MicroRNA-383 regulates the apoptosis of tumor cells through targeting Gadd45g

PLoS One. 2014 Nov 21;9(11):e110472. doi: 10.1371/journal.pone.0110472. eCollection 2014.

Abstract

Background: MicroRNAs (miRNAs) are a class of small non-coding single-stranded RNA molecules that inhibit gene expression at post-transcriptional level. Gadd45g (growth arrest and DNA-damage-inducible 45 gamma) is a stress-response protein, which has been implicated in several biological processes, including DNA repair, the cell cycle and cell differentiation.

Results: In this work, we found that miR-383 is a negative regulator of Gadd45g. Forced expression of miR-383 decreased the expression of Gadd45g through binding to the 3' untranslated region (3'-UTR), whereas inhibition of miR-383 increased Gadd45g expression. The presence of miR-383 increased the cellular sensitivity to DNA damage in breast cancer cells, which was rescued by ectopic expression of Gadd45g without the 3'-UTR. miR-383 also regulates the expression of Gadd45g in embryonic stem (ES) cells, but not their apoptosis under genotoxic stress. miR-383 was further showed to negatively regulate ES cell differentiation via targeting Gadd45g, which subsequently modulates the pluripotency-associated genes. Taken together, our study demonstrates that miR-383 is a negative regulator of Gadd45g in both tumor cells and ES cells, however, has distinct function in regulating cell apoptosis. miR-383 may be used as antineoplastic agents in cancer chemotherapy.

Conclusion: We demonstrate for the first time that miR-383 can specifically regulates the expression of Gadd45g by directly targeting to the 3-UTR region of Gadd45g mRNA, a regulatory process conserved in human tumor cells and mouse embryonic stem cells. These two compotents can be potentially used as antineoplastic agents in cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Cell Differentiation
  • Cisplatin / pharmacology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / radiation effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MCF-7 Cells
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Protein Binding
  • Ultraviolet Rays

Substances

  • 3' Untranslated Regions
  • Antineoplastic Agents
  • GADD45G protein, human
  • Intracellular Signaling Peptides and Proteins
  • MIRN383 microRNA, human
  • MicroRNAs
  • Cisplatin

Grant support

This work was supported by the 973 program of the Ministry of Science and Technology of China (Grant No.: 2011CB965302, 2013CB967600, 2014CB964603), the National Natural Science Foundation of China (Grant No.: 31330043, 31201051, 31271534, 91319306, 81400152). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.