miR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue

Gene. 2019 Jul 15;705:167-176. doi: 10.1016/j.gene.2019.04.058. Epub 2019 Apr 23.

Abstract

Hemorrhoid is a common and recurrent proctological disease, which is often accompanied by angiogenesis and edema. MicroRNAs in the DLK1-DIO3 imprinted clusters are involved in the development and pathogenesis of mammalian hemorrhoids. Results of the present study indicated multiple, differential expression of DLK1-DIO3 imprinted cluster microRNA between hemorrhoid and normal tissues, where miR-412-5p expression in hemorrhoid tissue was significantly decreased. Fluorescein reporter assays showed that miR-412-5p silenced Xpo1 mRNA expression by targeting its 3'-UTR. Overexpression of miR-412-5p in human umbilical vein endothelial cells (HUVECs) indicated that proliferation, migration and formation of vascular structures in HUVECs were inhibited in vitro. In addition, overexpression of miR-412-5p significantly inhibited Xpo1 expression and promoted upregulation of the p53 protein and its retention in the nucleus. Simultaneously, expression of p66SHC and p16 proteins was activated. In summary, downregulation of endogenous miR-412-5p expression in hemorrhoid vascular endothelial cells leads to high expression of the target gene Xpo1 and translocation of the p53 protein out of the nucleus, rendering it unable to activate p66SHC and p16. This ultimately weakens regulation of the vascular endothelial cell cycle, thereby accelerating the division of hemorrhoid vascular endothelial cells, leading to angiogenesis.

Keywords: Angiogenesis; DLK1-DIO3 imprinted cluster; Exportin-1/Chromosome Region Maintenance 1 (Xpo1); Hemorrhoid; microRNA.

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Cell Movement
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Down-Regulation
  • Female
  • Gene Expression Regulation
  • Genomic Imprinting
  • Hemorrhoids / genetics*
  • Hemorrhoids / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Karyopherins / genetics*
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Signal Transduction
  • Src Homology 2 Domain-Containing, Transforming Protein 1 / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • 3' Untranslated Regions
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Karyopherins
  • MIRN412 microRNA, human
  • MicroRNAs
  • Receptors, Cytoplasmic and Nuclear
  • SHC1 protein, human
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • exportin 1 protein