Yash Narsian

Background: Osteosarcoma (OS) is the most common malignancy of the bone with the highest incidences in 18- & 60-year-olds. OS originates from aberrant mesenchymal stem cells.¹ In the 1980s, multiagent chemotherapy as standard treatment improved 5-year survival rates from ~20% to ~60%. However, since then, there has been little advancement, and the current survival rate is still 60%. ² This plateau in efficacy stems from the varied tumor responses to treatment. Furthermore, current methods for disease characterization (tumor size, location, histologic variance) cannot accurately characterize prognosis. Thus, it is imperative to identify genetic markers that can help us predict treatment response. ^2,3 Circular RNAs (circRNAs), a type of non-coding RNAs (ncRNAs) have emerged as a marker for OS prognosis. Levels of certain circRNAs are altered in an OS patient’s blood compared to a healthy patient and can serve as a clue for more accurately predicting interventional response in OS. ⁴

Objectives: In this narrative review we explored mechanisms of OS progression, drug resistance, and metastatic ability via altered levels of circular RNAs.

Methods: An online search in the PubMed database was conducted from 2019-2026 using the following key words: “Osteosarcoma”, ”Circular RNA”, “Drug Resistance”, ”Metastasis.”

Results: Studies indicate that circRNAs heavily influence OS malignancy. Modeling malignant transformation in human bone marrow mesenchymal stem cells (hbMSCs) showed that hsa_circ_0003611 knockout significantly increases cell proliferation, migration, and invasive capacity in vitro. In vivo experiments demonstrated tumor formation and MYC expression.⁵ Mechanistically, hsa_circ_0003611 serves a preventative role by stopping MYC mRNA stabilization; its loss unleashes MYC to precipitate tumor formation.⁵ Similarly, hsa_circ_0069117 acts as a tumor suppressor which is highly downregulated in OS.⁶ Its depletion elevates miR-875-3p levels and suppresses PF4V1, leaving the ERK1 and AKT cell growth pathways hyperactive via constitutive phosphorylation.⁶ Regarding chemoresistance, hsa_circ_0000073 is significantly upregulated in patient samples and correlates with metastatic disease and methotrexate (MTX) resistance.⁷ It competitively binds tumor-suppressor miR-145-5p and miR-151-3p to drive oncogenesis, whereas in vivo, has_circ_0000073 knockout restored MTX sensitivity and lowered proliferation.⁷ Similarly, circ_ANKIB1 is elevated in doxorubicin (DXR) resistant OS, where it sponges miR-26b-5p to increase free EZH2 levels.⁸ This upregulation drives the production of multi-drug resistance pumps (MRP1, P-gp, LRP) that expel DXR to block apoptosis.⁸ Finally, advanced Tumor-Node-Metastasis (TNM) stages correlate with overexpressed circ_0096041, which excessively binds miR-556-5p to upregulate the cell growth signaling protein LIN28A, accelerating aggressive metastatic spread.⁹

Conclusions: Studies demonstrate that certain circRNAs heavily dictate OS malignancy by modulating proliferation, metastasis, and drug resistance mechanisms. While hsa_circ_0003611 and hsa_circ_0069117 serve tumor-suppressive roles by inhibiting MYC mRNA stabilization and hyperactive ERK1/AKT signaling, their losses precipitate rapid oncogenesis. Furthermore, overexpression of hsa_circ_0000073, circ_ANKIB1, and circ_0096041 actively drives chemoresistance against methotrexate and doxorubicin alongside aggressive TNM-stage metastatic spread via miRNA sponging. Consideration of these specific regulatory circRNAs to stage/characterize OS and as therapeutic targets could provide avenues to overcome multi-drug resistance and lead to new effective, personalized therapies against osteosarcoma.

Work Cited:

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8. Tang J, Duan G, Wang Y, Wang B, Li W, Zhu Z. Circular RNA_ANKIB1 accelerates chemo-resistance of osteosarcoma via binding microRNA-26b-5p and modulating enhancer of zeste homolog 2. Bioengineered. 13(3):7351-7366. doi:1080/21655979.2022.2037869
9. Zhou F, Wu H, Yin Z, Zhou W, Chen W. Circular RNA circ_0096041 promotes osteosarcoma cell proliferation and migration via sponging miR-556-5p and regulating LIN28A expression. Cell Mol Biol (Noisy-le-grand). 2024;70(2):113-119. doi:14715/cmb/2024.70.2.16