Circular RNAs (circRNAs) are formed by alternative splicing of the 5′ and 3′ ends of RNA molecules. They are significantly more stable than the associated linear RNAs and demonstrate resistance to RNase R digestion (8). Therefore, circRNAs have a unique covalently closed circular structure that gives them stability and the potential as a target for a variety of therapies. For example, circAKT3 is significantly overexpressed in cisplatin (CDDP)-resistant GC tissues and cells and eliminates the inhibition of miR-198 to activate the PI3K/AKT signaling pathway in GC cells, leading to CDDP-based DNA-damaging chemotherapy resistance (9) (Figure 1; Supplementary Table S1). However, the molecular mechanisms by which circRNAs regulate the therapeutic effects of drugs in GC remain unclear. Further research is needed to study the drug resistance mediated by circRNAs in GC. The present review summarizes the roles of circRNAs in drug resistance during several GC treatments and discusses their potential mechanisms. Clinical application of circRNAs as a therapeutic target needs to be discussed further.

CircRNAs are stable covalently closed ncRNAs that were first identified in plant viruses in the 1970s (10). They were deemed to be miscleavage byproducts during precursor messenger RNA (pre-mRNA) processing (11). With the development of biomolecular techniques, circRNAs have been found to have potential biological functions that play vital roles in cancers (8). In addition, circRNAs can be divided into exon-derived circRNAs (ecRNAs) (8), exon-intron circRNAs (EIciRNAs) (12), and intron-derived circRNAs (ciRNAs) based on their composition (13). The ecRNAs can be formed via intron- or lariat-driven circularization (Figures 2A, C). The mechanism for intron-driven circularization is mediated by base pairing between introns located on the exon flanks (Alu repeats or non-repeating elements with a length of about 300 nt) or dimerization of RNA-binding proteins (RBPs), which leads to the tight binding of the upstream 3′ splice site to the 5′ splice site that forms a circular structure after the introns are removed. The mechanism for lariat-driven circularization relies on exon skipping in pre-mRNA during post-transcription and can decrease the distance between non-adjacent exons. Furthermore, ecRNAs can be formed by removing introns. EIciRNAs are formed by intron-driven circularization (Figure 2B). They are generated when the introns between the acceptor and the donor are not removed. In addition, ciRNAs that originate from tRNA intronic circular RNAs or pre-mRNAs are produced by forming a 2ʹ-5ʹend linkage. This linkage is a branchpoint between the 5ʹ splice site after the release of the 3ʹ exon and terminal 2ʹ-OH intron group (Figures 2B, C) (14).

With the advent of the sequencing technology age, more and more circRNA have been discovered to be widely expressed in eukaryotes and participating in various human pathological and physiological processes (15). The circRNAs affect numerous cancer hallmarks by sponging microRNA (miRNA), mutual effecting with and translating into proteins, regulating gene transcription, and competing with mRNA linear splicing. Among them, miRNA sponging is the most iconic circRNA feature (Figure 2D). For example, circVAPA is upregulated in CDDP-resistant GC cell lines (16). It has been reported that constitutive activation of signal transducer and activator of transcription 3 (STAT3) contributes to the chemotherapy resistance of GC cells (16). Researchers have found that circVAPA as a sponge for miR-125b-5p can act on STAT3 in GC via the miR-125b-5p/STAT3 axis to promote chemotherapy resistance of GC (17) (Figure 1; Supplementary Table S1). RBPs regulate at the post-RNA transcriptional level (Figure 2E) (18). For instance, heterogeneous nuclear ribonucleoprotein U-like 1 (HNRNPUL1) belongs to the family of RBPs and is involved in DNA damage repair. Through regulation of CDDP sensitivity-inhibited circMAN1A2 formation, HNRNPUL1 can inhibit CDDP sensitivity of esophageal cancer (19). In addition to interacting with RBPs, circRNAs also function as protein scaffolds, decoys, and recruiters (16, 20–22). The translation of circRNAs requires an internal ribosome entry site sequence (IRES) located in RNA to initiate cap-independent translation (23). IRES initiates the open reading frame for translation (24). In addition, m6A-induced ribosomal binding sites may be another mechanism that is independent of cap translation (Figure 2F) (25). ASK1-272a.a is a novel protein encoded by circASK1 that mediates the chemosensitivity-inducing effect of epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (26). Furthermore, ASK1-272a.a has a function of competing with ASK1 for Akt1 binding, which competes with Akt1-induced ASK1 phosphorylation and inactivation, resulting in the activation of ASK1-induced apoptosis and alleviating gefitinib resistance (26). EIciRNAs and intron-derived RNAs are located in the nucleus, where they perform transcriptional regulation and other functions (27, 28). Studies have shown that EIciRNAs form the EIciRNA-U1 snRNP complex by binding with U1 snRNP, which ultimately enhances gene expression after interacting with Pol II at the gene promoter (28). Similarly, intron-derived RNAs can adjust the transcription of their parental genes by facilitating the elongation activity of Pol II (Figure 2G) (13). Flanking intron sequences are the main factor determining the efficiency of exon circularization. Moreover, circRNAs containing cyclization-promoting sequences can result in reduced efficiency of the flanking exon linear splicing, thereby competing with linear splicing of mRNAs (29).

In conclusion, circRNAs play important roles in cancer through their various functions. Multiple pathways dominated by circRNAs regulate the expression of the downstream genes. Therefore, an in-depth study of specific circRNA mechanisms in cancer drug resistance is crucial, which will contribute to the rapid development of cancer treatment.

Chemotherapy has shown good efficacy as the main treatment for advanced cancer, but the occurrence of chemotherapy resistance hinders the integrity of the course of treatment and is a mainspring for chemotherapy failure in improving patients (30). Diverse mechanisms are involved in drug resistance, including DNA damage repair, operation of cell death-related pathways, regulation of cell viability and proliferation, modification of drug efflux, and metabolism (31), in which circRNAs play a crucial part. Moreover, circFAM114A2 is downregulated in GC and sponged miR-421 to upregulate the expression level of ATM (ATM serine). At the same time, circFAM114A2 inhibits the chemoresistance of L-OPH (Oxaliplatin) through the activation of the ATM/Chk2 (checkpoint kinase 2)/p53-dependent pathway. ATM is a master gene regulator in the DNA damage response. Its activation leads to the execution of DNA repair or initiation of apoptosis (32). Furthermore, circHECTD1 expression is significantly upregulated in GC and facilitates GC cell glutaminolysis, growth, and invasiveness (33). In addition, circHECTD1 has been found to target miR-1256 to regulate ubiquitin-specific peptidase 5 expression levels and modulate the downstream β-catenin/c-Myc signaling pathway (33). Therefore, circHECTD may serve as a latent chemotherapy drug target for GC treatment (Figure 1; Supplementary Table S1).

CDDP is the first-line chemotherapy drug for GC that blocks transcription and DNA replication by forming intra-strand DNA cross-links, resulting in apoptosis (34). However, tumor cells can develop resistance to CDDP by interfering with CDDP-induced apoptosis via unique mechanisms, which ultimately limits the overall medical efficacy of the treatment (35).

The mechanisms of resistance to CDDP are varied, in which circRNAs play an important part. In particular, circCUL2 inhibits the proliferation, migration, invasion, and drug resistance of GC cells (36). Studies have shown that abnormally activated autophagy induced by chemotherapeutic drugs can offer energy to cancer cells (36). Interestingly, circCUL2 inhibits autophagy in CDDP-resistant GC cells through miR-142-3p/ROCK2 (Rho-associated coiled-coil containing protein kinase 2), thus affecting the CDDP sensitivity of GC cells (36). Researchers have found that circCCDC66 was significantly overexpressed in CDDP-resistant GC cells (37). In addition, circCCDC66 induces CDDP resistance in GC cells via miR-618, significantly inhibiting the mRNA and protein levels of BCL2 (BCL2 apoptosis regulator), which is a key regulator of the apoptosis signaling pathway (37). Sun et al. have found that circMCTP2 upregulation suppressed the proliferation of CDDP-resistant GC cells and induced CDDP-resistant GC cell apoptosis (38). It also reduced autophagy in CDDP-resistant GC, which has been demonstrated to promote resistance to tumor chemotherapy. In addition, as a sponge of miR-99a-5p, circMCTP2 inhibits the resistance of GC to CDDP by upregulating myotubularin-related protein 3 (MTMR3). Therefore, circMCTP2 might be a new therapeutic strategy for interference with CDDP resistance in GC (38). Furthermore, circFN1 is a novel circRNA that reinforces CDDP resistance in GC by sponging miR-182-5p, which has the capacity of activating apoptosis via the caspase-3 signaling pathway (39). Moreover, circFN1 functions as a ceRNA, abolishing the ability of miRNA to activate apoptosis and enhancing CDDP resistance (39). In addition, circASAP2 is upregulated in CDDP-resistant GC tissues and cells. Knockdown of circASAP2 promotes CDDP sensitivity and inhibited malignant behaviors of CDDP-resistant GC cells by targeting the miR-330-3p/NT5E (5′-nucleotidase ecto) axis (40). Zhang et al. have found that enhancing the expression of circXPO1 promoted the apoptosis of CDDP-resistant GC cells and inhibited their growth and metastasis. In other words, circXPO1 has the ability to sensitize the GC patients to CDDP therapy (41). Knockdown of miR-543 can promote tumor-suppressor factor leucine-rich repeat protein phosphatase 2 (PHLPP2), which can impact CDDP-resistant cell behaviors and chemotherapy sensitivity. Thus, circXPO1 can act as a sponge for miR-543 and be a latent therapeutic agent against CDDP-resistant GC (41). Prior research has shown that circDONSON can promote the resistance of GC cells to CDDP (42). In addition, miR-802 was determined to be a tumor suppressor in many human cancers. Targeting circDONSON can promote CDDP resistance in GC cells. Furthermore, BMI1 proto-oncogene (BMI1) is an oncogene that was found to be an miR-802 target that was overexpressed in CDDP-resistant GC tissues and cells (42). Therefore, these findings demonstrated that circDONSON regulated the sensitivity of CDDP resistance in GC via the miR-802/BMI1 axis (42). Exosomes are endocytosis extracellular lipid bilayer vesicles that can transport specific proteins or nucleic acids to the corresponding recipient cells through intercellular communication mechanisms (43, 44). They are stable in a variety of extracellular fluids, including blood and urine (45). It is important that circRNAs are enriched and stable in exosomes, and that exosomal circRNAs can regulate the occurrence and development of GC by acting as a sponge of miRNAs (46). Exosomal circPVT1 might be a prospective indicator for GC in CDDP therapy (47). CircPVT1 knockdown suppressed CDDP resistance in CDDP-resistant GC cells by promoting apoptosis and inhibiting invasion or autophagy by negatively targeting miR-30a-5p. Yes1-associated transcriptional regulator (YAP1) is a direct target of miR-30a-5p, and reduction of its level by miR-30a-5p can promote CDDP resistance (47). In addition, circPIP5K1A knockdown enhances CDDP sensitivity of GC via the miR-299-3p/ENDOPDI (thioredoxin domain containing 5) axis (48). CircCOL1A2 induces GC CDDP resistance by effecting the miR-646/CDK6 (cyclin dependent kinase 6) pathway (49). CircKRT7 heightens CDDP resistance in GC via the miR-1200/POLD4 (DNA polymerase delta 4) pathway (50). CircSMC is an miR-129-5p sponge that can promote the CDDP resistance of GC by upregulating matrix metallopeptidase 11 (MMP11) (51). In addition, circFAM73A has the ability to facilitate in vitro CDDP resistance in GC (52). CircHNRNPU facilitates cisplatin resistant of GC through miR-637/caudal type homeobox 2 (CDX2) (53). Exosomal circRANGAP1 promotes GC resistance to CDDP by regulating the miR-449a/serine hydroxymethyltransferase 2(SHMT2) axis (54). circLDLRAD3 knockdown can reduce CDDP resistance by regulating miR-588/SRY-box transcription factor 5 (SOX5) pathway and block the malignant development of CDDP resistant GC (55) (Figure 1; Supplementary Table S1).

The 5-fluorouracil (5-FU) was first synthesized in 1957 and quickly became a routine anticancer drug that remains essential in many chemotherapy regimens today (56). The 5-FU cytotoxicity occurs due to the mistaken entrance of fluoronucleotides into RNA and DNA as well as nucleotide synthetic enzyme thymidylate synthase (TS) inhibition (57). Furthermore, circRNAs may participate in these mechanisms to regulate the sensitivity of 5-FU in GC. Research has shown that autophagy dysregulation may be one of the main reasons for drug resistance in cancer, in which circCPM participates (31). CircCPM was overexpressed in 5-FU resistant GC cell lines and tissues. It improves the expression level of protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) by directly binding to miR-21-3p and leading to the activation of autophagy and chemoresistance (31). In addition, silencing circCPM can improve chemosensitivity of 5-FU in GC (31). Emerging proof has shown that glycolysis plays an important role in hypoxia-induced chemoresistance. HIF-1α is one of the major regulators in the metabolic process. Downregulation of circNRIP1 can sensitize GC cells to 5-FU under hypoxic conditions (58). The miR-138-5p is a circNRIP1 sponge that can inhibit the effect of hypoxia-induced 5-FU resistance via circNRIP1 through HIF-1α (58) (Figure 1; Supplementary Table S1).

Oxaliplatin (OXA) is an alkylating agent that inhibits DNA replication by forming adducts between two adjacent guanine or guanine and adenine molecules and is the third-generation derivative of platinum complex anticancer drugs. At present, the resistance mechanism for GC to OXA is very complex, involving microenvironmental, cell mitochondrial, cell membrane, cell protein, signal transduction, and other factors related to tumor growth. Morevoer, circRNAs are a novel landmark in OXA resistance in GC (59). The Gao et al. study has led to the identification of circSLAMF that promoted GC oxaliplatin resistance by regulating the miR-502-5p/ADAM9 (ADAM metallopeptidase domain 9) axis (60). CircSLAMF is overexpressed in OXA-resistant tissues and cells. In addition, miR-502-5p efficiently inhibited OXA resistance in OXA-resistant GC cells, reversing the promoting effect of circSLAMF (60). Finally, ADAM9 upregulation may act as an oncogene aggravating OXA resistance to GC treatment (60). CircCEP128 is highly expressed in OXA-resistant GC cells and its exosomes. It has the ability to boost OXA resistance of GC cells partly via the miR-515-5p/SOX9 (SRY-box transcription factor 9) pathway, which is a promising therapeutic target (61) (Figure 1; Supplementary Table S1).

Paclitaxel (PTX) is a stable tubulin cytotoxic agent that has become the first-line treatment for various cancers, including GC (62). It can induce cellular processes by disrupting normal microtubule dynamics required for cell division and interphase processes and by inducing tumor necrosis factor-alpha gene expression, leading to apoptosis or programmed cell death (63). PTX resistance in tumors has been reported to be associated with increased drug efflux, alteration of intercellular signaling, tubulin mutation, and overexpression of β-tubulin isotype composition (64). In addition, circRNAs have been found to be associated with the mechanisms of PTX resistance. For example, circPVT1 downregulation can result in a noteworthy decrease in P-gp and GST-π, which can reduce cytotoxicity by reducing the concentration of antineoplastic drugs (65). As the target of circPVT1, miR-124-3p promotes sh-circ-PVT1-caused PTX sensitivity in PTX-resistant GC cells and the expression of zinc finger E-box binding homeobox 1 (ZEB1). Overexpression can promote PTX resistance of GC cells (65). Thus, circPLEC can interact with miR-198 in GC cells and through miR-198 to regulate the downstream gene mucin 19 and oligomeric (MUC19). MUC19 downregulation weakened GC resistance to PTX and improved the apoptosis of PTX-resistant GC cells (66). Therefore, circPLEC can promote PTX resistance through the miR-198/MUC19 axis, which has the potential to be a therapeutic target (66) (Figure 1; Supplementary Table S1).

Pemetrexed is an antifolate analog that inhibits enzyme thymidylate synthase (TS) and is also active on dihydrofolate reductase and glycine ribonucleotide folate-dependent enzymes, which forms an effective combination with OXA for locally advanced or metastatic disease treatment (67). Drug resistance is common in cancer. Thus, determining the mechanism of pemetrexed resistance is vital for improving treatment. Prior research has shown that cell drug resistance increased significantly in the circMTHFD2 overexpression group (68). In addition, miR-124 is a target of circMTHFD2 that can increase the protein expression of TS and ATP-binding cassette subfamily C member 11 (ABCC11) and decrease the protein expression of RCF1 (respiratory supercomplex factor 1, mitochondrial). There are also reports that ABCC11 is a drug efflux pump used for drug metabolism. Thus, circMTHFD2 has the ability of enhancing the pemetrexed resistance in GC (68) (Figure 1; Supplementary Table S1).