title: microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer.
abstract: BACKGROUND
  miR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC).
  
  
  METHODS
  The biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot.
  
  
  RESULTS
  miR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002).
  
  
  CONCLUSIONS
  miR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhang
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Dong
authors.forename: Nana
authors.initials: N
authors.lastname: Zhu
authors.forename: Ho
authors.initials: H
authors.lastname: Tsoi
authors.affiliation: Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key laboratory of Digestive Disease, Prince of Wales Hospital, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China. zzr-doctor@163.com.
authors.forename: Zengren
authors.initials: Z
authors.lastname: Zhao
authors.forename: Chung Wah
authors.initials: CW
authors.lastname: Wu
authors.forename: Kunning
authors.initials: K
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.forename: Simon Sm
authors.initials: SS
authors.lastname: Ng
authors.forename: Francis Kl
authors.initials: FK
authors.lastname: Chan
authors.forename: Joseph Jy
authors.initials: JJ
authors.lastname: Sung
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C555098:MIRN139 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1