MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling

PLoS One. 2017 Oct 10;12(10):e0186245. doi: 10.1371/journal.pone.0186245. eCollection 2017.

Abstract

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of cardiovascular diseases. Studies have shown the great impact of microRNAs (miRNAs) on the cell proliferation of VSMCs. This study examined the effects of miR-137 on the cell proliferation and migration of VSMCs and also explored the underlying molecular mechanisms. The mRNA and protein expression levels were determined by qRT-PCR and western blot assays, respectively. The CCK-8 assay, wound healing assay and transwell migration assay were performed to measure cell proliferation and migration of VSMCs. The miR-137-targeted 3'untranslated region of insulin-like growth factor-binding protein-5 (IGFBP-5) was confirmed by luciferase reporter assay. Platelet-derived growth factor-bb (PDGF-bb) treatment enhanced cell proliferation and suppressed the expression of miR-137 in VSMCs. The gain-of-function and loss-of-function assays showed that overexpression of miR-137 suppressed the cell proliferation and migration, and also inhibited the expression of matrix genes of VSMCs; down-regulation of miR-137 had the opposite effects on VSMCs. Bioinformatics analysis and luciferase report assay results showed that IGFBP-5 was a direct target of miR-137, and miR-137 overexpression suppressed the IGFBP-5 expression and down-regulation of miR-137 increased the IGFBP-5 expression in VSMCs. PDGF-bb treatment also increased the IGFBP-5 mRNA expression. In addition, enforced expression of IGFBP-5 reversed the inhibitory effects of miR-137 on cell proliferation and migration of VSMCs. More importantly, overexpression of miR-137 also suppressed the activity of mTOR/STAT3 signaling in VSMCs. Taken together, the results suggest that miR-137 may suppress cell proliferation and migration of VSMCs via targeting IGFBP-5 and modulating mTOR/STAT3 signaling pathway.

MeSH terms

  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Base Sequence
  • Becaplermin
  • Binding Sites
  • Cell Line
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Computational Biology
  • Diffusion Chambers, Culture
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5 / genetics*
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Proto-Oncogene Proteins c-sis / pharmacology
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Insulin-Like Growth Factor Binding Protein 5
  • MIRN137 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-sis
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Becaplermin
  • Luciferases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases

Grants and funding

This project was supported by Soft Science Project of Shaanxi Science and Technology Department (www.sninfo.gov.cn/), 2012KRM64 to JP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.