Exosomal circ_0004136 enhances the progression of pediatric acute myeloid leukemia depending on the regulation of miR-570-3p/TSPAN3 axis

Anticancer Drugs. 2021 Apr 12. doi: 10.1097/CAD.0000000000001068. Online ahead of print.

Abstract

Circular RNAs (circRNAs) have been implicated in the progression of pediatric acute myeloid leukemia (AML). Although circ_0004136 has been found to play a crucial role in AML, our understanding of its molecular mechanism remains very limited. The levels of circ_0004136, miR-570-3p and tetraspanin 3 (TSPAN3) were determined by quantitative real-time PCR or western blot. Cell viability, migration, invasion, cell cycle and apoptosis were detected using the Cell Counting Kit-8, transwell and flow cytometry assays. Targeted relationships among circ_0004136, miR-570-3p and TSPAN3 were validated by dual-luciferase reporter and RNA immunoprecipitation assays. Our data showed that circ_0004136 could be transmitted by exosomes, and exosomal circ_0004136 was highly expressed in AML serum and cells. Circ_0004136 was unusually stable and mainly localized in the cytoplasm. Circ_0004136 knockdown mediated by exosomes hampered AML cell viability, cell cycle progression, migration and invasion, and promoted cell apoptosis. Moreover, circ_0004136 worked as a sponge of miR-570-3p and TSPAN3 was a functional target of miR-370-3p in AML cells. The suppression of circ_0004136 knockdown mediated by exosomes on AML cell malignant progression was reversed by miR-570-3p downregulation, and the increased miR-570-3p expression hindered the progression of aggressive AML by downregulating TSPAN3. Furthermore, circ_0004136 worked as a miR-570-3p sponge to modulate TSPAN3 expression. Our findings identified a novel regulatory mechanism in which exosome-mediated circ_0004136 knockdown restrained AML cell malignant progression at least partly through targeting the miR-570-3p/TSPAN3 axis, highlighting a novel therapeutic strategy for AML management.