the effects of miR-181a on cell proliferation and apoptosis in keloid fibroblast cells. Furthermore, miR-181a mimics increased normal skin fibroblast proliferation.
  
  
  CONCLUSIONS
  Our results highlight a novel pathway mediated by miR-181a, which may be effectively used as a therapeutic target for treatment of keloids.
authors.affiliation: Institute of Dermatology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Rang
authors.forename: Zong-Yang
authors.initials: ZY
authors.lastname: Wang
authors.forename: Qiu-Yu
authors.initials: QY
authors.lastname: Pang
authors.forename: You-Wei
authors.initials: YW
authors.lastname: Wang
authors.forename: Ge
authors.initials: G
authors.lastname: Yang
authors.forename: Fan
authors.initials: F
authors.lastname: Cui
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007627:Keloid / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics
chemical_list: C000608460:MIRN-181 microRNA, human; D035683:MicroRNAs; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt; C541572:PHLPP2 protein, human; D010749:Phosphoprotein Phosphatases