MiR ‐22 is Frequently Downregulated in Medulloblastomas and Inhibits Cell Proliferation via the Novel Target PAPST 1

Medulloblastoma is the most frequent malignant central nervous system tumor in children. Micro RNA s ( miRs ) are small, non‐coding RNAs that target protein‐coding and non‐coding RNAs , and play roles in a variety of cellular processes through regulation of multiple targets. In the present study, we analyzed mi R ‐22 expression and its effect in cell proliferation and apoptosis in medulloblastomas. Quantitative reverse transcription PCR ( RT ‐ PCR ) revealed significantly lower expression of mi R ‐22 in 19 out of 27 (70%) medulloblastomas, D 341, DAOY , ONS ‐76 medulloblastoma cell lines, compared with normal cerebellum. Forced expression of mi R ‐22 by lentiviral vector transfection reduced cell proliferation and induced apoptosis, while knockdown of mi R ‐22 increased proliferative activity in DAOY and ONS ‐76 cells. DAOY cells with mi R ‐22 overexpression in nude mice yielded tumors smaller than those originated from control DAOY cells. Microarray analysis in DAOY cells with forced mi R ‐22 expression showed significant changes in expression profiles, PAPST 1 being the most significantly (10 folds) downregulated gene. Quantitative RT ‐ PCR revealed PAPST 1   mRNA upregulation in 18 out of 27 (67%) medulloblastomas. In addition, a luciferase reporter assay in ONS ‐76 and DAOY cells suggested that mi R ‐22 directly targets the PAPST 1 gene, and lentivirus‐mediated knockdown of PAPST 1 suppressed proliferation of DAOY and ONS ‐76 medulloblastoma cells. These results suggest that frequently downregulated mi R ‐22 expression is associated with cell proliferation in medulloblastomas, and this may be at least in part via PAPST 1 , which is a novel target of mi R ‐22.