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

Abstract

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.

MicroRNA-26b-5p suppresses the proliferation of tongue squamous cell carcinoma via targeting proline rich 11 (PRR11)

“…In the last decade, several studies have identified miR-26b-5p to be crucial in the development and progression of cancers. As reported, miR-26b-5p is a tumor suppressor and modulator in cell cycle regulation that targets different genes, including CCND2, PLOD2, JAG1, MAP3K9 and KPN2 [ 6 , 8 , 23–25 ]. Notably, the ceRNA hypothesis sparked another miRNA-mediated mechanism, in which miRNA acts as the key modulator linking competing endogenous RNAs, including long non-coding RNA (lncRNA), circular RNA (circRNA), pseudogenes and protein-coding genes.…”

“…For instance, miR-26b-5p inhibites cell proliferation and induces apoptosis in multiple myeloma cells by targeting JAG1, and maintains the stemness of hepatocellular carcinoma cells by inhibiting HSC71/HSPA8. miR-26b-5p inhibition promoted the growth of Burkitt lymphoma cells by repressing the KPNA2 expression [ 8 ]. Additionally, miR-26b-5p upregulation restricted the malignant features of human apillary thyroid cancer by degrading beta-catenin [ 9 ].…”

Prognostic Value and Related Regulatory Networks of MRPL15 in Non-Small-Cell Lung Cancer

“…MRPL15 is a member of MRPL, which provides energy in the form of ATP for cell growth. MRPL15 has been reported to have a predictive value in breast cancer metastasis (19) and can promote Burkitt lymphoma growth (20). Little research has reported the predictive value of MRPL15 in NSCLC.…”

Increased expression of KPNA2 predicts unfavorable prognosis in ovarian cancer patients, possibly by targeting KIF4A signaling

“…Studies have determined that KPNA2 is associated with modulating both the nuclear import and the cytoplasm export of molecules [ 4 , 9 , 20 ]. Recently, higher expression of KPNA2 was demonstrated in breast cancer [ 8 ], burkitt lymphoma [ 23 ], melanoma [ 33 ], bladder cancer [ 25 ], and correlated with the poor prognosis of patients. However, the exact role of KPNA2 in ovarian cancer and its underlying molecular mechanism have not been elucidated.…”