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1. Introduction

Ovarian cancer (OC) is the most lethal tumor of the female genital system, and caused an estimated 13,270 deaths in the USA in 2023 (1). The poor prognosis of OC is largely attributed to the insidious onset of the disease leading to a delayed diagnosis. Furthermore, the pathogenesis of OC has not been well characterized. The known risk factors of OC include genetic, hormonal, reproductive and lifestyle-related factors (2). At present, surgery and chemotherapy are the standard treatment modalities for OC (3). Chemotherapy is the first-choice treatment for advanced and recurrent OC, which includes conventional platinum-based drugs and paclitaxel, targeted anti-angiogenic drugs, poly (ADP-ribose) polymerase inhibitors and immunotherapy (4). Despite the efficacy of these drugs, the 5-year survival rate of patients with OC remains low, which is 50% in USA (1). Therefore, the identification of novel therapeutic targets for OC is imperative.

Circular RNAs (circRNAs) are highly conserved and stable structures that may serve as novel diagnostic and prognostic biomarkers, as well as chemotherapeutic targets, in the context of tumors (5). The proposed concept of competing endogenous RNA (ceRNA) illustrates a new mechanism of post-transcriptional gene regulation. The phenomenon wherein non-coding RNA (ncRNA) sequester microRNAs (miRNAs) and remove the inhibition of their targets was initially observed in both plant and animal cells (6,7). This phenomenon is the core mechanism of ceRNAs. circRNAs can act as ceRNAs (8), and certain studies have identified numerous circRNAs as potential prognostic biomarkers and therapeutic targets for OC (9,10). The present review aims to discuss current knowledge on the molecular mechanisms by which circRNAs, through miRNA sponging, influence the pathobiology of OC. Furthermore, the present review highlights the clinical applicability of circRNAs as predictive markers and therapeutic targets in OC.

2. circRNA

ncRNAs refer to the RNA molecules that do not encode proteins transcribed from the genome (11). circRNAs belong to the class of regulatory ncRNAs and have both the commonality of ncRNAs and a unique structure and function. circRNAs were first found in viroids by Sanger et al (12) over 40 years ago and were shown to have a covalently closed loop structure, initially thought to be the aberrant product of mis-splicing (13). The loop structure formed by the reversed splicing of circRNA results in the absence of a 5' cap or 3' poly A tail (14). This confers high stability to the molecular structure of circRNA. circRNAs can exist and accumulate in specific cells for long periods due to their ability to avoid digestion by RNA enzymes (15). Most circRNAs are located in the cytoplasm. circRNAs are significantly enriched in the brain, human platelets, during epithelial-mesenchymal transition (EMT) and during the differentiation of hematopoietic progenitor cells into lymphoid and myeloid cells (16).

circRNAs can be categorized based on the composition of exons and introns as follows: Exonic circRNA (ecircRNA), intronic circRNA and exon-intron circRNA (17). ecircRNAs are reported to function in the circRNA sponging of miRNA (18). There are four main mechanisms of circRNAs: i) Sponging miRNA (19); ii) binding to diverse RNA binding proteins (20) or acting as a protein sponge; iii) regulating transcription (21); and iv) participating in the translation progress (22). The generation and mechanism of circRNAs is presented in Fig. 1. The ability of circRNAs to act as ceRNAs has been verified in a number of diseases such as neurological diseases, cardiovascular diseases and tumors, as well as in the context of the immune response (such as the antivirus and antitumor response) (23-26). Functionally, circRNAs have been observed to exert oncogenic or tumor-suppressive effects. At the cellular level, they are instrumental in modulating processes such as proliferation, migration, invasion, apoptosis and chemoresistance (27). In vivo studies, particularly those utilizing animal models, have demonstrated that circRNAs influence tumor growth and metastasis (28,29). Moreover, akin to other ncRNAs such as miRNAs (30,31), circRNAs are emerging as vital prognostic and diagnostic biomarkers for a multitude of diseases such as neurologic diseases (32), diabetic complications (33) and tumors (34).

Figure 1 Formation and mechanism of circRNA. (A) circRNA formation and classification. (B) circRNA sponges miRNA to regulate the targeted mRNA. (C) circRNA interacts with protein as a protein sponge (left) or a protein scaffold (right). (D) circRNA is involved in transcription regulation. (E) circRNA is involved in translation. circRNA, circular RNA; ecircRNA, exonic circRNA; elciRNA, exon-intron circRNA; miRNA, microRNA; RBPs, RNA binding proteins; snRNA, small nuclear RNA; UTR, untranslated region.

3. ceRNA

ceRNA mechanism

The ceRNA hypothesis has been proposed to describe the mechanism by which ncRNAs that harbor miRNA response elements (MREs) can sequester miRNAs from other targets that share the same MREs, thereby regulating their expression (35). Specifically, ncRNAs competitively bind to miRNAs to reduce the inhibition of mRNA and regulate the corresponding gene expression. Long ncRNAs (lncRNAs), mRNAs, pseudogenic RNAs and circRNAs can act as ceRNAs, among which circRNAs have the strongest binding ability to miRNA, and therefore may be the main type of ncRNAs participating in observed oncogenic effects.

Interaction of circRNAs and miRNAs

The resulting effect of an interaction between circRNAs and miRNAs depends on the number of binding sites among them (36). The higher the number of competitive binding sites, the greater the potential of a circRNA to act as a ceRNA. ciRS-7 is the most well-known ceRNA, has >70 conserved miR-7 binding sites and has high levels of stable expression in the brain (37). Generally, circRNAs that act as ceRNAs negatively regulate miRNA. This implies that when the expression of circRNAs, which act as ceRNAs, increases, the expression of miRNA is reduced (38) and vice versa. The presence of miRNA binding sites on a circRNA does not necessarily imply that it will inhibit miRNA, as whether a circRNA negatively or positively regulates miRNA is related to the stoichiometric relationship between the MREs in the potential sponge and the target mRNA (39).

ceRNA network and tumors

A number of studies have demonstrated the role of circRNAs in respiratory system (40), digestive system (41,42) and female reproductive system tumors (43,44). circRNAs can be upregulated or downregulated in tumors, which regulates mRNA expression in tumor cells by regulating miRNA. ceRNAs of malignant tumors competitively bind to miRNAs in the MREs of the 3' untranslated region (UTR) (35). 3'UTR shortening caused by the reduction of MREs alters the ability of ceRNAs to compete for miRNAs and function as ceRNAs. In a study by Sang et al (45), hsa_circ_0025202 was found to act as a ceRNA in breast cancer by sponging miR-182-5p, further regulating the expression and activity of FOXO3a. Moreover, functional studies demonstrated that hsa_circ_0025202 suppresses tumorigenesis and improves sensitivity to tamoxifen via the miR-182-5p/FOXO3a axis. In a study by Wang et al (46), has-circRNA-002178 was found to enhance programmed death-ligand 1 expression in lung cancer cells by sponging miR-34, which induced T cell failure. In addition, hsa_circRNA_104348 may act as a ceRNA to promote the progression of hepatocellular carcinoma by targeting the miR-187-3p/rhotekin2 axis and activating the Wnt/β-catenin pathway (47). In conclusion, circRNAs play important roles as ceRNAs in tumors and influence the biological activity of tumor cells.

4. Biological functions of circRNAs as ceRNAs in OC

Cell proliferation

Cell growth is a critical factor in the proliferation of tumors and sustained growth is one of the key attributes of malignant tumors. Proliferation of normal cells in the human body is closely regulated; however, tumor cells evade this regulation and achieve sustained proliferation through four mechanisms: i) Autocrine growth signals; ii) stimulation of normal cells to secrete growth signals; iii) increase in receptor expression and therefore amplification of growth signals; and iv) altered receptor structure, resulting in receptor activation (48). The studies described below demonstrate that circRNAs can act as ceRNAs, sponging miRNAs as well as targeting mRNAs to affect cell proliferation (Fig. 2A).

Figure 2 Mechanisms of circRNA as a competing endogenous RNA to affect cellular functions in ovarian cancer. circRNA in (A) cell proliferation, (B) angiogenesis, (C) autophagy, (D) metabolism and (E) EMT. circRNA, circular RNA; EMT, epithelial-mesenchymal transition; G, glucose; G-6-P, glucose-6-phosphate; HK, hexokinase; ATP, adenosine triphosphate; ADP, adenosine diphosphate; PHI, phosphohexose isomerase; F-6-P, fructose-6-phosphate; PFK, phospho fructo kinase; F-1,6-2P, fructose-1,6-biophosphate; DHAP, dihydroxyacetone phosphate; G-3-P, glyceraldehyde-3-phosphate; GAPDH, glyceraldehyde-3-phosohate dehydrogenase; NAD+, nicotinamide adenine dinucleotide; 1,3-DPG, 1,3-biphodpho-glycerate; 3-PG, 3-phosoho-glycerate; BPG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; PK, pyruvate kinase; PYR, pyruvic acid; Acetyl-CoA, acetyl coenzyme A; Gln, glutamine; TCA, triose carbonate cycle; LAC, lactic acid; Ala, alanine.

The cell cycle, which spans from the conclusion of one cell division to the completion of the next, is a critical phase during which circRNAs can exert influence. circ-BNC2 can inhibit the transition of OC cells from the G0/G1 phase into the G2/M phase through the miR-223-3p/F-box/WD repeat-containing protein 7 axis (49). The circUBAP2/miR-382-5p/pre-mRNA-processing-splicing factor 8 axis is another regulatory pathway inducing G0/G1 phase arrest (50). Additionally, circPVT1 promotes OC cell viability through the miR-149-5p/forkhead box protein M1 (FOXM1) pathway (51). Furthermore, circ_0013958, found to be upregulated in OC, targets plexin-B2 (PLXNB2) via miR-637 sponging, promoting OC proliferation (52). PLXNB2 mediates intracellular RNA processing and contributes to cell proliferation and survival (53).

Autophagy

Autophagy is an evolutionarily conserved, self-degrading, normal cellular metabolic process. Cells can degrade harmful intracellular components to ensure normal cell growth and operation via autophagy. As such, autophagy is a mechanism with a dual role in both the apoptosis and survival of cells. Autophagic levels can be assessed in studies by detecting proteins such as autophagy-related gene (ATG), LC3, p62 and Beclin1 (54). circRNAs regulate autophagy-related proteins to mediate autophagy (55). The studies demonstrating that circRNAs can act as ceRNAs, sponging miRNAs as well as targeting mRNAs, to affect cellular autophagy are described below (Fig. 2B).

CircRAB11FIP1, which is upregulated in OC, has been implicated in targeting ATG7 and ATG14 by sponging miR-129, and therefore engaging in the autophagic process (56). Meanwhile, circRAB11FIP1 also directly binds to desmocollin 1 to mediate autophagy. It has been demonstrated that circMUC16 is upregulated in OC tissues compared with normal ovary tissues, which inhibits the autophagy flux of OC (57). The assessment of autophagic flux in the aforementioned study was based on the expression of Beclin1, a key autophagy-related factor active in the initial stages of autophagy. circRNF144B has been shown to sponge miR-342-3p, thereby regulating F-box and leucine-rich repeat protein 11 (FBXL11) and influencing the ubiquitination and subsequent degradation of Beclin1 (58). The autophagy of OC can be inhibited through the circRNF144B/miR-342-3p/FBXL11 axis. In summary, although all three aforementioned circRNAs are upregulated in OC, they exhibit divergent effects on autophagy; while circMUC16 and circRNF144B suppress autophagy, circRAB11FIP1 enhances ATG expression and promotes the autophagic pathway.

Angiogenesis

Angiogenesis is a physiological process wherein capillary or post-capillary veins form following neovascularization. circRNAs are notably abundant in angiogenesis-related diseases, which indicates an association between circRNA and angiogenesis. The studies described below demonstrate that circRNAs can act as ceRNAs, sponging miRNAs as well as targeting mRNAs, to affect angiogenesis (Fig. 2C).

Tumor angiogenesis is largely dependent on vascular endothelial growth factor A (VEGFA)-driven responses, which largely contribute to dysregulation of vascular function (59). circATRNL1 targets Smad4 by sponging miR-378, which mediates the AKT signaling pathway and inhibits cell proliferation, migration and invasion, and is involved in anti-angiogenesis in OC (60). Angiogenesis is affected by the restoration of Smad, which downregulates the expression of VEGF and upregulates the expression of thrombospondin-1 to inhibit angiogenesis (61). In addition, circASH2L silencing was found to inhibit the invasion and growth of OC cells and to inhibit the angiogenesis and lymphangiogenesis of transplanted tumors via the miR-665/VEGFA axis (62). Furthermore, circ_0061140 is elevated in OC tissues and cells, and promotes proliferation, migration, invasion and angiogenesis through the miR-761/leucine zipper-EF-hand containing transmembrane protein 1 axis (63).

EMT

EMT is a highly complex phenotypic transition during embryonic development that drives tissue formation and is important for tumor metastasis (64). EMT is also a cause of tumor progression and poor prognosis in patients with cancer. A study has suggested that circRNAs are associated with EMT transcription factors (such as snail, vimentin and twist) and EMT-related signaling pathways (such as the TGF-β/Smad and Wnt signaling pathways) (65). The studies described below demonstrate that circRNAs can act as ceRNAs, sponging miRNAs as well as targeting mRNAs, to affect EMT (Fig. 2E).

EMT can be assessed via the detection of EMT-related proteins such as E-cadherin, N-cadherin and Vimentin (65). circPLEKHM3 mediates OC cell migration and EMT by sponging miR-9 and targeting BRCA1/DNAJ homolog subfamily B member 6 (DNAJB6)/Krüppel-like factor 4 (KLF4) (66). BRCA1, DNAJB6 and KLF4 contribute to the metastasis of tumors. GATA binding protein 3 mediates BRCA1 to suppress EMT, inhibiting the metastasis of breast cancer (67). DNAJB6, a member of HSP40 family, inhibits the EMT of tumors (68). KLF4 activates the expression of epithelial genes, playing a notable role in EMT (69). circCELSR1 targets bromodomain-containing protein 4 (BRD4) by sponging miR-598 to promote the EMT of OC cells (70). BRD4 also inhibits EMT in renal cell carcinoma (71). In summary, circRNAs mediate the EMT of OC cells by targeting EMT-related mRNA. circFGFR3 (72), circPTK2 (73), ciRS-7 (74) and hsa_circ_0061140 (75) all regulate downstream genes to promote EMT in OC (76-79).

Metabolism

Tumor metabolism mainly includes glucose, lipid and amino acid metabolism. Tumor cells mainly produce nutrients through aerobic glycolysis to maintain the basal cellular requirements for upregulated proliferation. The 'Warburg effect' is a process in which tumor cells convert glucose to lactate in the presence of oxygen (80). It is considered that circRNAs are associated with lipid metabolism in hepatocytes, adipocytes and macrophages (81). Glutamine is an essential source of energy for cell survival, and tumor cells will overtake glutamine to maintain abnormal cell growth. A previous study has indicated that ncRNAs can regulate tumor metabolism and thus participate in the biological functions of tumors (82). The studies described below demonstrate that circRNAs can act as ceRNAs, sponging miRNAs as well as targeting mRNAs, to affect tumor metabolism (Fig. 2D).

circRNAs have a significant impact on glycolysis in OC. For example, circITCH has been shown to attenuate cell proliferation, invasion and glycolysis in OC through the miR-106a/E-cadherin axis (83). Additionally, has_circ_0002711 facilitates aerobic glycolysis via the miR-1244/Rho-associated protein kinase 1 pathway in OC (84). circ_0025033 targets LSM4 through the sponging of miR-184 to promote glycolytic metabolism in OC (85). Furthermore, LSM4 is closely associated with cell cycle, cell replication, focal adhesion and multiple metabolism-related pathways, including fatty acid metabolism, in hepatocellular carcinoma (86). Moreover, silencing circ_0023033 enhances glutamine metabolism in OC (87). However, the role of circRNA in the regulation of lipid metabolism within tumors remains to be thoroughly investigated. The role of circRNAs as ceRNAs in OC is shown in Fig. 2.

5. Clinical applications of circRNAs as ceRNAs in OC

Prognostic biomarkers

Due to the highly stable and specific expression of circRNAs in OC, certain circRNAs may serve as useful diagnostic and prognostic biomarkers. A study demonstrated that circ-ABCB10 may help distinguish OC tissue from adjacent tissue, affirming its value as a diagnostic biomarker [area under the curve (AUC)=0.766; 95% confidence interval (CI), 0.690-0.842] (88). circBNC2 has also demonstrated value in distinguishing OC tissue from benign ovarian cysts [receiver operating characteristic (ROC) AUC=0.879; 95% CI, 0.822-0.937; sensitivity, 96.4%; specificity, 80.7%] (89). Plasma circN4BP2L2 expression significantly differentiated OC tissue from benign ovarian tumor tissue (ROC AUC=0.82; sensitivity, 72%; specificity, 87%) and from normal ovarian tissue (ROC AUC=0.90; sensitivity, 77%; specificity, 88%) (90). In addition, high expression of circ-ABCB10 was associated with significantly decreased overall survival (OS) time in patients with OC [hazard ratio (HR)=2.994; P<0.05] (88), and high expression of circ-ITCH was associated with a significantly longer OS in patients with OC (HR=0.207; 95% CI, 0.066-0.065; P<0.05) (83). A recent study has also demonstrated specific expression of circRNAs in the blood (91). Therefore, this non-invasive test (just withdrawing blood) may provide portability in detecting circRNAs as tumor markers in the future, meaning that it would not be necessary to obtain pathological tissue through invasive methods to detect circRNA.

Therapeutic targets

The aforementioned studies indicate that circRNAs play an important role in the progression of OC. Therefore, circRNAs may also act as molecular targets for targeted therapy, in which the target circRNA is overexpressed or knocked down to affect tumor progression or drug resistance, thus impacting patient treatment outcomes. Upregulation of circEXOC6B tends to imply an earlier TNM stage, less lymph node metastasis and a higher survival rate, and is associated with decreased paclitaxel resistance in OC (92). Conversely, circ_0061140 is known to enhance paclitaxel resistance by sponging miR-136 and targeting chromobox 2, showing significant upregulation of circ_0061140 in paclitaxel-resistant OC tissues and cells (93). circ_0025033 targets FOXM1 by sponging miR-532-3p, and circ_0025033 is significantly upregulated in paclitaxel-resistant cells of OC (94). Furthermore, downregulation of circ_0025033 in the exosomes of paclitaxel-resistant cells inhibits the malignant effects of OC cells. circTNPO3 and circCELSR1 have also been implicated in paclitaxel resistance, sponging miR-1299 and miR-1252, respectively, to target NIMA related kinase 2 and FOXR2 in OC, respectively (16,95). Resistance to cisplatin (DDP), another cornerstone in OC chemotherapy, has also been associated with circRNAs. Downregulation of circ_0067934 was shown to decrease DDP resistance in OC (96), while overexpression of circFoxp1 was associated with increased DDP drug resistance (97). In addition, circ-LPAR3 promotes DDP resistance by sponging miR-634 and targeting pyruvate dehydrogenase kinase 1 in OC (98). The aforementioned studies have therefore demonstrated that circRNAs may be used as therapeutic targets in OC, to affect drug resistance such as for the two classic chemotherapy drugs, paclitaxel and DDP. Beyond OC, circRNAs synthesized in vitro have shown promise in gastric cancer treatment strategies by sponging miRNAs to target genes (99). This insight verifies the possibility of circRNAs, functioning as ceRNAs, as targeted therapeutic markers in the management of OC.

6. Signaling pathways involving circRNAs in OC

As aforementioned, circRNAs mediate biological processes, including proliferation, migration and invasion,in various diseases through regulating signaling pathways. The signaling pathways mainly include Notch, janus kinase (JAK)/STAT, Wnt/β-catenin, TGF-β/Smad and AMP-activated protein kinase signaling pathways (100). Wang et al (101) demonstrated that differential circRNAs in the serum of 20 patients with OC were enriched in Fcγ R-mediated phagocytosis, VEGF signaling, transcriptional misregulation in cancer, chemokine signaling, ErbB signaling and TNF signaling pathways, according to a Kyoto Encyclopedia of Genes and Genomes analysis. Recent studies have demonstrated that circRNAs mainly participate in the Wnt/β-catenin, AKT, MAPK, JAK/STAT and CDK/retinoblastoma protein signaling pathways in OC (Table I). The specific signaling pathways involving circRNAs are presented in Fig. 3.

Figure 3 circRNA-related signaling pathways in ovarian cancer. circRNA, circular RNA. LRP, lipoprotein Receptor-Related Protein; APC, adenomatous polyposis coli; CK1, Casein kinase 1; DVL, dishevelled; GSK3β, Glycogen synthase kinase 3; AXIN, axis inhibition; TCF, T-cell factor; LEF, lymphoid enhancer factor; EGFR, epidermal growth factor receptor; RTKS, receptor tyrosine kinase; GRB2, growth factor receptor-bound protein 2; SOS, son of sevenless; JAK, Janus kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog; PDK1, 3-phosphoinositide-dependent protein kinase-1; TSC1/2, tuberous sclerosis complex; mTOR, mammalian target of rapamycin; PRR5, proline rich 5; RB, retinoblastoma protein.

Table I circRNA-related signaling pathways in ovarian cancer progression.

Table I

circRNA-related signaling pathways in ovarian cancer progression.

First author, year	circRNA	Regulation	Axis	Signaling pathway	Biological process	(Refs.)
Gong et al, 2020	circ9119	↓	miR-21-5p/PTEN	AKT signaling pathway	Proliferation, apoptosis	(103)
Wang et al, 2021	circATRNL1	↓	miR-378/Smad	AKT signaling pathway	Proliferation, invasion, migration, angiogenesis	(60)
Zhang et al, 2019	circPLEKHM3	↓	miR-9/BRCA1/DNAJB6/KLF4	AKT1 signaling pathway Wnt/β-catenin signaling pathway	Proliferation, migration	(66)
Guo et al, 2020	Has_circ_0000714	↑	miR-370-3p/RAB17	CDK6/RB signaling pathway	Proliferation, PTX resistance	(104)
Ji et al, 2022	Has_circ_0001756	↑	IGF2BP2-RAB5A	EGFR/MAPK signaling pathway	Proliferation, invasion, EMT	(105)
Zhang et al, 2020	circPGAM1	↑	miR-542-3p/CDC5L/PEAK1	ERK1/2 signaling pathway, JAK signaling pathway	Proliferation, invasion, migration, apoptosis	(106)
He et al, 2022	circAHNAK	↓	miR-28/EIF2B5	JAK2/STAT3 signaling pathway	Proliferation, invasion, migration, apoptosis, EMT	(107)
Lu et al, 2021	circVPS13C	↑	miR-145	MEK/ERK signaling pathway	Proliferation, cell cycle, invasion, migration, apoptosis	(108)
Fu et al, 2023	circFAM169A	↓	miR-160a-5p, miR-519d-3p/RPS6KA2	p38/MAPK signaling pathway	Proliferation	(109)
Wang et al, 2021	Has_circ_0000745	↑	miR-3187-3p/ERBB4	PI3K/AKT signaling pathway	Proliferation, invasion, migration, stemness	(110)
Wu et al, 2022	circFBXO7	↓	miR-96-5p/MTSS1	Wnt/β-catenin signaling pathway	Proliferation, migration	(111)
Lin et al, 2021	circABCB10	↑	miR-1271/Capn4	Wnt/β-catenin signaling pathway	Proliferation, invasion, apoptosis	(112)
Wu et al, 2023	Hsa_circ_0001445	↓	miR-576-5p/SFRP1	Wnt/β-catenin signaling pathway	Proliferation, invasion, migration	(113)

[i] PTEN, phosphatase and tensin homolog; Smad, small mothers against decapentaplegic; BRCA1, breast cancer gene 1; DNAJB6, DnaJ heat shock protein family (Hsp40) member B6; KLF4, Kruppel-like factor 4; RAB17, member RAS oncogene family; IGF2BP2, insulin like growth factor 2 mRNA binding protein 2; JAK, Janus kinase; RAB5A, member RAS oncogene family; CDC5L, cell division cycle 5-like protein; PEAK1, pseudopodium enriched atypical kinase 1; RPS6KA2, S6 kinase ribosomal protein S6 kinase 2; ERBB4, erb-b2 receptor tyrosine kinase 4; MTSS1, metastasis suppressor 1; Capn4, calpain small subunit 1; circRNA, circular RNA; EMT, epithelial-mesenchymal transition; miR, microRNA.

7. Conclusions and outlook

In recent years, the role of circRNAs in tumors has become a research hotspot. In OC, circRNAs are mainly studied extensively as ceRNAs. circRNAs affect the proliferation, invasion, migration and apoptosis of OC cells through sponging miRNA and subsequently modulating the target genes, thus changing the clinical course of solid tumors. circRNAs can also regulate OC progression through mediating autophagy, angiogenesis, the cell cycle, EMT and metabolism. Autophagy, a process with dichotomous roles in tumor promotion and suppression, requires further investigation to elucidate its dual regulatory mechanisms within the OC context. Currently, research regarding circRNA-mediated metabolism mainly focuses on glycometabolism and amino acid metabolism, and lipid/nuclear acid metabolism is rarely involved. circRNAs mainly participate in the Wnt/β-catenin, AKT and MAPK signaling pathways. Moreover, circRNAs may serve as valuable predictive markers and therapeutic targets for OC. In addition, recent studies have not only focused on the downstream mechanisms of circRNAs, but also on the upstream mechanisms. One study found that circRNAs also play a role in the tumor microenvironment, which is involved in the immunotherapy of tumors (102). circUHRF1, secreted by hepatocellular hepatoma cells in exosomes, is involved in immunosuppression by inducing natural killer cell dysfunction. Moreover, overexpression of circUHRF1 was found to decrease the effect of anti-programmed cell death 1 (PD-1) drug therapy, while the targeting of circUHRF1 restored the sensitivity of anti-PD1 therapy (102). However, this research is still in the nascent phase and requires further exploration. In view of the research described in the present review, circRNAs have a certain prospect as biomarkers and therapeutic targets not only in OC but also in other tumors and diseases.

Availability of data and materials

Not applicable.

Authors' contributions

NX, QW and WLY contributed to the study conception and design, material preparation, literature collection and conclusion. The first draft of the manuscript was written by YML and WLY, and all authors commented on subsequent versions of the manuscript. All authors read and approved the final version of the 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.

Acknowledgments

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of Liaoning Province (2019ZD0790).

References