MicroRNA-542-3p Suppresses Tumor Cell Invasion via Targeting AKT Pathway in Human Astrocytoma

J Biol Chem. 2015 Oct 9;290(41):24678-88. doi: 10.1074/jbc.M115.649004. Epub 2015 Aug 18.

Abstract

The molecular mechanism underlying constitutive activation of AKT signaling, which plays essential roles in astrocytoma progression, is not fully characterized. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of astrocytoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we found that microRNA (miR)-542-3p expression was decreased in glioblastoma cell lines and astrocytoma tissues, and reduced levels of miR-542-3p expression correlated with high histopathological grades and poor prognosis of astrocytoma patients. Exogenous miR-542-3p suppressed glioblastoma cell invasion through not only targeting AKT1 itself but also directly down-regulating its two important upstream regulators, namely, integrin-linked kinase and PIK3R1. Notably, overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of β-catenin to exert its anti-invasive effect. Furthermore, the miR-542-3p expression level negatively correlated with AKT activity as well as levels of integrin-linked kinase and PIK3R1 in human astrocytoma specimens. These findings suggest that miR-542-3p acts as a negative regulator in astrocytoma progression and that miR-542-3p down-regulation contributes to aberrant activation of AKT signaling, leaving open the possibility that miR-542-3p may be a potential therapeutic target for high grade astrocytoma.

Keywords: AKT signaling; Akt PKB; astrocytoma; cancer biology; cell invasion; invasiveness; microRNA-542-3p; neurobiology; signal transduction; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Base Sequence
  • Cell Line, Tumor
  • Disease Progression
  • Down-Regulation / genetics
  • Glioblastoma / diagnosis
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • MicroRNAs / genetics*
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases / genetics
  • Prognosis
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / genetics*
  • Up-Regulation / genetics
  • beta Catenin / metabolism

Substances

  • 3' Untranslated Regions
  • MIRN542 microRNA, human
  • MicroRNAs
  • beta Catenin
  • PIK3R1 protein, human
  • Phosphatidylinositol 3-Kinases
  • integrin-linked kinase
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt