A Screen Identifies the Oncogenic Micro-RNA miR-378a-5p as a Negative Regulator of Oncogene-Induced Senescence

• Published in: PloS one Vol. 9; no. 3; p. e91034
• Main Authors: Kooistra, Susanne Marije, Nørgaard, Lise Christine Rudkjær, Lees, Michael James, Steinhauer, Cornelia, Johansen, Jens Vilstrup, Helin, Kristian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.03.2014; Public Library of Science (PLoS)
• Subjects: Bioinformatics; Biology and life sciences; Cell cycle; Cell Line; Cellular Senescence - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Ectopic expression; Epigenetics; Fibroblasts; Galactosidase; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Humans; INK4a protein; Kinases; Lung cancer; Medicine and Health Sciences; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Oncogenes; Oral cancer; p16 Protein; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Senescence; Stem cells; Target recognition; Transcription factors; Tumorigenesis; β-Galactosidase; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0091034

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.