Circular RNAs in osteosarcoma: An update of recent studies (Review)
Corrigendum in: /10.3892/ijo.2024.5696
- Authors:
- Published online on: September 6, 2023 https://doi.org/10.3892/ijo.2023.5571
- Article Number: 123
Abstract
Introduction
Osteosarcoma (OS) typically originates from the long bones, including the distal femur (30%), proximal tibia (15%) and proximal humerus (15%). As a primary malignant bone tumor of mesenchymal origin, OS exhibits osteoblastic differentiation and malignant osteoid (1). The clinical treatment of OS primarily includes surgical intervention, radiotherapy, and chemotherapy. Although a combination of chemotherapy and surgical intervention has resulted in an ~60% increase in the survival rate of patients with OS, the 5-year survival rate and prognosis of patients with OS remain unsatisfactory due to a lack of early diagnostic and effective treatment methods (1–3). In particular, OS is prone to multidrug resistance and lung metastasis (4,5). Tumor suppressor genes p53 and Retinoblastoma (Rb) are typically observed to be mutated in clinical samples of patients with OS and are closely associated with susceptibility to OS (6). The molecular pathogenesis of OS involves the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3, nuclear factor κB (NF-κB), phosphatidylinositol 3 kinase (PI3K)/serine/threonine kinase (AKT) and Wingless/Integrated (Wnt)/β-catenin signaling pathways, among others. These signaling pathways play crucial roles during the onset and development of OS (7–10).
Non-coding RNAs (ncRNAs) are a class of RNAs that lack the ability to encode proteins. Over the course of the past decade, ncRNAs have been found to play vital roles in gene expression regulation. ncRNAs can be classified based on their length as follows: small RNAs, which are defined as those that are <200 nt in length, and long non-coding RNAs (lncRNAs), which are those that are ≥200 nt (11). Small RNAs can be further classified into small interfering RNAs (siRNAs), microRNAs (miRNAs/miRs), Piwi-interacting RNAs (piRNAs), etc. miRNAs are ~22 nt in length and regulate gene expression by binding to response elements [also known as miRNA response elements (MREs)] on target RNAs (12). Circular RNAs (circRNAs) are covalently closed RNA molecules formed through back-splicing, a process that differs from the classical splicing mechanism. These molecules lack a 5′ end cap structure and 3′ end polyadenylate tail, rendering them resistant to degradation by endonucleases and conferring a longer half-life (>48 h) (13). In addition, circRNAs are expressed in specific cells and tissues, and a number of them are evolutionarily conserved (14,15). Owing to their unique and novel biological structure and function, circRNAs have emerged as a prominent area of research following miRNAs and lncRNAs.
Several studies have reported that circRNAs play critical roles in the pathogenesis of various diseases by regulating various cellular processes, including the cell cycle, tumorigenesis, invasion, metastasis, apoptosis and angiogenesis (16–20). circRNAs have shown promise as novel biomarkers for diagnosis and as therapeutic targets for various diseases (21). Functional analyses on circRNAs have demonstrated that circRNAs regulate the expression of particular mRNAs by adsorbing their corresponding binding miRNAs from targeted sites (22). Additionally, circRNAs also directly modulate the functions of proteins by binding to RNA-binding proteins (RBPs) (23). Moreover, certain circRNAs are directly translated into proteins/peptides, thereby exerting their functions in the form of proteins/peptides (24). For examples, protein C-E-Cad encoded by the circular E-cadherin RNA (circ-E-Cad) facilitates the proliferation and migration of gastric cells by the PI3K/AKT pathway (25). Protein EIF6-224aa translated from circRNA Circ-EIF6 contributes to the breast cancer progression via stabilizing MYH9 and activating the Wnt/beta-catenin pathway (26). In two recently related reviews, ~30 proteins/peptides translated from circRNAs were experimentally validated to have importantly physiological and pathological functions (27,28). Numerous aberrantly expressed circRNAs have been identified and shown to be involved in the occurrence and development of OS (29,30). Although an increasing number of aberrantly expressed circRNAs have been identified in OS, their functions and molecular mechanisms remain unclear. Therefore, the present review provides an overview of the aberrantly expresssed circRNAs, the primary types of circRNAs, the functions and mechanisms of circRNAs, and the potential clinical application of circRNAs in OS, in an aim to provide new insight into the diagnosis and treatment of OS.
Types of circRNAs
As early as 1976, Sanger et al (29) and Kolakofsky (31) first identified circRNAs in plant viruses and Sendai viruses, respectively. Since then, circRNAs have been observed in the cytoplasm of eukaryotic cells through electron microscopy (32–34). Previous studies have posited that circRNAs are abnormal RNAs that arise from erroneous splicing events, often referred to as ‘junk molecules’ and ‘splicing noise’. Thus, for a considerable amount of time, the functional aspects of circRNAs were disregarded (35). In 2013, thousands of well-expressed, stable circRNAs were identified in humans, mice and nematodes, and certain circRNAs were revealed to function as miRNA sponges. Thereafter, scholars in the field have increasingly focused on the biogenesis and functional studies of circRNAs (15,22).
At present, the understanding of the biogenesis of circRNAs is incomplete (36). circRNAs can be classified into six groups based on their constituent sequences as follows: Exonic circRNAs (ecircRNAs) (14,15,37,38), exon-intron circRNAs (EIciRNAs) (14,37), circular intronic RNAs (ciRNAs) (15,39,40), antisense circular RNAs (anti-circRNAs) (15,41), tRNA intronic circular RNAs (tricRNAs) (38) and intergenic circRNAs (15,41) (Fig. 1). ecircRNAs are only formed of exon sequences, whereas EIciRNAs are formed of a mixture of ciRNAs and ecircRNAs, encompassing both exon and intron sequences. ciRNAs contain only intron sequences. Anti-circRNAs include antisense ecircRNAs, antisense EIciRNAs and antisense ciRNAs, which are generated from the antisense strand. triRNAs are produced from pre-tRNAs introns. Intergenic circRNAs are circRNAs produced by the sequence between two distinct protein-coding genes. Although circRNAs are of distinct types, the majority of the circRNAs identified to date are ecircRNAs, according to circRNA-related databases such as circRNADb and TRCirc (42,43).
The biogenesis of ecircRNAs is closely associated with their host pre-mRNAs. When the splicing receptor of the upstream exon of a pre-mRNA and its downstream exon donor are in close proximity, a lasso structure containing both exons and introns is produced. As the introns in the lasso structure are excised, ecircRNAs are formed through the formation of phosphate ester bonds. Another mechanism through which ecircRNAs are produced involves RBPs. Specifically, RBPs facilitate the interaction between the upstream and downstream introns of pre-mRNAs, thereby enabling the formation of ecircRNAs (44). The production of EIciRNAs is primarily associated with circularization driven by intron pairing. In this process, the downstream intron splicing donor and the upstream intron splicing receptor are paired, based on the Alu complementary base sequences. Subsequently, introns are either retained or excised. Finally, EIciRNAs or ecircRNAs may be produced through a third mechanism (37). ciRNAs contain only introns, and their biogenesis primarily relies on a 7-nt GU-rich sequence proximal to the 5′ splicing site and an 11-nt C-rich sequence proximal to the branching point site, which serves to prevent degradation by exonucleases, with ciRNAs forming after cyclization (39). Anti-circRNAs, including antisense ecircRNAs, antisense EIciRNAs, and antisense ciRNAs, are transcribed from non-coding gene loci on the antisense strand (15,45).
tricRNAs are a specific type of intronic circRNAs that have been exclusively detected in Archaea and Drosophila. During the pre-tRNA splicing process, the conserved tRNA sequence and splicing enzymes are required. The enzymes cleaves pre-tRNAs into two parts: tricRNAs are generated from 3′ to 5′ phosphate bonds, and the other portion gives rise to tRNAs (41,45). Intergenic circRNAs are formed by the cyclization of intergenic sequences situated between two protein-coding genes (15).
Functions of circRNAs in OS
circRNAs are primarily classified into six categories based on their origin and are notably plentiful. According to the latest records available on circRNADb and TRCircle, there are at least 90,000 circRNAs in human cells (42,43). However, the majority of aberrantly expressed circRNAs in OS were identified between 2018 and 2022. Furthermore, to date, the functions of only ~20 circRNAs have been reported (46–81) (Table I). Functional analyses on circRNAs in OS have beeb primarily centered around miRNA sponges (Fig. 2A). miRNA sponges, also referred to as competitive endogenous RNAs (ceRNAs), are RNA transcripts that share MREs to regulate gene expression by competing with miRNAs. Theoretically, any transcripts containing MREs, including mRNAs, lncRNAs, pseudogene RNAs and circRNAs, have the potential to function as ceRNAs (82). For example, upregulated Circ_0005909 functions as a sponge for miR-936, thereby rendering the translation of high mobility group protein 1 (HMGB1), which is targeted by this miRNA, impervious to its effects. Hence, OS growth, proliferation, epithelial-mesenchymal transformation (EMT), migration and invasion are promoted (55). A given circRNA can be targeted by multiple distinct miRNA pairs. Additionally, a single miRNA can target various circRNAs. Circ_0001649 and Circ_0001649 have been reported as sponges of various miRNAs that inhibit cell proliferation (62,83). In OS, circ-XPO1 and its host gene Exportin 1 (XPO1) are upregulated (84). The adsorption of miR-23a-3p, miR-23b-3p, miR-23c and miR-130a-5p by circ-XPO1 leads to the upregulation of XPO1 protein. Therefore, inhibiting the expression of circ-XPO1 or XPO1 may be a novel therapeutic strategy for OS (84). Certain cytoplasmic circRNAs exhibit open reading frames and ribosomal binding sites, indicating their potential for translation (85). Owing to the absence of an m7G cap structure at the 5′ end and a polyadenylated tail at the 3′ end, which are essential for linear mRNA translation, circRNAs are translated in a cap-independent manner (Fig. 2B). circRNAs are primarily translated through three mechanisms as follows: Internal ribosome entry site (IRES)-mediated translation, m6A-dependent translation and rolling circle amplification (RCA) translation. One of the translation mechanisms that has gained wide recognition involves the direct recognition of circRNAs possessing natural IRESs by non-standard eukaryotic translation initiation factor 4 gamma (eIF4G) proteins (eIF4G2 or DAP-5). eIF4G2 contains eukaryotic translation initiation factor 4A (eIF4A) and eukaryotic translation initiation factor 3 (eIF3) binding regions, but lacks the eukaryotic translation initiation factor 4E (eIF4E) binding site (86–89). IRESs assemble the eIF4 complex in the absence of eIF4E and thereby, directly initiate circRNA translation (90). In glioblastoma cells, LINC-PINT, which is a long-chain gene spacer non-coding RNA molecule, is translated into a peptide consisting of 87 amino acids through IRES translation (91). m6A is one of the most prevalent base modifications in RNAs, exhibiting a notable enrichment in circRNAs. The translation of circRNA is facilitated by the initiation factor eukaryotic translation initiation factor 4 gamma 2 (eIF4G2) and the m6A reader YTH N6-methyladenosine (m6A) RNA binding protein F3, whereby the ribosome operates in a manner similar to IRES. A single m6A site has been observed to be sufficient to drive translation initiation (92). This mode of translation of circRNAs can be enhanced by the methyltransferase methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL)3/14, whereas it can be inhibited by the demethylase alpha-ketoglutarate dependent dioxygenase (17,92). During RCA translation, the length of circRNAs should be a multiple of three, with the inclusion of the starting codon AUG, but without IRES or termination codons. Therefore, in theory, once the translation of circRNAs begins, the elongated portion can rotate around the ring multiple times, thereby yielding high molecular weight proteins (93). Circ-EGFR, which arises from the aberrant activation of epidermal growth factor receptor (EGFR) in adult glioblastomas, is translated into repetitive amino acid sequences through RCA, ultimately resulting in the formation of a new polymeric protein complex (94). Generally, the reported quantity of circRNAs with functional proteins/peptide is ~30 (27,28). Herein, several peptides/proteins with critical physiological and pathological functions encoded by circRNAs are summarized (Table II). Owing to the fact that a number of circRNAs contain some of the same codons as their host genes, proteins/peptides translated from circRNAs are usually truncated and their functions are mostly similar to the full-length proteins encoded by their host genes (92,95). However, the functions of certain proteins/peptides encoded by circRNAs are independent of their corresponding host gene products. In fact, several functions are opposite to those of the proteins encoded by the host genes (96). A list of functional peptides/proteins encoded by circRNAs under different physiological and pathological states is presented in Table II (96–107).
 | Table II.Functional peptides/proteins encoded by circRNAs under different physiological and pathological states. |
Since circRNAs interact with proteins, they primarily bind to RBPs, thereby affecting cellular processes such as proliferation, metastasis and apoptosis (Fig. 2C). For example, circRNA poly(A) binding protein nuclear 1 (PABPN1; circPABPN1), which is produced from the precursor mRNA of PABPN1, PABPN1 translation by blocking the binding of RBP HuR to PABPN1 mRNA, thereby attenuating the proliferation of tumor cells (108). Circular RNA forkhead box (Fox) O3 (Circ-Foxo3) is primarily distributed in the cytoplasm and is highly expressed in cardiac tissue samples from geriatric patients and mice. Circ-Foxo3 promotes cardiac aging by enhancing its interaction with the anti-aging protein inhibitor of DNA binding 1 (ID-1), E2F transcription factor 1, anti-stress protein focal adhesion kinase (FAK) and hypoxia inducible factor 1 subunit α (109). RBPs interacting with circRNAs regulate the expression of circRNAs. Nuclear factor of activated T-cells 90 kDa (NF90) and its subtype NF110 bind to intron pairs within the nucleus to form regions of ecircRNA, thereby promoting the production of circRNAs. However, during viral infections, NF90/NF110 is rapidly transported into the cytoplasm, where it binds to viral RNA with consequent reduction in the generation of corresponding circRNAs (110).
In addition to sponging miRNAs, undergoing translation and interacting with RBPs, circRNAs regulate alternative splicing and gene transcription (Fig. 2D and E). Although the majority of circRNAs are distributed in the cytoplasm, EIciRNAs and ciRNAs have been observed primarily in the nucleus (111). Both EIciRNAs and ciRNAs regulate the expression of host genes in cis within the nucleus. For example, the EIciRNAs circEIF3J and circPAIP2 interact with the Pol II transcription complex on the promoter of their host genes via U1 small nuclear RNA, thereby ultimately promoting the transcription of their host genes (111). The ciRNA ci-ankrd52 aggregates at its host gene transcription site, thereby forming RNA:DNA hybrids that regulate the Pol II elongation process.
As this circRNA is a positive regulator of Pol II transcription, its downregulation decreases its host gene expression (39). In addition to regulating the transcription of host genes, nuclear circRNAs directly participate in the processing and maturation of their host genes. For example, nuclear circRNA derived from exon 6 of SEPALLATA3 (SEP3) regulates splicing of its linear precursor host mRNA (112). Although circRNAs enriched in the nucleus can pair with genomic DNA to form RNA:DNA hybrids, whether they affect DNA replication remains unknown.
circRNAs exhibit functional diversity based on their distinct subcellular locations. Nuclear circRNAs are primarily associated with the transcriptional regulation and the processing or/and maturation of mRNAs. Cytoplasmic circRNAs are primarily associated with post-transcriptional regulation. Mitochondrial circRNAs are closely associated with the function of mitochondria. Exosome circRNAs typically serve as signal molecules (113). In addition to serving as miRNA sponges, circRNAs interact with RBPs, regulate gene splicing or transcription, and undergo translation to give rise to proteins or small peptides (36,44). However, functional studies of circRNAs have mostly centered around miRNA sponges. The functions of circRNAs are dynamically regulated under various physiological and pathological conditions. Thus, the functions and mechanisms of circRNAs in OS remain unclear, and additional investigations are required to enhance our understanding of them.
Mechanisms of circRNAs in OS
circRNAs exhibit versatility by engaging in interactions with DNA, RNA and RBPs during the pathogenesis and development of OS. Mechanistic analyses have revealed that circRNAs function by primarily participating in key signaling pathways within the cell, including the JAK/STAT3, NF-κB, PI3K/AKT and Wnt/β-catenin signaling pathways (30) Herein, these pathways are summarized and emphasized (Fig. 3).
STATs are highly conserved in eukaryotes and essential for various biological processes, such as embryonic development, immunity, hematopoiesis and cell migration (114). STAT3, a member of the STAT family, is ubiquitously expressed in the cytoplasm in an inactive form. During the signal cascade process, STAT3 is rapidly activated by the interleukin (IL)-6 family members, EGF and platelet derived growth factor. Upon activation, STAT3 undergoes dimerization, translocates to the nucleus and subsequently regulates downstream gene transcription (44). A high expression of STAT3 usually indicates a poor prognosis in OS, and the transformation, proliferation, tumorigenesis, invasion, metastasis and drug resistance of OS cells (115). The circRNA hsa_circ_0009910 is overexpressed in OS cells and tissues (49). This circRNA promotes the expression of IL-6R by sponging miR-449a, which targets IL-6R. Therefore, the activation of the JAK1/STAT3 signal downstream of IL-6R by hsa_circ_0009910 leads to the development of OS (49). Circ_ANKIB1 sponges miR-19b, which targets suppressor of cytokine signaling 3 (SOCS3), thereby activating the STAT3 pathway downstream of SOCS3 (57). In addition to activating the STAT3 pathway, circRNAs in OS also exert adverse effects through this pathway. The low expression of Circ_0001649 in OS is associated with the increased expression of apoptotic peptidase activating factor 1, cleaved caspase-3 and caspase-9, which results in the apoptosis of OS cells. Mechanistic analyses have revealed that this circRNAs sponges miR-338-5p, miR-647 and miR-942 to inhibit the activation of STAT3/5 (62).
NF-κB is a member of a family of transcription factors that not only play crucial roles in the regulation of immune response and inflammation, but have also been increasingly validated to play vital roles in tumorigenesis (116). The increased expression of EGFR, insulin growth factor receptor and tumor necrosis factor receptor family members, and the activation of Ras/mitogen-activated protein kinase (MAPK) and PI3K/AKT leads to the activation of NF-κB (117). Upon activation, NF-κB triggers downstream signaling pathways, thereby resulting in the aberrant expression of various genes associated with tumor cell proliferation, migration and apoptosis, ultimately leading to the occurrence and development of tumors. For example, HMGB1 activates the Ras oncogene by binding to the RAGE receptor, leading to the activation of MAPK-mediated NF-κB inflammatory pathway, thereby promoting the expression of related downstream proinflammatory cytokines, and ultimately promoting cancer progression (118). In OS, the aberrant upregulation of Circ_0005909, which sponges miR-936, prevents the targeting of HMGB1 by miR-936. Consequently, HMGB1 induces the persistent activation of the downstream NF-κB pathway, ultimately leading to cell growth, migration, invasion, and EMT in OS (55).
The PI3K/AKT pathway, which is negatively regulated by phosphatase and tensin homolog (PTEN) by mediating AKT dephosphorylation, activates the protein activity of many downstream genes by phosphorylation, such as mammalian target of rapamycin (mTOR). This pathway plays crucial roles in many physiological and pathological processes (119). Upon activation of the PI3K/AKT signaling pathway, PI3K triggers the conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate (PIP3). Subsequently, PIP3 phosphorylates and activates AKT in a pyruvate dehydrogenase kinase 1-dependent manner, with mTORC2 also contributing to AKT activation. Activated AKT increases Ras homolog enriched in brain-GTP levels by inhibiting the formation of the tuberous sclerosis complex 1 (TSC1)/TSC1 heterodimers, thereby activating mTORC1. Subsequently, mTORC1 mediates the phosphorylation of S6 kinase and eukaryotic translation initiation factor 4E binding protein 1, which promotes the release of eIF4E, thereby increasing the rate of protein synthesis and leading to more rapid cell growth. In addition, an increase in inhibitor of kappa B kinase (IKK) activity induced by AKT promotes inhibitor of NF-κB (IκB) degradation, thereby resulting in the release of NF-κB and its translocation into the nucleus for gene transcription. AKT also negatively regulates glycogen synthase kinase 3β (GSK3β) and FOXO1, thereby enhancing cyclin-dependent kinase expression to promote cell cycle progression. In addition, AKT inhibits cell apoptosis by upregulating Bcl-xL, Bcl-2 and Mcl1, and downregulating Bad, Bax and p53 (10). In OS, the expression of PTEN is typically decreased or absent, resulting in the activation of the PI3K/AKT signaling pathway (120,121). The expression of hsa_circ_0007534 is positively associated with p-AKT and p-GSK3β in OS. By regulating the AKT/GSK3β signaling pathway, this circRNA promotes OS progression (46). The overexpression of Circ_001422 promotes the activation of PI3K/AKT signal transduction and subsequent OS progression by sponging miR-195-5p, the target of which is fibroblast growth factor 2 (63). Similarly, highly expressed Circ_0001785 adsorbs miR-1200, the target of which is the gene HOXB2, leading to the activation of the Bcl-2 family and the PI3k/AKT/mTOR signaling pathway (52). It has been shown that high mobility group AT-hook 1 (HMGA1) activates the MAPK/ERK1/2 and PI3K/AKT signaling pathways (122). Moreover, both the MAPK/ERK1/2 and PI3K/AKT signaling pathways exhibit increased activation in OS (10). Circ_0005909 adsorbs miR-338-3p, the target of which is HMGA1, thereby leading to the development and progression of OS (64). These findings suggest that Circ_0005909 may lead to OS progression through the MAPK/ERK1/2 and PI3K/AKT signaling pathways. Notably, Circ_ORC2 enhances the inhibitory effects of miR-19a on PTEN expression by binding to miR-19a, thereby activating the PI3K/AKT signaling pathway and promoting the proliferation and invasion of OS cells (51). Of note, the majority of circRNAs that function as miRNA sponges typically protect miRNA targets. The circRNA Circ_ORC2 has been discovered to exhibit an additional function as an miRNA sponge, thereby exhibiting a novel role of circRNAs. In addition to highly expressed circRNAs, the downregulated expression of circRNA circ-ITCH decreases cell viability, proliferation, migration and invasion by inhibiting the PTEN/PI3K/AKT and Sp1 transcription factor signaling pathways (53).
Wnt-mediated intracellular signaling pathways include the classical Wnt/β-catenin pathway, Wnt/Ca2+ pathway, Wnt/PCP pathway and Wnt/PKA pathway (123). It has been demonstrated that Wnt-mediated signal transduction pathways regulate various cellular processes, including cell growth, proliferation and differentiation (124). In OS, the aberrant expression of a number of Wnt components, including Wnt ligands and Frizzled and lipoprotein receptor-related protein (LRP) receptors, affects the development and progression of OS (125). In OS, various circRNAs have been found to inhibit or activate the Wnt/β-catenin signaling pathway. Circ_001569 (hsa_circ_0000677) is significantly overexpressed in OS tissue and its upregulation promotes the resistance of OS cells to chemotherapy (48). The knockdown of Circ_001569 in OS cell lines has been shown to reduce p-GSK3β and β-catenin expression, but to increase GSK3β expression. Conversely, the upregulation of Circ_001569 has been shown to increase p-GSK3β and β-catenin expression, but decrease GSK3β expression (48). Tet methylcytosine dioxygenase 1 (TET1) inhibits the Wnt/β-catenin signaling pathway by activating dickkopf WNT signaling pathway inhibitor 1 and secreted frizzled related protein 2, thereby preventing the EMT of OS cells (126). Hsa_circ_0002052 is significantly downregulated in OS tissues and cell lines. This circRNA inhibits the Wnt/β-catenin signaling pathway by sponging miR-767-5p, the target of which is TET1. Furthermore, this circRNA also sponges miR-1205, the target of which is adenomatosis polyposis coli 2 (APC2), a negative regulator of the Wnt/β-catenin signaling pathway. Hence, hsa_circ_0002052 functions as an inhibitor of the Wnt/β-catenin signaling pathway by promoting TET1 and APC2 expression via miRNA sponging, ultimately resulting in the delayed development of OS (50). However, a recent study demonstrated that hsa_circ_0002052 was upregulated in OS and activated the Wnt/β-catenin pathway by sponging miR-382, the target of which is syntaxin 6 (56). These findings demonstrate the complex nature of OS, underscoring the requirement for comprehensive studies on circRNAs in OS.
Potential clinical applications of circRNAs
It has been widely reported that aberrantly expressed circRNAs are more abundant and stable than linear RNAs, and are closely associated with the occurrence and development of various diseases. Therefore, they could be highly valuable in clinical diagnosis and treatment. As regards tumor molecular markers, circRNAs exhibit more promising potential than existing markers. The area under the receiver operating characteristic curve (AUC) of Circ_0008717 in OS is 0.73. The diagnostic sensitivity and specificity of this circRNA are 80.00 and 73.33%, respectively (127). CircRNA-PVT1 is a more representative molecule that is significantly upregulated in OS tissue, serum, and drug-resistant cell lines. It exhibits an AUC of 0.871, which is comparable to the level of lactate dehydrogenase (LDH) (0.852) but superior to that of alkaline phosphatase (ALP) (0.673), which are commonly used diagnostic biomarkers of OS in clinical settings (128). Furthermore, the AUC of hsa_circ_0003074 is 0.93, which is significantly superior to that of LDH and ALP in the diagnosis of OS (129).
In addition to diagnostic biomarkers, aberrantly expressed circRNAs in OS may be used as therapeutic molecules or targets. For example, hsa_circ_0003074 is highly expressed in OS tissues, peripheral blood, and cell lines (129). However, following surgical intervention or chemotherapy, this circRNA is substantially reduced in the peripheral blood of patients with OS. Furthermore, hsa_circ_0003074 is closely associated with tumor size, lung metastasis, Enneking stage, chemotherapy resistance and other prognostic factors (129). Hence, targeting this circRNA may be beneficial for patients with OS. Similarly, circPVT1 is significantly upregulated in OS tissues, serum and drug-resistant cells, and its increased expression is significantly associated with the Enneking stage, lung metastasis and chemotherapeutic resistance. The expression of circPVT1 is higher in patients with lung metastasis or resistance to chemotherapy than in those who do not exhibit lung metastasis or those who are sensitive to chemotherapy. The downregulation of circPVT1 expression reduces the expression of the drug resistance-related gene ABCB1, thereby increasing the sensitivity of OS cells to cisplatin and doxorubicin. Additionally, Kaplan-Meier survival analysis has revealed that patients with high expression of circPVT1 exhibit a shorter overall survival period than those with low expression (128). The overexpression of Circ_001569 activates the Wnt/β-catenin signaling pathway, thereby increasing the half maximal inhibitory concentration value of cisplatin, doxorubicin, or methotrexate for OS (48). Therefore, the detection of these aberrantly expressed circRNAs in OS can indicate the effect of OS treatment and prognosis. Furthermore, these circRNAs can also potentially serve as therapeutic targets in OS.
Conclusions and future perspectives
Although chemotherapy combined with surgery has made tremendous progress in the treatment of OS, this disease remains difficult to be diagnosed and treated. Therefore, it is of utmost urgency to conduct in-depth research into the molecular mechanisms responsible for its occurrence and development (130). With the rapid development of high throughput sequencing technologies, an increasing number of abnormally expressed circRNAs are found to be critical during the pathogenesis of OS. circRNAs can regulate various pathological processes of OS by participating in cellular proliferation, apoptosis, migration, invasion, drug resistance, stemness, EMT, angiogenesis and cell cycle arrest (30). Although circRNAs functioning as miRNA sponges have been extensively studied, studies have indicated that circRNAs can also function via other mechanisms, such as for example the regulation of gene expression at the transcriptional level, or affect functions of RBPs by binding to them, and even directly be translated into proteins/polypeptides (36,44). In addition, circRNAs can also function in the tumor microenvironment (131). This provides a theoretical basis for its potential applications as molecular markers, therapeutic molecules or target genes in the clinical diagnosis and treatment of OS.
Although circRNAs have been well documented in different diseases, functional and mechanistic studies on circRNAs in OS are just beginning and a number of issues remain to be elucidated. First, the biogenesis of circRNAs and their corresponding regulatory mechanisms have not yet been fully elucidated (132). Secondly, circRNAs in OS related to metastasis, drug resistance, prognosis and survival are mostly clinically observed, and their function and mechanism studies are few and relatively unclear (133). Thirdly, functional and mechanistic analyses on circRNAs in OS, as well as in other diseases mainly focus on miRNA sponges. Constructing an RNA interaction network using circRNAs may aid in the identification of related miRNAs, although their interactions still need to be determined using more accurate methods (134,135). Fourthly, it is difficult to obtain a large number of OS samples due to its low incidence rate. Hence, a greater number of clinical medical centers are required to cooperate and share resources with each other.
Acknowledgements
Not applicable.
Funding
The present study was supported by the Training Programs for Innovation and Entrepreneurship (grant no. 202110413017), the Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular of Ministry of Education of Gannan Medical University (grant no. XN202013), the Science and Technology Research Project of Jiangxi Provincial Department of Education (grant no. GJJ201528), and the Startup Foundation for Advanced Talents of Gannan Medical University (grant no. QD202124).
Availability of data and materials
Not applicable.
Authors' contributions
WJN, FX and XML conceived the study, LZ and LL were involved in literature search, collection and analysis. LZ, WJN and XML were involved in the acquisition of funding. LZ, LL, WJN, FX and XML were involved in the design of the tables and figures. XML was involved in project administration. FX and XML supervised the study. LZ and LL were involved in the writing of the original draft. WJN, FX and XML were involved in the writing, reviewing and editing of the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
OS |
osteosarcoma |
|
ncRNAs |
non-coding rnas |
|
circRNAs |
circular RNAs |
|
lncRNAs |
long non-coding RNAs |
|
siRNAs |
small interfering RNAs |
|
miRNAs/miRs |
microRNAs |
|
piRNAs |
Piwi-interacting RNA |
|
MREs |
miRNA response elements |
|
RBPs |
RNA-binding proteins |
|
EMT |
epithelial-mesenchymal transition |
|
IRES |
internal ribosome entry site |
|
RCA |
rolling circle amplification |
|
snRNA |
small nuclear RNA |
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