Abstract
Osteosarcoma is the most common bone cancer in children and young adults. Surgery and multi-agent chemotherapy are the standard treatment regimens for this disease. New therapies are being investigated to improve overall survival in patients. Molecular targets that actively modulate cell processes, such as cell-cycle control, cell proliferation, metabolism, and apoptosis, have been studied, but it remains a challenge to develop novel, effective-targeted therapies to treat this heterogeneous and complex disease. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating cell processes including growth, development, and disease. miRNAs function as oncogenes or tumor suppressors to regulate gene and protein expression. Several studies have demonstrated the involvement of miRNAs in the pathogenesis of osteosarcoma with the potential for development in disease diagnostics and therapeutics. In this review, we discuss the current knowledge on the role of miRNAs and their target genes and evaluate their potential use as therapeutic agents in osteosarcoma. We also summarize the efficacy of inhibition of oncogenic miRNAs or expression of tumor suppressor miRNAs in preclinical models of osteosarcoma. Recent progress on systemic delivery as well as current applications for miRNAs as therapeutic agents has seen the advancement of miR-34a in clinical trials for adult patients with non-resectable primary liver cancer or metastatic cancer with liver involvement. We suggest a global approach to the understanding of the pathogenesis of osteosarcoma may identify candidate miRNAs as promising biomarkers for this rare disease.
Highlights
Osteosarcoma (OS) is an aggressive bone cancer that affects children and adolescents
Osteosarcoma is characterized by complex, unbalanced karyotypes, and the pattern of abnormalities varies among patients
Genomic amplifications occur in approximately 30% of OS cases [20], which are associated with the action of oncogenes, such as apurinic/apyrimidinic exonuclease 1 (APEX1), cellular homolog of avian myelocytomatosis virus (MYC), RecQ protein-like 4 (RECQL4), CDK4, mouse double minute 2 (MDM2), RUNX2, and vascular endothelial growth factor A (VEGFA) [51]
Summary
Osteosarcoma (OS) is an aggressive bone cancer that affects children and adolescents. Downregulation of the miR-15/16 family increases expression of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid leukemia cell differentiation protein (Mcl-1) [14] and loss of let-7a facilitates amplification of the c-myelocytomatosis virus (MYC) oncogene to promote B-cell tumorigenesis [15] Characterization of these miRNAs that display altered expression in OS may provide distinct miRNAs or miRNA signatures related to particular molecular patterns associated with this disease. The molecular analysis of solid tumors (MAST) clinical trial (NCT01050296) is designed to prospectively characterize the molecular, cellular, and genetic properties of primary and metastatic solid tumors in patients including OS These studies present a novel opportunity to investigate the expression of miRNAs in the blood, body fluids, and tissue of patients as an early predictor of cancer as well as a marker of response to therapy. This review discusses some of the prominent pathological factors of OS that may be regulated by miRNAs and highlights miRNAs that are validated in preclinical OS models
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