miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma

Nat Commun. 2014 Aug 6;5:4620. doi: 10.1038/ncomms5620.

Abstract

The strength and duration of phosphoinositide signalling from phosphatidylinositol-3-kinase (PI3K) activation to Akt is tightly balanced by phosphoinositide kinases and phosphatases. However, how phosphatase-mediated negative regulatory effects are concomitantly disrupted in cancers, which commonly exhibit constitutively activated PI3K/Akt signalling, remains undefined. Here we report that miR-508 directly suppresses multiple phosphatases, including inositol polyphosphate-5-phosphatase J (INPP5J), phosphatase and tensin homologue (PTEN) and inositol polyphosphate 4-phosphatase type I (INPP4A), resulting in constitutive activation of PI3K/Akt signalling. Furthermore, we find that overexpressing miR-508 promotes, while silencing miR-508 impairs, the aggressive phenotype of oesophageal squamous cell carcinoma (ESCC) both in vitro and in vivo. Importantly, the level of miR-508 correlates with poor survival and activated PI3K/Akt signalling in a large cohort of ESCC specimens. These findings uncover a mechanism for constitutive PI3K/Akt activation in ESCC, and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cohort Studies
  • Disease Progression
  • Epigenesis, Genetic
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / metabolism
  • Esophageal Squamous Cell Carcinoma
  • Esophagus / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositols / chemistry*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Sequence Homology, Nucleic Acid
  • Signal Transduction

Substances

  • 3' Untranslated Regions
  • MIRN508 microRNA, human
  • MIRN508 microRNA, mouse
  • MicroRNAs
  • Phosphatidylinositols
  • Phosphatidylinositol 3-Kinases
  • Phosphoric Monoester Hydrolases
  • INPP5J protein, human
  • INPP5J protein, mouse