title: microRNA-224 promotes cell proliferation and tumor growth in human colorectal cancer by repressing PHLPP1 and PHLPP2.
abstract: OBJECTIVE
  To investigate the clinicopathologic significance, role, and mechanism of action of microRNA-224 (miR-224) in colorectal cancer.
  
  
  METHODS
  Real-time PCR was used to quantify miR-224 expression. The association of miR-224 with the clinicopathologic features and survival was evaluated in 110 colorectal cancer patients. The role of miR-224 in colorectal cancer was investigated using in vitro and in vivo assays. Luciferase reporter assays were conducted to confirm target gene associations.
  
  
  RESULTS
  miR-224 was overexpressed in colorectal cancer. High-level expression of miR-224 was significantly associated with an aggressive phenotype and poor prognosis. Overexpression of miR-224 promoted colorectal cancer cell proliferation in vitro and tumor growth in vivo. Specifically, miR-224 accelerated the G1-S phase transition through activation of AKT/FOXO3a signaling, downregulation of p21Cip1 and p27Kip1, and upregulation of cyclin D1. Moreover, both PH domain leucine-rich-repeats protein phosphatase 1 (PHLPP1) and PHLPP2, antagonists of PI3K/AKT signaling, were confirmed as bona fide targets of miR-224. miR-224 directly targeted the 3'-untranslated regions of the PHLPP1 and PHLPP2 mRNAs and repressed their expression.
  
  
  CONCLUSIONS
  This study reveals functional and mechanistic links between miRNA-224 and the tumor suppressors PHLPP1 and PHLPP2 in the pathogenesis of colorectal cancer. miR-224 not only plays important roles in the regulation of cell proliferation and tumor growth in colorectal cancer, but also has potential as a prognostic marker or therapeutic target for colorectal cancer.
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liao
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Li
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Wang
authors.forename: Shu-Yang
authors.initials: SY
authors.lastname: Wang
authors.forename: Mei-Rong
authors.initials: MR
authors.lastname: He
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Ye
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Cui
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Hong-Li
authors.initials: HL
authors.lastname: Jiao
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Xie
authors.forename: Jun-Xian
authors.initials: JX
authors.lastname: Wang
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Ding
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: C546140:MIRN224 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; C400601:PHLPP1 protein, human; C541572:PHLPP2 protein, human; D010749:Phosphoprotein Phosphatases