Mechanism of bone-marrow mesenchymal stem cell-derived exosomes mediating microRNA-139-5p to regulate β-catenin in the modulation of proliferation and apoptosis of acute myeloid leukemia cells.

Objective: Acute myeloid leukemia (AML) stands out as a malignancy of the stem cell precursors of the myeloid lineage. Bone-marrow mesenchymal stem cell-derived exosomes (BMSC-exos) affect AML progression. We explored the effects and mechanism of BMSC-exos on AML cell proliferation and apoptosis.

Methods: Human AML cells (MOLM-16, MV-4-11) and normal human hematopoietic cells (GM12878) cultured in vitro were treated with exos extracted from BMSCs that transfected with microRNA (miR)-139-5p-mimics, ovβ-catenin, or miR-139-5p-inhibitor. BMSC morphology was observed by a microscopy, and its adipogenic and osteogenic differentiation abilities were assessed by oil red O staining and alizarin red S staining. BMSC-exos were extracted by ultracentrifugation, and their morphology was observed by a transmission electron microscopy. BMSC-exos were identified by nanoparticle tracking analysis and Western blot. The binding sites between miR-139-5p and β-catenin were predicted by TargetScan database, and then validated by dual-luciferase reporter assay. mRNA levels of miR-139-5p and β-catenin, cell proliferation, and apoptosis were evaluated by RT-qPCR, CCK-8, and flow cytometry. The expressions of CD63, CD81, TSG101, and GRP94 and the proteins of β-catenin, Bax, and Bcl-2 were determined by Western blot.

Results: miR-139-5p was poorly expressed in AML cell lines. miR-139-5p overexpression reduced AML cell viability/proliferation/Bcl-2 level, and raised apoptosis/Bax level. BMSC-exos repressed AML cell proliferation and promoted apoptosis via miR-139-5p. miR-139-5p targeted to inhibit β-catenin expression. Subsequently, up-regulated β-catenin partially counteracted the effects of miR-139-5p in BMSC-exos on AML cell proliferation and apoptosis.

Conclusion: BMSC-exos targeted to repress β-catenin expression by miR-139-5p, limited AML cell proliferation and facilitated apoptosis.