A screen identifies the oncogenic micro-RNA miR-378a-5p as a negative regulator of oncogene-induced senescence

PLoS One. 2014 Mar 20;9(3):e91034. doi: 10.1371/journal.pone.0091034. eCollection 2014.

Abstract

Oncogene-induced senescence (OIS) can occur in response to hyperactive oncogenic signals and is believed to be a fail-safe mechanism protecting against tumorigenesis. To identify new factors involved in OIS, we performed a screen for microRNAs that can overcome or inhibit OIS in human diploid fibroblasts. This screen led to the identification of miR-378a-5p and in addition several other miRNAs that have previously been shown to play a role in senescence. We show that ectopic expression of miR-378a-5p reduces the expression of several senescence markers, including p16(INK4A) and senescence-associated β-galactosidase. Moreover, cells with ectopic expression of miR-378a-5p retain proliferative capacity even in the presence of an activated Braf oncogene. Finally, we identified several miR-378a-5p targets in diploid fibroblasts that might explain the mechanism by which the microRNA can delay OIS. We speculate that miR-378a-5p might positively influence tumor formation by delaying OIS, which is consistent with a known pro-oncogenic function of this microRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oncogenes*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • MIRN378 microRNA, human
  • MicroRNAs
  • RNA, Messenger

Grants and funding

SMK was supported by a postdoctoral fellowship from the Netherlands Organisation for Scientific Research (NWO). The work in the Helin laboratory was supported by, the Danish National Advanced Technology Foundation, the Novo Nordisk Foundation, the Lundbeck Foundation, and the Excellence program of the University of Copenhagen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.