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Open AccessArticle

The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth

1
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
2
Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
3
Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
4
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
5
Division of Microbiology and Immunology, Huntsman Cancer Institute, Department of Pathology at the University of Utah, Salt Lake City, UT 84112, USA.
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(6), 1464; https://doi.org/10.3390/cancers12061464
Received: 11 May 2020 / Revised: 29 May 2020 / Accepted: 31 May 2020 / Published: 4 June 2020
The expression of several microRNAs (miRNAs) is known to be changed in Burkitt lymphoma (BL), compared to its normal counterparts. Although for some miRNAs, a role in BL was demonstrated, for most of them, their function is unclear. In this study, we aimed to identify miRNAs that control BL cell growth. Two BL cell lines were infected with lentiviral pools containing either 58 miRNA inhibitors or 44 miRNA overexpression constructs. Eighteen constructs showed significant changes in abundance over time, indicating that they affected BL growth. The screening results were validated by individual green fluorescent protein (GFP) growth competition assays for fifteen of the eighteen constructs. For functional follow-up studies, we focused on miR-26b-5p, whose overexpression inhibited BL cell growth. Argonaute 2 RNA immunoprecipitation (Ago2-IP) in two BL cell lines revealed 47 potential target genes of miR-26b-5p. Overlapping the list of putative targets with genes showing a growth repression phenotype in a genome-wide CRISPR/Cas9 knockout screen, revealed eight genes. The top-5 candidates included EZH2, COPS2, KPNA2, MRPL15, and NOL12. EZH2 is a known target of miR-26b-5p, with oncogenic properties in BL. The relevance of the latter four targets was confirmed using sgRNAs targeting these genes in individual GFP growth competition assays. Luciferase reporter assay confirmed binding of miR-26b-5p to the predicted target site for KPNA2, but not to the other genes. In summary, we identified 18 miRNAs that affected BL cell growth in a loss- or gain-of-function screening. A tumor suppressor role was confirmed for miR-26b-5p, and this effect could at least in part be attributed to KPNA2, a known regulator of OCT4, c-jun, and MYC. View Full-Text
Keywords: Burkitt lymphoma; miR-26b-5p; microRNA; KPNA2 Burkitt lymphoma; miR-26b-5p; microRNA; KPNA2
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Niu, F.; Kazimierska, M.; Nolte, I.M.; Terpstra, M.M.; de Jong, D.; Koerts, J.; van der Sluis, T.; Rutgers, B.; O’Connell, R.M.; Kok, K.; van den Berg, A.; Dzikiewicz-Krawczyk, A.; Kluiver, J. The miR-26b-5p/KPNA2 Axis Is an Important Regulator of Burkitt Lymphoma Cell Growth. Cancers 2020, 12, 1464.

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