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Introduction

Circular RNAs (circRNAs/circs) are a type of noncoding RNA lacking 5′-3′ ends and poly(A) tails, with a closed-loop structure that is more stable than that of linear RNA (1). circRNAs were first revealed to exist via electron microscopy in 1976 (2). In 1991, the first spliced circRNAs were discovered through analyses of a human candidate tumor suppressor gene (3). Despite extensive research, no evidence of the translation of circRNAs has been found, and researchers typically considered circRNAs to be the result of splicing errors (3). However, in early 2012, researchers were surprised to find that circRNA was a transcriptional product of thousands of human and mouse genes (4).

circRNAs can be roughly divided into three categories based on their genomic origin. Exonic circRNAs, the main type of circRNA, are formed via exon skipping or head-to-end connection. Intronic circRNAs are composed of lariat introns (5). Exon-intron circRNAs, which comprise the third category, consist of both exons and introns (5). Exonic circRNAs indicate the development of disease, and can be used as noninvasive biomarkers for diagnosis and prognosis in a number of diseases (6).

In the last few decades, the development of improved chemotherapy regimens with multiple chemotherapeutics, such as 5-fluorouracil (5-FU), and molecular targeting drugs, such as erlotinib and gemcitabine, have provided various treatments and significantly extended the survival time of patients with cancer (7). However, the acquisition of resistance to chemotherapeutics is an intractable problem in clinical chemotherapy for cancer, reducing the effectiveness of treatment. To escape the attack of multiple chemotherapeutics, cancer cells have evolved multiple strategies, including promoting drug transport, altering drug targets, elevating DNA repair capacity, evading apoptosis and autophagy, and promoting adaptive responses (8). Nevertheless, the exact mechanisms of chemotherapy resistance remain to be fully elucidated.

With increasing in-depth research, circRNAs have been found to serve important roles in cancer development, including cancer proliferation, metastasis, chemoresistance and radioresistance, suggesting the potential of circRNA as a new tool for overcoming tumor resistance. The present study focused on the signaling pathways via which circRNAs promote the development of tumor chemoresistance, with the aim of finding general molecular mechanisms that stimulate further exploration of the pathway(s) through which circRNAs are involved in chemoresistance and therapeutic targets associated with these pathways.

Function of circRNAs

Multiple functions of circRNAs have been revealed; circRNAs can not only act as microRNA (miRNA/miR) sponges, protein sponges, and transcriptional and translational regulators, but also interact with proteins and translated peptides, and compete with pre-mRNA splicing (9). These functions may provide insight into the roles of circRNAs in the chemoresistance pathway.

miRNA sponges

Endogenous circRNAs can act as sponges of miRNAs and modulate the effects of miRNAs on target genes (10). miRNA dysregulation has been confirmed to play important roles in cancer growth via several mechanisms, including changes in genomic miRNA copy numbers and gene locations (11,12). The discovery of the circRNA-miRNA code has increased understanding of the dysregulation of miRNAs. For example, circ-DOCK1 can regulate baculoviral IAP repeat-containing protein 3 by sponging miR-196a-5p and thereby participating in the regulation of oral squamous cell carcinoma (OSCC) (13). However, the effects of circRNAs on their potential sponge miRNAs in chemoresistance remain largely undiscovered (14). Furthermore, concerns regarding the quantity of circRNAs required to achieve a measurable effect have been proposed due to the low levels of circRNAs and limited binding sites with miRNAs in cells (15).

Protein sponges and interactions with proteins

In addition to interacting with miRNA, circRNAs are processed cotranscriptionally to combine with various proteins as protein sponges or protein scaffolds (14). An example of circRNAs serving as protein scaffolds is the feedback loop between mannose-binding lectin (MBL) and circ-MBL (16). Excess levels of MBL promote the expression of circ-MBL, which absorbs the excess MBL, thereby decreasing its own mRNA expression and maintaining a balance in MBL production (14). Furthermore, circRNAs have been reported to engage with proteins and sequester proteins. For example, it was reported that the CDK2 and p21 can bind to circ-FoxO3 and form a circ-FoxO3-p21-CDK complex; the formation of this circ-FoxO3-p21-CDK2 complex can inhibit the function of CDK2 and induce cell cycle disorders (17). Furthermore, circ-FoxO3 can also interact with E2F1, ID-1, hypoxia-inducible factor 1α and focal adhesion kinase as an upstream signaling molecule (9). Thus, circRNAs can participate in and regulate a variety of cellular behaviors through proteins.

Transcriptional and translational regulators

To regulate gene transcription, the sequence of the circRNA itself is duplicated with the DNA sequence of the host gene. When circRNA stays in the nucleus for a certain period of time, it will form an RNA:DNA hybrid strand with the maternal DNA double strand. Under these circumstances, the maternal DNA transcription of other transcripts will be halted, which is referred to as negative feedback loop regulation (18). In addition, circRNAs have the potential to be pseudogenes; some circRNAs can be inserted into the genome to alter the genetic information of the genome via retrotransposition, regulating gene expression (19). A computational pipeline, CIRCpseudo, was developed to identify potential circRNA-derived pseudogenes in the mouse reference genome, and it was found that circ-SATB1 from mouse can be inserted into the CTCF gene sequence as a pseudogene (19).

Although circRNAs have been found to be predominantly located in the cytoplasm, circRNAs in the nucleus are involved in the regulation of transcription, alternative splicing and chromatin looping (20). circRNAs formed by processed intron lariats (ciRNAs) or by back-splicing with retained introns (EIciRNAs) are limited to the nucleus in human cells (14). RNA polymerase II (Pol II) consists of U1 small nuclear ribonucleoprotein (snRNP) and other proteins, and EIciRNA-U1 snRNP complexes can combine with RNA Pol II at the promoters of their parent genes to enhance gene expression (14). Additionally, a ciRNA called ci-ankrd52 was revealed to modulate RNA Pol II transcription by accumulating at its own sites of transcription (21).

Furthermore, circRNAs have been found to play an essential regulatory role in translation. circ-polyadenylate binding protein 1 (PABPN1) has been shown to sequester HuR to regulate the translation rate of the PABPN1 gene and reduce PABPN1 translation (22). The ribosome is the main organelle involved in translation; it was reported that the circ-ANRIL can modulate ribosomal RNA maturation to control ribosome biogenesis and nucleolar stress (23), which highlights the association between circRNA and translation regulation.

circRNAs can be translated

Most endogenous circRNAs cannot be translated, as they lack a 5′ 7-methylguanosine triphosphate cap and a 3′-end poly(A) tail (20). However, studies have shown that certain endogenous circRNAs can be translated into proteins or peptides (24). The majority of circRNAs spliced from coding genes contain open reading frames (ORFs) and thus have protein coding potential (25). Although thousands of circRNAs are predicted to contain putative ORF and upstream internal ribosome entry sites (IRESs), to date only a few endogenous circRNAs, such as circ-PINTexon2, circ-F-box/WB repeat-containing protein 7, circ-Mb1, circ-zinc finger protein 609 (ZNF609) and circ-SHPRH, have been shown to be useful protein templates (26). Recently, it was found that ~50% of male germ cell circRNAs exhibited protein-coding potential, containing large ORFs and m6A-modified start codons in junction sequences (25). Additionally, a ~10 kDa protein encoded by circ-MBL3 has been detected via mass spectrometry (24). circ-ZNF609 contains an ORF and is translated into a protein in a splicing-dependent/cap-independent manner (26). Furthermore, circRNAs can promote the direct binding of translatable circRNAs to initiation factors or ribosomes, acting as IRESs (14). Furthermore, as circRNA-derived peptides are typically truncated forms of standard proteins lacking essential functional domains (26), they may serve as dominant-negative protein variants, decoys or modulators of alternative protein complexes.

Mechanisms of drug resistance in cancer

Chemotherapy is one of the main methods for treating malignancy, and multidrug resistance (MDR) is the main problem limiting the success of chemotherapy. The resistance of cancer cells can be categorized as primary resistance or acquired resistance. The former is resistance that existed in the tumor cells before the use of antitumor drugs, and is unassociated with their use. The latter is resistance induced by drug administration; that is, the cells were sensitive to the drug(s) before drug administration and became resistant afterwards. Acquired resistance may limit the application of chemotherapeutics and involves the gradual loss of the initial promising effect of chemotherapy. Numerous mechanisms have been described to explain MDR, including mechanisms involving drug transport and metabolism, alterations of drug targets, DNA damage repair, downstream resistance mechanisms, adaptive responses and the tumor microenvironment (Fig. 1) (8).

Figure 1. Mechanisms of circRNA involvement in chemotherapy resistance. Typical circRNAs are formed by precursor mRNA back-splicing or exon-skipping events in eukaryotes. (A) General mechanisms of circRNA functions in chemotherapy resistance. (1) circRNAs can sponge miRNAs, resulting in enhanced levels of ribosome binding and translation of target RNAs. (2) circRNAs with internal ribosome entry site elements and AUG sites may be translated and generate unique peptides. (3) Certain circRNAs can bind proteins to form circRNA-ribonucleoproteins, such as circ-FoxO3-p21-CDK, thus regulating their functions. (4) circRNAs can act as transcriptional regulators by recruiting specific proteins to certain loci or subcellular compartments. (B) Mechanisms via which circRNAs participate in chemotherapy resistance. (1) Alterations of drug targets. Drug inactivation resulting from alterations of drug targets is an important means of drug resistance. For example, increased expression of AR in prostate cancer has been found to reduce the efficacy of AR antagonists such as bicalutamide. (2) Drug transport and metabolism. Tumor cells can resist drug actions by promoting drug efflux via several cell membrane transporter proteins, such as members of the ATP-binding cassette transporter family, or drug inactivation; for instance, platinum drugs can be inactivated by the thiol GSH. (3) Downstream resistance. After drugs have inhibited their cellular target, various innate adaptive responses can be triggered to promote the survival of cancer cells, such as dysregulation of apoptosis pathways. (4) DNA damage repair. Tumor cells can avoid cell death and cell cycle arrest by promoting the repair of DNA damage induced by agents such as cisplatin. circRNA/circ, circular RNA; AR, androgen receptor; GSH, glutathione.

Drug transport and metabolism

Reducing the intracellular concentration of the drugs is an effective method for cancer cells to avoid the damage induced by drugs. A group of membrane proteins have been found to contribute to the drug resistance of commonly used antitumor drugs by promoting drug efflux. For example, multi-drug resistance (MDR)1, a member of the ATP-binding cassette (ABC) transporter family, has been reported to regulate the absorption, distribution and excretion of various anticancer drugs and inhibit the efficacy of chemotherapy in numerous cancers (27). Other ABC family transporters associated with MDR include multidrug resistance-associated protein 2 and breast cancer resistance protein (28). These three ABC transporters are commonly co-expressed in cancer and exhibit a wide range of substrate specificity overlap involving drugs such as doxorubicin, epirubicin, etoposide, irinotecan and mitoxantrone (28). Drug metabolism is another important means to induce drug resistance, particularly when a chemotherapeutic drug is combined with a specific targeting molecule. For example, metallothionein and glutathione can bind cisplatin (CDDP), leading to drug inactivation (29).

Alterations to drug targets

Alterations to drug targets, such as mutations or changes in expression levels, may affect drug response and resistance. For example, altered expression of thymidylate synthase and ribonucleotide reductase reduces the effectiveness of inhibitors of these targets (30). Furthermore, cases of alterations to genes, including EGFR and anaplastic lymphoma kinase (ALK), leading to drug resistance have been observed. For example, a common drug resistance-related mutation, EGFR T790M, is associated with the acquisition of drug resistance (31). Additionally, in non-small cell lung cancer (NSCLC), gefitinib and erlotinib can activate mutations in the EGFR tyrosine kinase domain (32). In ALK-positive patients with NSCLC treated with tyrosine kinase inhibitor (TKI), ALK tyrosine kinase domain mutations or ALK fusion gene amplifications may occur (33).

DNA damage repair

A number of drugs, such as platinum and topoisomerase inhibitors, can lead to cell cycle arrest by inducing DNA damage, which will result in cancer cell death (34). However, some tumor cells can escape drug-induced damage by means of DNA damage repair, thus achieving drug resistance. The level of ERCC1-XPF has been found to be elevated in CDDP-treated testis tumor cells and result in increased DNA repair (35). It has been established that p53 is an important tumor suppressor protein for various types of human tumor; when platinum drugs cause damage to the DNA of tumor cells, p53 can initiate DNA damage repair and cell cycle arrest, and its mutation is frequently associated with drug resistance (36). To block the activation of DNA damage repair mechanisms, molecular targeting drugs have been developed, such as inhibitors of the single-strand-break DNA repair enzyme poly(ADP-ribose) polymerase 1; these drugs have proved effective against breast and ovarian tumors that involve mutations in the BRCA1 or BRCA2 genes (37). Therefore, targeting or blocking DNA repair processes is an effective treatment strategy.

Downstream resistance mechanisms

Even if enough active drug molecules accumulate on a cellular target, numerous intrinsic adaptive responses can be triggered that promote cancer cell survival (8). Under such conditions, cancer cells can evade drug-induced cell death in two ways: Apoptotic evasion and autophagy (8). Apoptosis is triggered when cells are in an adverse environment, such as the environment observed during anticancer therapy. Tumor cells have evolved multiple strategies to limit or evade apoptosis. One common way to block apoptosis is via the loss of the damage sensor TP53 (38). Autophagy is the process of phagocytosis and decomposition of cytoplasmic proteins or organelles by lysosomes; this process allows the resulting catabolites to be recycled to maintain cellular biosynthesis and viability (39). Paradoxically, nutritional starvation, radiation therapy and certain cytotoxic drugs can lead to elevated levels of autophagy, which instead of promoting the anticancer effects of chemotherapeutic drugs, has a protective effect on cancer cells (40). Numerous anticancer treatments can activate the autophagy pathway; conversely, hydroxychloroquine, an autophagy inhibitor, has been developed, and it can cause human cancer cells to become sensitive to chemotherapy (41).

Promotion of adaptive responses

The promotion of adaptive responses consists of three parts: Activation of prosurvival signaling, oncogenic bypass and pathway redundancy, and epithelial-mesenchymal transition (8). The addition of EGFR-targeted therapies to irinotecan-based chemotherapy in KRAS-wild-type colorectal cancer has shown beneficial effects. However, KRAS-mutant colorectal cancer is unresponsive to EGFR inhibitors as oncogenic KRAS is not dependent upon upstream activation by EGFR; this is an example of both activation of prosurvival signaling and oncogenic bypass resistance to EGFR inhibitors that was observed in cell lines undergoing epithelial-mesenchymal transition (42,43). EGFR-targeted drugs are promising for drug resistance treatment.

Tumor microenvironment

In both solid tumors and hematological malignancies, the complex tumor microenvironment provides shelter for cancer cells, protecting them from chemotherapeutic drugs and facilitating disease relapse. In addition, communication between cancer cells may mediate the development of chemoresistance (43). For example, increased expression of integrins can promote drug resistance (44). Furthermore, cytokines and growth factors are associated with resistance. Wilson et al (45) found that hepatocyte growth factor in the tissue microenvironment can induce drug resistance by reactivating either or both of the PI3K-AKT and MEK-ERK pathways. Moreover, exosomes play roles in the regulation of drug resistance. It has been shown that CDDP-resistant ovarian cancer cells release more protein and export higher levels of CDDP through exosomes than CDDP-sensitive cells (46). Exosomes containing miR-21 from CDDP-resistant OSCC cells were found to promote chemoresistance by targeting PTEN and programmed cell death protein 4 (PDCD4) in recipient OSCC cells (47).

Extrachromosomal circular DNA (ecDNAs)

ecDNA, a type of circular DNA structure found outside of the normal chromosome structure, has begun to receive increasing attention. A previous study reported a novel targeted drug resistance mechanism mediated by ecDNA in glioblastoma: Tumor cells could show resistance to EGFR TKI by eliminating mutant EGFR in ecDNA (48). It is hypothesized that ecDNA is related to resistance mechanisms; however, there remains a lack of research in this area.

The mechanisms of drug resistance for different anticancer drugs during the process of drug resistance in different tumors do not exist independently. Multifaceted drug resistance pathways may complement each other during the development of drug resistance. An example is EGFR, which has been extensively studied; EGFR is involved in multiple mechanisms, including alterations of drug targets, dysregulation of apoptosis, activation of prosurvival signaling and epithelial-mesenchymal transition (8).

Mechanisms of circRNAs in cancer drug resistance

The mechanisms via which circRNAs promote drug resistance were divided into four categories: circRNA-miRNA patterns; fusion circRNAs; circRNA in exosomes; and mechanisms mediating chemoresistance potentially related to circRNAs in cancers. This classification emphasizes the roles of circRNAs in various drug-resistant pathways, providing a theoretical basis for future research aimed at overcoming tumor drug resistance with circRNAs as the targets.

circRNA-miRNA patterns

miRNAs serve important roles in cell development, cell differentiation, chemoresistance and the immune system, and function as oncogenes and tumor suppressors (49). For example, the FOXC1/miR-31-5p/large tumor suppressor kinase 2 pathway can modulate chemoresistance in colorectal cancer (50). Additionally, miR-375 can promote colorectal cancer cell sensitivity to 5-FU by directly targeting yes-associated protein 1 and SP1 (51). As sponges of miRNAs, circRNAs can modulate cancer cell chemoresistance by absorbing and degrading miRNAs (52). Identified circRNA-miRNA pathways involved in the development of cancer drug resistance are summarized in Table I. Most of the contributing studies aimed to elucidate the regulatory effects of circRNA-miRNA interactions on target proteins involved in chemoresistance. Several proteins listed in Table I, such as STAT3, EGFR and p53, are associated with the dysregulation of apoptosis, the activation of prosurvival signaling and DNA damage repair, respectively. Interactions between circRNAs and miRNAs can promote drug resistance by regulating protein expression (Fig. 2).

Figure 2. Network regulation of chemotherapy resistance via circRNA-miRNA interactions. In the apoptosis pathway, circ-PAN3 elevate the expression of XIAP by sponging miR-153-5p and miR-183-5p, thereby promoting DNA damage repair. circ-0001427 sponges miR-181c-5p, which targets AR-V7 and increases its expression, resulting in the reduced efficacy of AR antagonists. In the AKT-ERK regulatory network, circ-000652/miR-7-5p/c-Raf, circ-00025202/miR-744-3p/FoxO, circ-0060060/miR-144-3p/IGF, circ-0004015/miR-1183/PDK1, circ-0007031/miR-885-3p/AKT, circ-000652/miR-7-5p/MDM2, circ-0091931/miR-34c-5p/p53 and circ-CDR1as/miR-7/CDK2-cyclin E axes may induce proliferation signal transmission, leading to evasion of drug-induced cell death. By sponging miR-744-3p, circ-0001258 could increase the levels of MRP2, which can transfer chemotherapeutics out of cancer cells. circRNA/circ, circular RNA; miRNA/miR, microRNA; AR-V7, androgen receptor V7; DFF, DNA fragmentation factor; MDM2, mouse double minute homolog 2; MRP2, multidrug resistance-associated protein 2; PDK1, phosphoinositide-dependent protein kinase 1; RTK, receptor tyrosine kinase; XIAP, X-linked inhibitor of apoptosis protein.

Table I. circRNAs-miRNAs and drug resistance.

Table I.

circRNAs-miRNAs and drug resistance.

First author, year	Cancer type	circRNA	Expressiona	Validated/putative targets/pathways	Drug resistance-related effects	(Refs.)
Yan et al, 2019	Renal clear cell carcinoma	circ-0035483	Up	miR-335	Promotes gemcitabine resistance	(53)
Yang et al, 2019	Breast cancer	circ-CDR1as	Up	miR-7/CCNE1	Promotes docetaxel resistance	(79)
Huang et al, 2019	Gastric cancer	circ-AKT3	Up	miR-198/PIK3R1	Promotes CDDP resistance	(52)
Yu et al, 2019	Lung adenocarcinoma	circ-0003998	Up	miR-326	Promotes doxorubicin resistance	(80)
Shang et al, 2019	Acute myeloid leukemia	circ-PAN3	Up	miR-153-5p and miR-183-5p-XIAP	Promotes doxorubicin resistance	(81)
Kun-Peng et al, 2018	Osteosarcoma	circ-0004674	Up	miR-490-3p/ABCC2 and miR-1254/EGFR	Promotes doxorubicin/cisplatin/methotrexate resistance	(82)
Liu et al, 2018	Thyroid cancer	circ-0060060	Up	miR-144-3p/TGF-α	Promotes CDDP resistance	(83)
Gao et al, 2019	Breast cancer	circ-000652	Up	miR-7-5p/Raf1	Promotes adriamycin resistance	(84)
Zhou et al, 2019	NSCLC	circ-0004015	Up	miR-1183/PDPK1	Promotes gefitinib resistance	(85)
Xu et al, 2018	NSCLC	circ-0000567	Up	miR-141	Promotes taxol resistance	(5)
Xu et al, 2018	NSCLC	circ-0091931	Down	miR-34c-5p/p53	Promotes taxol resistance	(5)
Hua et al, 2019	NSCLC	circ-0000567	Up	miR-124	Promotes pemetrexed resistance	(86)
Xiong et al, 2017	Colorectal cancer	circ-0000504	Up	miR-485-5p on STAT3	Promotes 5-FU resistance	(87)
Xiong et al, 2017	Colorectal cancer	circ-0007031	Up	miR-885-3p/AKT3/BCL2	Promotes 5-FU resistance	(87)
Xiong et al, 2017	Colorectal cancer	circ-0048234	Down	miR-671-5p/EGFR	Promotes 5-FU resistance	(87)
Sang et al, 2019	Breast cancer	circ-0025202	Down	miR-182-5p/FoxO3a	Suppresses tamoxifen resistance	(76)
Zhu et al, 2019	Osteosarcoma	circ-0001258	Down	miR-744-3p/GSTM2	Suppresses drug resistance	(88)
Chi et al, 2019	Bladder cancer	circ-0000285	Down	miR-124 or miR-558	Suppresses CDDP resistance	(89)
Wu et al, 2019	Prostate cancer	circ-0001427	Down	miR-181c-5p/ARv7	Suppresses enzalutamide resistance	(90)

a Expression in chemoresistant tumor tissue compared with non-tumor tissue. circRNA/circ, circular RNA; miRNA/miR, microRNA; 5-FU, 5-fluorouracil; CDDP, cisplatin; NSCLC, non-small cell lung cancer.

Research into circRNA-miRNA-protein three-stage regulatory networks has added an extra layer of complexity to understanding of cancer drug resistance; however, it also provides numerous potential targets to reverse chemoresistance that cover proteins and RNAs at same time. A recent study suggested that circRNA can promote gemcitabine resistance via autophagy regulation (53). Furthermore, numerous studies have found that circRNAs can influence tumor cell resistance to chemotherapy drugs via miRNA-mRNA axes (54–56). However, certain studies lack detailed resistance mechanisms; studies into the regulation of drug resistance via circRNA-protein pathways may neglect the involvement of miRNAs. The detailed mechanisms through which circRNAs are involved in tumor resistance remain unclear. At present, most research into modulation of cancer cell chemoresistance by circRNAs has focused on circRNA-miRNA pathways, which may overshadow circRNAs that regulates cancer drug resistance via other mechanisms.

Fusion circRNAs (f-circRNAs)

As genes are misallocated due to abnormal chromosome translocations and chromosomal rearrangements, complementary repeating intron sequences such as the Alu-sequence may be introduced close enough to facilitate novel reverse splicing events during RNA maturation, leading to the production of abnormal circRNAs (57). Therefore, the juxtaposition of complementary sequences in the upstream and downstream introns of the translocation breakpoint region may form new circRNAs, called f-circRNAs, which are formed from the fusion of two translocation genes (57). Roles for this new type of circRNA in chemotherapy resistance have been identified. For example, in acute promyelocytic leukemia, general translocation occurs between the promyelocytic leukemia protein (PML) and retinoic acid receptor (RAR) genes, which then form f-circRNAs (58). F-circ-M9_1 and f-circ-M9_2 are two f-circRNAs formed via MLL/AF9 translocation in acute myeloid leukemia; it was reported that f-circM9 can promote chemotherapy resistance in acute myeloid leukemia (57). Furthermore, an f-circRNA from the BCR-ABL1 fusion gene, circ-BA9.3, was found to be associated with resistance to TKIs by increasing the production of C-ABL1 or BCR-ABL1 protein in leukemic cells (59).

circRNA in exosomes

Exosomes, containing a variety of proteins, DNA, mRNA, miRNA and other molecules, serve important roles in intercellular communication and the triggering of physiological responses (60). It has been reported that exosomes released from CDDP-resistant OSCC cells transmit miR-21, which targets PTEN and PDCD4 to decrease the drug resistance of OSCC cells (47). circ-CDR1as, which suppresses CDDP resistance in ovarian cancer, has been reported to be downregulated in serum exosomes from CDDP-resistant patients (61). However, the mechanism via which exosomes regulate drug resistance in ovarian cancer cells is unclear. Additionally, exosomal circ-Myc in the serum is associated with recurrence and bortezomib resistance in multiple myeloma (62). Recently, it was observed that exosomal circ-nuclear factor 1 X-type (NFIX) was upregulated in the serum of temozolomide (TMZ)-resistant patients and exosomal circ-NFIX from TMZ-resistant cells conferred TMZ resistance to recipient sensitive cells in glioma (63). This newly identified resistance mechanism may provide novel resistance targets.

Mechanisms mediating chemoresistance potentially related to circRNAs in cancers

circRNAs participate in the regulation of cancer cell chemoresistance not only by interacting with miRNAs, but also by affecting certain signaling pathways. Tumor resistance involves the mutual regulation of signaling networks. For example, BRCA1 serves an important role in the homology-directed repair of DNA double-strand breaks, which modulates chemotherapy resistance (64). AKT activation regulates resistance to CDDP-induced apoptosis by inhibiting apoptosis-inducing factor-related pathways (65). Furthermore, circ-PAN3 facilitates drug resistance in acute myeloid lymphoma cells via the AMPK/mTOR pathway (66). circ-mitochondrial tRNA translation optimization 1 reverses monastrol resistance by regulating the TNF receptor associated factor 4/Eg5 axis (67). In addition, circ-plasmacytoma variant translocation 1 facilitates the expression of ABCB1 to enhance the doxorubicin and CDDP resistance of osteosarcoma cells (67). It has been reported that lung adenocarcinoma can activate autophagy via the AMPK/mTOR signaling pathway and thus induce CDDP resistance (68). Additionally, ABCB1 is involved in drug transport and metabolism (69). However, there are few studies concerning the direct binding of circRNAs to proteins to regulate drug resistance.

circRNAs are involved in multiple drug resistance pathways and can form complex drug-resistance networks. The roles of circRNAs in resistance, including circRNA-miRNA interactions, circRNA-protein interactions and F-circRNAs, have been reviewed. However, some circRNAs have been identified to be associated with cancer drug resistance, but information concerning their mechanisms is lacking. For example, circ-0004350 and circ-0092857 are involved in the drug sensitivity of lung cancer, and circ-elongator complex protein 3 contributes to CDDP resistance (70,71). Additionally, circ-100053 can promote imatinib resistance in chronic myeloid leukemia (72), and circ-coiled-coil domain containing 66 can increase the EGFR resistance of lung adenocarcinoma cells (73). Nevertheless, the mechanisms via which these circRNAs alter drug resistance remain unclear. This topic merits further investigation, and future research may lead to the identification of potential protein targets to overcome chemotherapy resistance.

Potential applications of circRNAs in cancer drug resistance treatment

With developments in molecular oncology, targeted drugs that regulate drug resistance genes have become an important tool for reversing drug resistance. A previous study found that RNA interference can significantly reduce the expression of STAT3, allowing the resensitization of resistant cancer cells (74). Findings concerning the multiple mechanisms of circRNA in cancer drug resistance have indicated the potential of circRNAs to serve as a new treatment tool.

One important mechanism of tumor resistance entails modulation of the regulatory effects of miRNA. In vitro research has suggested that certain miRNA mimics or antagomirs can enhance the treatment effect of anticancer drugs by regulating target protein expression (75). In the case of imbalanced circRNAs in drug-resistant cancer, circRNA levels could be adjusted by cloning the circRNA sequence and its regulatory flanking regions or by using small interfering RNA (siRNA). In various animal experiments, it has been shown that circRNA can be used as a target to achieve substantial therapeutic efficacy (52,76). Additionally, it has been reported that packaging siRNA in extracellular vesicles via a pre-microRNA backbone can allow a reduced therapeutic dose of siRNA (77). It is hypothesized that circRNA may serve as a novel type of miRNA vector with multiple miRNA adsorption target sites that promote chemoresistance in order to block drug resistance, utilizing the function of circRNA as a miRNA sponge.

It is proposed that circRNAs could be designed to sponge miRNAs and proteins that promote chemoresistance; due to the size of circRNAs, multiple sponge sites could be designed and incorporated to enhance their function. Additionally, as circRNAs can function as transcriptional and translational regulators, it may be possible to design artificial circRNAs to regulate the transcription and translation of essential genes involved in the pathway of drug resistance by interacting with their promoters. However, a lack of information concerning the mechanisms via which circRNA can act as a transcriptional and translational regulator is an obstacle to realizing this possibility. It may also be possible to design certain circRNAs similar to plasmids that can carry a target gene sequence and transmit it into cancer cells to express specific proteins and inhibit drug resistance (Fig. 3). Furthermore, it may be possible to design circRNAs with several of the functions mentioned above to enhance their ability to regulate drug resistance.

Figure 3. Potential applications of circRNAs in cancer drug resistance treatment. Targeted chemoresistance-associated miRNA binding sites can be designed into circRNAs to enable miRNA sponging, resulting in disturbance in drug resistance pathways. Based on specific protein-binding elements, circRNA can be used as a trap to sponge target chemoresistance-associated proteins, leading improved efficacy of drugs. circRNAs with internal ribosome entry site elements and AUG sites that are translated to generate unique peptides could be used as fake proteins that form small molecular weight translation templates to interfere with chemoresistance. In addition, circRNAs could be designed to recruit specific transcription factors to certain loci or subcellular compartments, resulting in regulation of targeted chemoresistance-associated genes. circRNA, circular RNA; miRNA, microRNA.

circRNAs are increasingly recognized as important factors in maintaining cellular homeostasis. circRNAs are closely associated with chemoresistance and may be used as potential therapeutic targets and prognostic markers in solid tumors or hematological malignancies. Furthermore, circRNAs may be used as an early marker of tumor drug resistance, as they can readily enter the circulatory system by the exosome pathway (52,63,78).

Conclusions and perspectives

The present review provided a novel perspective on the roles of circRNAs in chemotherapy resistance. By consulting studies into the various resistance pathways, it was found that most research concerning the modulation of chemoresistance in cancer cells by circRNAs has focused on circRNA-miRNA pathways. Furthermore, a novel form of circRNA that has been discovered, f-circRNA, may play important roles in chemoresistance. circRNA research will increase present understanding of the mechanisms underlying tumor resistance and identify therapeutic targets to combat drug resistance. The detailed mechanisms via which circRNAs affect drug resistance remain to be elucidated.

Although not all drug resistance-associated circRNAs are included in this review, the studies summarized above demonstrate that circRNAs serve important regulatory roles in chemotherapy. circRNAs are involved in multiple drug resistance pathways and can form complex drug resistance networks. The roles of circRNA in resistance were reviewed, addressing circRNA-miRNA and circRNA-protein interactions, as well as f-circRNAs. However, some circRNAs have been identified to be associated with cancer drug resistance, but information on the mechanisms is lacking. Therefore, an in-depth understanding of the molecular mechanisms via which circRNAs participate in cancer resistance is required.

There is great promise concerning circRNAs that could serve as important biomarkers for diagnosis and prognosis in clinical settings. For example, Kaplan-Meier survival analysis revealed that recurrent patients with glioma in a low circ-NFIX expression group exhibited improved survival compared with those in the high circ-NFIX expression group (63). Additionally, a previous study reported that low levels of circ-AKT3 in patients with gastric cancer receiving CDDP therapy were associated with poorer 5-year disease-free survival (52). Furthermore, decreased expression of circ-KDM4C in breast cancer was associated with poorer overall survival (78). Accumulating evidence indicates that circRNAs may serve an important role in the diagnosis and prognosis of various tumors.

miRNAs and proteins that may be associated with drug resistance should be investigated for their relationships with circRNAs. There is great clinical potential for findings from research into circRNAs; however, due to the low intracellular concentrations of circRNAs, their adsorption and biological functions are limited. Additionally, the large number of resistance-related circRNAs may lead to failure in the treatment of drug resistance. Nevertheless, circRNAs exhibit great potential for overcoming drug resistance, especially for tumors that can readily develop chemoresistance.

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (grant nos. 81872211, 81672675 and 81771081), the 111 Project of MOE China (grant no. B14038), the Sichuan University Innovation and Entrepreneurship Training Program for Undergraduates (grant no. C2019106455) and the Graduate Student's Research and Innovation Fund of Sichuan University (grant no. 2018YJSY018).

Availability of data and materials

Not applicable.

Authors' contributions

CX, FH, JL and JKW wrote the manuscript and designed the figures. JL and JKW provided guidance and revised the manuscript. QC revised this manuscript. All authors 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.

References