RESUMO
Osteosarcoma (OS), which is a common and aggressive primary bone malignancy, occurs mainly in children and adolescent. Long noncoding RNAs (lncRNAs) are reported to play a pivotal role in various cancers. Here, we found that the lncRNA HOTAIRM1 is upregulated in OS cells and tissues. A set of functional experiments suggested that HOTAIRM1 knockdown attenuated the proliferation and stimulated the apoptosis of OS cells. A subsequent mechanistic study revealed that HOTAIRM1 functions as a competing endogenous RNA to elevate ras homologue enriched in brain (Rheb) expression by sponging miR-664b-3p. Immediately afterward, upregulated Rheb facilitates proliferation and suppresses apoptosis by promoting the mTOR pathway-mediated Warburg effect in OS. In summary, our findings demonstrated that HOTAIRM1 promotes the proliferation and suppresses the apoptosis of OS cells by enhancing the Warburg effect via the miR-664b-3p/Rheb/mTOR axis. Understanding the underlying mechanisms and targeting the HOTAIRM1/miR-664b-3p/Rheb/mTOR axis are essential for OS clinical treatment.
Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , RNA Longo não Codificante , Adolescente , Criança , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Osteossarcoma/patologia , Neoplasias Ósseas/patologia , Proliferação de Células/genética , Glicólise/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone. Recent studies have indicated that the inhibitory effects of microRNA (miR)-324-3p could affect the development of numerous cancers. However, its biological roles and underlying mechanisms in OS progression remain unexplored. In this study, miR-324-3p expression was markedly reduced in OS cell lines and tissues. Functionally, miR-324-3p overexpression suppressed OS progression and was involved in the Warburg effect. Mechanistically, miR-324-3p negatively regulated phosphoglycerate mutase 1 (PGAM1) expression by targeting its 3'-UTR. Moreover, high expression of PGAM1 promoted OS progression and aerobic glycolysis, which were associated with inferior overall survival in patients with OS. Notably, the tumor suppressor functions of miR-324-3p were partially recovered by PGAM1 overexpression. In summary, the miR-324-3p/PGAM1 axis plays an important role in regulating OS progression by controlling the Warburg effect. Our results provide mechanistic insights into the function of miR-324-3p in glucose metabolism and subsequently on the progression of OS. Targeting the miR-324-3p/PGAM1 axis could be a promising molecular strategy for the treatment of OS.
