Circ_0009910 shuttled by exosomes regulates proliferation, cell cycle and apoptosis of acute myeloid leukemia cells by regulating miR-5195-3p/GRB10 axis

Hematol Oncol. 2021 May 10. doi: 10.1002/hon.2874. Online ahead of print.

Abstract

The exosomes are involved in intercellular communication via RNA trafficking in human diseases. Hsa_circ_0009910 (circ_0009910) is a novel leukemia-related circular RNA. However, the mechanism of circ_0009910 in acute myeloid leukemia (AML) cell-to-cell communication remained obscure. Expression of circ_0009910, miRNA (miR)-5195-3p and growth factor receptor-bound protein 10 (GRB10) was detected by quantitative real-time polymerase chain reaction and Western blotting. A stable cell coculture model was established and functional experiment was performed using Cell Counting Kit-8 assay, flow cytometry, and Western blotting. The interaction among circ_0009910, miR-5195-3p and GRB10 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. As a result, circ_0009910 was upregulated in AML bone marrows and cells (HL-60 and MOLM-13), even higher in AML cells-derived exosomes. Functionally, blocking circ_0009910 via small interfering RNA (siRNA) suppressed cell proliferation and cell cycle progression, but facilitated apoptosis rate of HL-60 and MOLM-13 cells, accompanied with lower B-cell lymphoma 2 (Bcl-2) level and higher Bcl-2-associated X protein (Bax) level. circ_0009910 shuttled via exosomes negatively regulated miR-5195-3p expression by target binding. Furthermore, circ_0009910 knockdown via exosomes and miR-5195-3p overexpression via mimic resulted in similar results of circ_0009910 siRNA in proliferation, apoptosis and cell cycle progression of AML cells. Meanwhile, the role of circ_0009910 knockdown in AML cells was partially reversed by miR-5195-3p deletion, and restoring GRB10 could abrogate miR-5195-3p effect as well. Notably, GRB10 was a downstream target of miR-5195-3p. circ_0009910-containing exosomes mediated proliferation, apoptosis and cell cycle progression of AML cells partially through miR-5195-3p/GRB10 axis.

Keywords: AML; GRB10; circ_0009910; miR-5195-3p.