MiR-378a-3p Is Critical for Burkitt Lymphoma Cell Growth

Fubiao Niu, Agnieszka Dzikiewicz-Krawczyk, Jasper Koerts, Debora de Jong, Laura Wijenberg, Margot Fernandez Hernandez, Izabella Slezak-Prochazka, Melanie Winkle, Wierd Kooistra, Tineke van der Sluis, Bea Rutgers, Miente Martijn Terpstra, Klaas Kok, Joost Kluiver, Anke van den Berg

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Abstract

Simple Summary

MicroRNAs (miRNAs) are small RNAs that regulate expression of specific target genes. We observed elevated levels of miR-378a-3p in Burkitt lymphoma (BL) and studied its role in the pathogenesis of BL. Inhibition of miR-378a-3p reduced growth of BL cells, confirming its significance in BL. Identification of BL specific target genes of miR-378a-3p revealed four candidates. For two of them, MNT and IRAK4, miR-378a-dependent regulation was confirmed at the protein level. Overexpression of MNT and IRAK4 in BL cell lines resulted in a similar effect as observed upon miR-378a-3p inhibition, suggesting their involvement in the growth regulatory role of miR-378a-3p.

MicroRNAs (miRNAs) are small RNA molecules with important gene regulatory roles in normal and pathophysiological cellular processes. Burkitt lymphoma (BL) is an MYC-driven lymphoma of germinal center B (GC-B) cell origin. To gain further knowledge on the role of miRNAs in the pathogenesis of BL, we performed small RNA sequencing in BL cell lines and normal GC-B cells. This revealed 26 miRNAs with significantly different expression levels. For five miRNAs, the differential expression pattern was confirmed in primary BL tissues compared to GC-B cells. MiR-378a-3p was upregulated in BL, and its inhibition reduced the growth of multiple BL cell lines. RNA immunoprecipitation of Argonaute 2 followed by microarray analysis (Ago2-RIP-Chip) upon inhibition and ectopic overexpression of miR-378a-3p revealed 63 and 20 putative miR-378a-3p targets, respectively. Effective targeting by miR-378a-3p was confirmed by luciferase reporter assays for MAX Network Transcriptional Repressor (MNT), Forkhead Box P1 (FOXP1), Interleukin 1 Receptor Associated Kinase 4 (IRAK4), and lncRNA Just Proximal To XIST (JPX), and by Western blot for IRAK4 and MNT. Overexpression of IRAK4 and MNT phenocopied the effect of miR-378a-3p inhibition. In summary, we identified miR-378a-3p as a miRNA with an oncogenic role in BL and identified IRAK4 and MNT as miR-378a-3p target genes that are involved in its growth regulatory role.

Original languageEnglish
Article number3546
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - Dec-2020

Keywords

  • Burkitt lymphoma
  • miR-378a-3p
  • cell growth
  • microRNA
  • LONG NONCODING RNA
  • HODGKIN-LYMPHOMA
  • DOWN-REGULATION
  • MYC
  • MICRORNA
  • FOXP1
  • ACTIVATION
  • EXPRESSION
  • JPX
  • PROLIFERATION

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