New mechanism of miR-34a-5p in regulating the biological behavior of osteosarcoma by targeting FoxM1

Abstract

Osteosarcoma (OS), the most common primary malignant bone tumor in pediatric and adolescent populations, is characterized by significant morbidity and mortality. MicroRNAs (miRNAs) are essential non-coding RNAs that exert pivotal regulatory functions in diverse physiological and pathological processes, including tumorigenesis, disease progression, and drug resistance. The association of miR-34a-5p with osteosarcoma has been documented; However, its underlying mechanisms remain poorly understood.This investigation delineates the impact of miR-34a-5p on the proliferation, invasion, migration, and apoptosis of osteosarcoma cells via in vitro assays, aiming to elucidate the associated mechanisms. Employing up-regulation and knockdown strategies, this study evaluated the roles of miR-34a-5p and FoxM1 in modulating osteosarcoma cell behaviors.These effects were further validated through a rescue experiment, providing robust evidence of the miRNA's impact. Quantitative RT-PCR showed that, compared with normal tissues, miR-34a-5p was significantly downregulated while FoxM1 was markedly upregulated in nine osteosarcoma samples.Increased miR-34a-5p expression attenuated proliferation, migration, and invasion in MG-63 and U2OS cell lines, while enhancing apoptosis.Bioinformatic analyses and dual luciferase assays identified FoxM1 as a downstream target of miR-34a-5p, a finding corroborated by quantitative RT-PCR and Western blotting, which confirmed the negative regulation of FoxM1 by miR-34a-5p.Additionally, FoxM1 knockdown reduced tumor cell proliferation, migration, and invasion, concurrently promoting apoptosis; co-inhibition of miR-34a-5p and FoxM1 partially mitigated these effects. This study demonstrates that miR-34a-5p significantly inhibits osteosarcoma cell proliferation, migration, and invasion, while promoting apoptosis, by targeting and suppressing FoxM1. Our findings suggest that miR-34a-5p is a potential tumor suppressor with therapeutic value. The establishment of the miR-34a-5p/FoxM1 regulatory axis provides new insights into the molecular mechanisms of osteosarcoma. Targeting this axis could offer a promising strategy for improving the prognosis of osteosarcoma.

Keywords: FoxM1; Molecular targeting; Osteosarcoma; miR-34a-5p; miRNA.