Competitive endogenous network of circRNA, lncRNA, and miRNA in osteosarcoma chemoresistance

The competitive endogenous RNA mechanism plays a major role in the biological functions of circRNAs in cells because it contains miRNA-binding sites [12, 26]. CircCHI3L1.2 was found to be elevated in cisplatin-resistant OS cells [27], and the miR-340-5p and LPAAT axis could be used to make circCHI3L1.2-deficient OS cells more sensitive to cisplatin-resistant OS. They found that miR-340-5p could bind to circ-CHI3L1.2. Moreover, miR-340-5p's target, LPAATβ, had less protein expression when circ-CHI3L1.2 was knocked down. Notably, the effect of circ-CHI3L1.2 knockdown was mitigated by the miR-340-5p inhibitor. According to their findings, the miR-340-5p-LPAAT axis was involved in circ-CHI3L1.2's contribution to cisplatin resistance. The effects of circ-CHI3L1.2 knockdown were partially reversed by miR-340-5p suppression, which suggested that there were additional downstream pathways besides the miR-340-5p-LPAAT axis. Other potential mechanisms should be explored in future studies. Numerous cancers have been linked to the oncogene CircPVT1. CircPVT1 was found to be up-regulated in OS tissues resistant to cisplatin, doxorubicin or methotrexate [28]. The targeting relationships of circPVT1/miR-24-3p and miR-24-3p/KLF8 were verified. CircPVT1 could act as a sponge of miR-24-3p. A further confirmation of the negative regulation between circPVT1 and miR-24-3p was observed in OS cells. This research found that the overexpression of miR-24-3p inhibited the proliferation of OS cells, and increased the sensitivity of chemoresistant U2OS and MG63 cells to chemotherapy. The bioinformatics analysis suggested that KLF8 might be a downstream target of miR-24-3p. The binding association between miR-24-3p and KLF8 was confirmed by dual-luciferase reporter and RNA pull-down assays. KLF8 transcription factor played a vital role in oncogenic transformation. Nevertheless, the existing literature lacks a thorough discussion of the oncogenic role of KLF8 and its underlying mechanism. KLF8 was highly expressed in OS cell lines and was even further upregulated in chemoresistant OS cells, as confirmed by qRT-PCR and Western blotting assessments. The expression of KLF8 exhibited a positive correlation with that of circPVT1, while it demonstrated a negative association with that of miR-24-3p. Collectively, through the axis of miR-24-3p and KLF8, circPVT1 promotes OS cell proliferation and drug resistance. CircPVT1 is involved in drug resistance in OS tumor cells through multiple pathways. The overexpression of circPVT1 is responsible for OS cell drug resistance to doxorubicin and cisplatin by controlling the ATP-binding box (ABC) transporter ABCB1 [29]. OS cells resistant to cisplatin show elevated expression levels of CircuUBAP2 and SEMA6D. By activating the Wnt/β-catenin signaling pathway through the miR-506-3p/SEMA6D axis, circUBAP2 increases OS resistance to cisplatin [30]. CircDOCK1 [31] encourages OS cells to become cisplatin-resistant via the miR-339-3p and IGF1R axes. The circRNA LARP4 increases OS chemotherapy sensitivity to cisplatin and doxorubicin by sponging microRNA-424 [32]. The competitive endogenous RNA mechanism of circRNAs contributes to the resistance of OS to chemotherapy and several other biological functions.

By controlling miR-342-3p and FBN1, hsa_circ_0004674 [33] promotes resistance to doxorubicin through the Wnt/β-catenin pathway, suggesting that hsa_circ_0004674 could be a promising target for OS resistance. The researchers found high levels of hsa_circ_0004674 expression in osteosarcoma cells and tissues that were resistant to doxorubicin. OS tumors became more sensitive to doxorubicin when hsa_circ_0004674 was knocked out. Moreover, their study discovered that miR-342-3p was under expressed in the doxorubicin-resistant OS tissues and cells, inhibiting OS doxorubicin resistance. The anti-miR-342-3p reversal effect on si-hsa_circ_0004674 suggested that hsa_circ_0004674 modulated the doxorubicin resistance of OS by targeting miR-342-3p. Studies unveiled that miR-342-3p targeted FBN1, whose aberrant expression is linked to the malignant phenotype of several tumors, such as ovarian cancer [34] and papillary thyroid carcinoma [35]. The results showed that miR-342-3p increased resistance to doxorubicin through its interaction with FBN1. The research suggests that during the malignant progression of many cancers, the activity of the Wnt/β-catenin signaling pathway is significantly upregulated [36]. Related studies of osteosarcoma have shown that activation of the Wnt/β-catenin pathway is associated with chemoresistance, whereas inhibiting this pathway has been demonstrated to enhance chemotherapy sensitivity. Silencing hsa_circ_0004674 was found to inhibit the activity of the Wnt/β-catenin pathway. Further analysis revealed that hsa_circ_0004674 had a positive regulatory effect on the activity of the Wnt/β-catenin pathway through the miR-342-3p/FBN1 axis. It has been reported that circPVT1 [37] was concerned with OS cell drug resistance to doxorubicin by controlling TRIAP1 through miR-137. circPVT1 knockdown could boost doxorubicin sensitivity by inhibiting doxorubicin-caused proliferation and doxorubicin -induced apoptosis in doxorubicin-resistant osteosarcoma cells in vitro. The mechanical analysis revealed that circPVT1 functioned as a miR-137 sponge to regulate TRIAP1 expression. Furthermore, a mechanistic analysis confirmed that the miR-137 inhibitor was able to partially reverse the inhibitory effect of silencing circPVT1 on the TRIAP1 level in doxorubicin-resistant osteosarcoma cells. This validates the role of circPVT1 as a miR-137 sponge that upregulates TRIAP1 expression. Through the miR-524/RASSF6 axis, circITCH downregulation promotes OS development and doxorubicin resistance [38]. The interaction between circITCH, miR-524, and RASSF6 was confirmed through dual-luciferase reporter and RNA immunoprecipitation assays. By binding to microRNA-26B-5P and modulating EZH2, circular RNAANKIB1 promotes chemotherapy resistance in OS [39]. The expression of miR-26b-5p was suppressed in both OS tissues and cells, as well as doxorubicin-resistant OS tissues and cells, while the levels of circ_ANKIB1 and EZH2 were increased. Circ_ANKIB1 binds to miR-26b-5p. MiR-26b-5p directly targeted EZH2, and increasing the levels of EZH2 reversed the effect of elevated miR-26b-5p on doxorubicin-resistant cells. In vivo, silencing of circ_ANKIB1 suppressed the growth of doxorubicin-resistant OS cells.

It was discovered for the first time that hsa_circ_0000073 may enhance the proliferation, migration, invasion and methotrexate resistance of OS cells [40]. It was discovered that the expression of hsa_circ_0000073 was highly upregulated in both OS cells and tissues, which in turn led to poor OS survival. In order to determine whether hsa_circ_0000073 is involved in the competitive endogenous RNA model, predictions were made and it was observed that miR-145-5p and miR-151-3p directly bind to hsa_circ_0000073. At the same time, miR-145-5p and miR-151-3p exhibited a negative correlation with hsa_circ_0000073. miR-145-5p and miR-151-3p directly regulate NRAS. In OS cells, hsa_circ_0000073 upregulates NRAS by inhibiting miR-145-5p and miR-151-3p. According to their study, hsa_circ_0000073 may enhance the proliferation, migration and invasion of OS cells by directing the regulation of NRAS through miR-145-5p or miR-151-3p. The authors also hypothesized that methotrexate resistance in OS could be closely associated with the hsa_circ_0000073/miR-145-5p and miR-151-3p/NRAS axes. Circ_0081001 [41] has been implicated in regulating the sensitivity of OS cells to methotrexate by controlling the miR-494-3p/TGM2 axis. In methotrexate-resistant OS tissues and cells, expression levels of Circ_0081001 and TGM2 were upregulated while miR-494-3p was downregulated. Interference with Circ_0081001 resulted in increased cell sensitivity to methotrexate by promoting apoptosis and inhibiting cell viability and metastasis in vitro. Furthermore, a molecular sponge effect of circ_0081001 on miR-494-3p led to the upregulation of TGM2 level. Knockdown of circ_0081001 inhibited methotrexate resistance by upregulating miR-494-3p and downregulating TGM2. The downregulation of Circ_0081001 improved methotrexate sensitivity of OS in vivo.

Chemotherapy of osteosarcoma has evolved from the initial single-drug application to the current multidrug combination. The combination of a variety of chemotherapy drugs achieved a good therapeutic effect. At the same time, the efficacy and adverse reactions of the drug should be comprehensively considered when the combination of chemotherapy drugs is used. The adverse reactions should be minimized, and personalized treatment plans should be provided for patients. How to combine drugs reasonably become the future research direction of molecular targeted drugs.

The toxicity of a drug to normal tissue limits the potential dose, and the kinetics of the drug (including absorptive capacity, in vivo distribution, metabolism, and elimination) limit the concentration at which the drug can reach the tumor tissue. The recent advancements in cancer nanotechnology can offer chemotherapeutic drugs longer exposure times and extended circulating half-lives. Nevertheless, the most fundamental solution is to prevent and overcome multiple-drug resistance to chemotherapy drugs.

Before the stage of clinical and translational medicine research, it is necessary to combine in vivo pharmacology methods and genomics analysis platforms. Through the creation of animal models with drug-resistant tumors, the mechanism behind OS resistance can be better understood, and an optimal dosage regimen can be established. This approach can lead to the design of more effective OS drugs that demonstrate clinical benefits, ultimately fostering a new generation of anticancer medications. The establishment of dependable preclinical tumor drug-resistant cell models holds significant importance for delving further into the attributes of drug-resistant cells and for identifying novel clinical therapeutic strategies.

Through genetic testing, the type of genetic variation and level of biomarkers in a patient's body can be determined, and clinicians can make decisions based on a comprehensive analysis of these indicators. The established databases include mutation points associated with drug responses, providing a description of the possible role of gene mutation sites in drug resistance and the level of evidence to effectively address possible drug intolerance or toxic side effects in patients with cancer.

With the discovery, prediction, and clinical application of molecular diagnostic markers, precise treatments for different patients are also being promoted. The drug resistance of tumor cells can be viewed from an evolutionary perspective, and a variety of therapeutic methods used to combat tumor cells. The most important challenge in tumor resistance is to quickly identify biological indicators of multiple-drug resistance before the emergence of tumor resistance. Through high-throughput screening techniques and systems biology approaches, researchers can partially detect or predict the response of tumor cells to particular chemotherapeutic drugs, thus avoiding complications before administering chemotherapy. In the future, the research direction of tumor resistance may be to identify molecular markers of tumor resistance, predict and monitor chemotherapy efficacy, perform early detection and prognosis combined with laboratory and imaging examinations, and develop chemotherapy drugs for effective targets.