Circular RNAs in Cell Cycle Regulation of Cancers

Cancer has been one of the most problematic health issues globally. Typically, all cancers share a common characteristic or cancer hallmark, such as sustaining cell proliferation, evading growth suppressors, and enabling replicative immortality. Indeed, cell cycle regulation in cancer is often found to be dysregulated, leading to an increase in aggressiveness. These dysregulations are partly due to the aberrant cellular signaling pathway. In recent years, circular RNAs (circRNAs) have been widely studied and classified as one of the regulators in various cancers. Numerous studies have reported that circRNAs antagonize or promote cancer progression through the modulation of cell cycle regulators or their associated signaling pathways, directly or indirectly. Mostly, circRNAs are known to act as microRNA (miRNA) sponges. However, they also hold additional mechanisms for regulating cellular activity, including protein binding, RNA-binding protein (RBP) recruitment, and protein translation. This review will discuss the current knowledge of how circRNAs regulate cell cycle-related proteins through the abovementioned mechanisms in different cancers.


Introduction
In 2023, the United States reported that the number of new cancer cases reached 1,958,310, while the number of casualties was estimated at 609,820.Lung and colorectum cancers contribute to the highest number of cancer-related deaths in both men and women [1].Many internal biological factors have been identified to drive cancer progression, such as oncogenes, mutations in cell cycle-regulated genes, and aberrations in signaling pathways [2,3].It was shown that mutations in p53, a cell cycle suppressor gene, occurred in 60% of cancer cases [2].Furthermore, the mutated site in p53 usually occurs in the DNA-binding domain, thus disabling it from interacting with DNA [4].Amplification of cell cycle-encoding genes, including cyclin D, cyclin E, and cyclin-dependent kinase 4 (CDK4), can also occur in certain types of cancer [5].Additionally, several cancers were found to alter their signaling pathways that control the cell cycle [3,6].Numerous proteins in the signaling pathway, such as PI3K/Akt and MAPK signaling, can be dysregulated due to pathway hyperactivation, allowing excessive cell proliferation [5].
Discovered several decades ago, circular RNAs (circRNAs) were once identified as junk [7].However, high-throughput sequencing and bioinformatics analysis revealed that they are abundantly synthesized throughout all eukaryotes [8,9].In fact, circRNAs play an important role in many cellular and physiological processes under normal conditions [10].When dysregulated, several circRNAs are thus expected to participate in cancer development.Multiple studies also indicated that circRNAs are involved in abnormal signal transduction in cancer initiation, progression, metastasis, stemness, and resistance to therapy [11].For example, overexpression of circZNF609 activates the Hedgehog signaling pathway by sponging miR-15a-5p and miR-15b-5p to enhance the stemness of hepatocellular carcinoma (HCC) cells [12].CircPTK2 sponges miR-200a-3p to promote breast cancer tumorigenesis through the modulation of HIPPO/YAP signaling [13].Interestingly, dysregulated circRNAs may indirectly influence the alteration of cell cycle regulator expression via controlling signaling pathways.To illustrate, circSHPRH sponges multiple miRNA targets, a process which results in the inhibition of JAK/STAT signaling and a reduction in cyclin-dependent kinase (CDK) 4, and -6 expression [14].However, the signaling pathway that circRNAs mediate to control cell cycle regulator expression in many studies is still left unexplored and certainly requires more attention.This review will focus on the influence of circRNAs on cell cycle-related protein expression in different types of cancer and associated signaling pathways.
In addition to backsplicing, circRNAs can be generated from exon skipping in an alternative splicing event to form looped structures containing both exons and introns.This structure is called lariat, which can further undergo circularization and become exon-intron circRNA (EIcircRNA) or be processed by internal splicing to remove the intron, becoming exonic circRNA (ecircRNA) [25,26].In addition, the canonical splicing byproduct, intronic lariat, can also escape from debranching and eventually circularize into circular intronic RNA (ciRNA) [27].Interestingly, some studies have revealed that the fused gene in some cancers can give rise to circRNAs.For example, F-circBA1 is a product derived from a fusion of the BCR and ABL genes in chronic myeloid leukemia [28].F-circEA1 in non-small-cell lung cancer (NSCLC) also results from the fusion of the EML4 and ALK1 genes [29].CircRNA biogenesis and its functions.CircRNA is a product of backsplicing, which begins with the joining of the downstream splice-donor site and the upstream splice-acceptor site, forming a circular loop-like structure.Alu or RNA-binding proteins (RBPs) can stimulate this interaction.The current circular loop-like structure, EIcircRNA, can also be generated via an exon-skipping event, and it might proceed through an internal splicing event to eliminate the intron, resulting in an ecircRNA.Moreover, canonical splicing can generate the other type of circRNA, ciRNA, which is entirely composed of introns.CircRNAs might be imported to the cytoplasm, where they primarily function.Mostly, circRNAs possess the ability to bind to miRNAs to regulate gene expression.CircRNA was recently found to be a template for protein translation or to establish an interaction with proteins.It can act like a protein sponge, which might later facilitate or inhibit the interaction between two different proteins.Utilizing protein sponge activity, some proteins avoid ubiquitinmediated degradation by binding to circRNAs.Remarkably, some circRNAs have also been discovered to regulate their parental genes through various mechanisms, such as directly binding to the promotor or recruiting proteins to mediate gene expression.CircRNA biogenesis and its functions.CircRNA is a product of backsplicing, which begins with the joining of the downstream splice-donor site and the upstream splice-acceptor site, forming a circular loop-like structure.Alu or RNA-binding proteins (RBPs) can stimulate this interaction.The current circular loop-like structure, EIcircRNA, can also be generated via an exon-skipping event, and it might proceed through an internal splicing event to eliminate the intron, resulting in an ecircRNA.Moreover, canonical splicing can generate the other type of circRNA, ciRNA, which is entirely composed of introns.CircRNAs might be imported to the cytoplasm, where they primarily function.Mostly, circRNAs possess the ability to bind to miRNAs to regulate gene expression.CircRNA was recently found to be a template for protein translation or to establish an interaction with proteins.It can act like a protein sponge, which might later facilitate or inhibit the interaction between two different proteins.Utilizing protein sponge activity, some proteins avoid ubiquitin-mediated degradation by binding to circRNAs.Remarkably, some circRNAs have also been discovered to regulate their parental genes through various mechanisms, such as directly binding to the promotor or recruiting proteins to mediate gene expression.

Functions of circRNAs
The majority of circRNAs are proposed to act as miRNA sponges or decoys.Although miRNA was found to share a miRNA-binding element (MRE) not only with circRNA but also with other non-coding RNAs such as long-noncoding RNAs and pseudogenic RNAs.Competing endogenous RNAs (ceRNAs) were termed to describe the non-coding RNAs that are capable of binding to MRE.Therefore, it can be implied that the interaction between circRNA and its target miRNA might fall under the 'multiple-to-multiple' model, which is composed of a complex regulatory network involving ceRNAs [30,31].Factors known to influence ceRNA activity are its abundance, subcellular localization of ceRNAs and miRNAs, miRNA-ceRNA affinity, and interaction with RNA-binding proteins (RBPs) [32][33][34].However, more study is needed to completely clarify ceRNA activity, which might deeply affect the action of circRNAs on miRNAs.
In addition to being miRNA sponges, some circRNAs have been confirmed to encode a protein with biological function [35].More evidence also revealed that they can regulate the expression of the parental gene by interacting directly with the promoter or forming a protein complex.Indeed, circRNA is thus capable of recruiting RBPs, binding to proteins, or acting as a protein sponge [26].
Recent studies showed that circRNA plays an important role in several cellular activities via post-transcriptional regulation (Figure 1).Therefore, dysregulation in their expression could lead to abnormalities in many biological processes and might eventually lead to the development of disease, not only cancer.To illustrate, an upregulated circCHD2 promotes hepatic leukemia factor (HLF) expression to stimulate the activation of hepatic stellate cells, an essential driver of liver fibrosis [36,37].

Regulating the Transcription Activity of the Parental Gene
Interestingly, parental gene expression was found to be repressed by its transcribed circRNAs as they bind to the synthesis locus, forming an RNA-DNA hybrid called Rloop [38].The interaction halts the parental gene transcription activity [38].CircSEP3 and circSMARCA5 are known to mediate such functions [38,39].EIcircRNA establishes the complex with U1 small nuclear ribonucleoprotein (U1 snRNP) and binds to the promotor to upregulate the expression of the parental gene.Similar to EIcircRNA, ciRNAs accumulate at their synthesis site and elongate polymerase III activity to increase parental gene expression [27].

RNA Binding
Other than regulating its parental gene, circRNA has been mostly described as miRNA sponges or miRNA decoys as they contain many miRNA-binding sites, protecting mRNA targets from degradation.Moreover, recent studies also revealed that they can bind to mRNA to directly modulate post-transcriptional regulation.To illustrate, circPAN3 reinforces the stability of interleukin-13 (IL-13) mRNA through direct interaction [40].

Protein Translation
N6-methyladenosine (m 6 A) is a type of RNA modification that can be controlled by readers, writers, and erasers.The presence of m 6 A in circRNA can lead to various regulation mechanisms, including circRNA metabolism, localization, degradation, biogenesis, and protein encoding [41][42][43][44][45]. YTH N6-methyladenosine RNA-binding protein F3 (YTHDF3) recognizes the m 6 A-modified start codon and interacts with eIF4G2 to initiate protein translation.Mett13/14 was found to promote this activity, whereas fat mass and obesity-associated protein (FTO) inhibit the translation [45].With the presence of an internal ribosome entry site (IRES) in some circRNA, ribosomes can be recruited and begin translation [46].Moreover, circZNF609 utilizes the combination of the abovementioned processes to translate proteins, as m 6 A modification enhances the efficiency of IRES-mediated translation [47].However, the protein encoded from circRNA can act against or be analogous to that of its linear counterpart [48,49].

Protein Binding
Numerous studies have indicated the protein-binding function of circRNAs [15].However, bioinformatics analysis revealed that circRNA features a lower RBP binding density compared to linear RNA, suggesting that many circRNAs cannot interact with proteins [50].The binding of circRNA to proteins may result in a different action.CircRNA binds to two different proteins to facilitate their activity, acting as a scaffold.To illustrate, circFOXO3 recruits both p53 and mouse double minute 2 (MDM2), resulting in MDM2mediated p53 ubiquitination and degradation [51].Another example, circNFIX, binds to Y-box binding protein 1 (Ybx1) and Nedd4I, a ubiquitin ligase, to promote ubiquitination of Ybx1 by Nedd4I and trigger degradation [52].In other circumstances, circRNA binds to one protein and inhibits it from interacting with the other protein that does not bind directly to circRNA.For example, circGSK3β interacts with its parental gene product, GSK3β, which further phosphorylates β-catenin.By binding to circRNA, GSK3β is therefore prevented from exerting its function to induce β-catenin degradation [53].Similar to circGSK3β, polypyrimidine track-binding protein 1 (PTBP1) is targeted by circH19, and this interaction impedes PTBP1-mediated SREBP1 cleavage [54].CircRNA can also yield a similar result by attracting both proteins, which were originally combined in order to function, and preventing their association [15].Naturally, CCNB1 and CDK1 form a complex to initiate mitosis progression, including condensation of chromosomes, spindle pole assembly, and nuclear envelope breakdown [55,56].CircCCNB1 abolishes their activity by binding to both CCNB1 and CDK1, impairing complex formation [57].In addition, circRNA is also capable of recruiting RBPs, which regulate mRNA splicing, stability, and translation, thus forming the circRNA-protein-mRNA ternary complex.CircNSUN2 binds to IGF2BP2 and enhances its ability to stabilize HMGA2 mRNA [42].CircPOK was also shown to possess a similar mechanism by recruiting interleukin enhancer binding factor 2/3 (ILF2/3).The complex formation allows ILF2/3 to stabilize its target, IL-6, and VEGF mRNA [58].

Cell Cycle and Regulators
The cell cycle is a biological process involving cellular growth and proliferation.It can be divided into four separate phases: G1, S, G2, and M phase or mitotic phase.G1, S, and G2 phases are included in interphase, while M phase can be divided into mitosis and cytokinesis [59,60].Although cells can exit the cell cycle into a quiescent state (G0) under specific conditions [61].The progression to the next phase is mainly regulated by CDK and cyclin [62].
During the G1 phase, CDK4 or CDK6 associates with cyclin D to form cyclin D-CDK4/6 complex, which partially phosphorylates retinoblastoma protein (RB) [63,64].The RB phosphorylation triggers detachment between RB and its target, E2F, a transcriptional factor that facilitates early cell cycle gene expression [65].E2F upregulates the protein levels of cyclin A, cyclin E, and c-Myc [66].With the activation of c-Myc, CDK2 can bind to cyclin E to establish cyclin E-CDK2 complex and then fully phosphorylate RB, proceeding to the S phase [64].In the S phase, cyclin A joins CDK2 to form cyclin A-CDK2 complex, which is essential in stimulating the expression of proteins involved in DNA synthesis [67].After entering the G2 phase, cyclin B-CDK1 complex gradually increases throughout the phase from the beginning to the end, promoting cells to the M phase.However, cyclin B-CDK1 complex begins to decline slowly in the M phase, which in turn drives the completion of mitosis [68].
In order to be tightly controlled, cyclin or CDK are regulated by several cell cycle regulators, such as inhibitors of the CDK4 (INK4) family, which impede cell cycle progression at the G1 phase by competitively binding to CDK4 or CDK6.This prevents the association with D-type cyclins.The INK4 family contains p15 INK4b (Cdkn2b), p16 INK4a (Cdkn2a), p18 INK4c (Cdkn2c), and p19 INK4d (Cdkn2d).WEE1 kinase can also phosphorylate CDK1 and lead to its inactivation.Another well-known cell cycle inhibitor is the CIP/KIP protein family.Cdkn1a (p21 CIP1 ), Cdkn1b (p27 KIP1 ), and Cdkn1c (p57 KIP2 ) are included in this protein family [69].With the activation of p53, CIP/KIP could inhibit the kinase activity of CDK1, CDK2, and other cyclin-CDK complexes.The cell division cycle 25 (CDC25) protein family also participates in cell cycle regulation by dephosphorylating CDK, resulting in CDK activation.For instance, CDC25A dephosphorylates CDK2 in the cyclin A-CDK2 complex, while CDC25C removes phosphate from CDK1 in the cyclin A/B-CDK1 complex [63].In addition, there are several cellular signaling pathways indirectly affecting the cell cycle such as the PI3K/Akt, Wnt/β-catenin, JAK/STAT, Hedgehog, and MAPK signaling pathways.

CircRNA and Cell Cycle Regulators in Cancer
CircRNAs have become important mediators in the biology of cancer, deeply entwined with cell cycle regulation.Their carcinogenic potential is demonstrated in Figure 2, where specific circRNAs influence cell cycle regulators to cause abnormal cell proliferation.On the other hand, circRNAs with tumor-suppressive characteristics are shown in Figure 3, frequently through the inhibition of important cell cycle machinery components.Table 1 presents a thorough summary of the varied functions of circRNAs in different types of cancer, emphasizing their complex significance in carcinogenesis and their potential as targets.Tumor-suppressing circRNAs and their path of action through various cell cycle regulators in bladder cancer, breast cancer, gastric cancer, glioma, hepatocellular carcinoma, lung cancer, multiple myeloma, oral squamous cell carcinoma, pancreatic ductal adenocarcinoma, thyroid cancer, and urothelial carcinoma.

Bladder Cancer
Numerous cellular signaling pathways contribute to the progression of the cell cycle, and certain circRNAs utilize these pathways to manipulate the behavior of cancer cells.For instance, it has been demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathway positively regulates cyclin D1 expression and enhances the activation of the cyclin-CDK complex during the G1 phase [195].CircLRBA, a circRNA that is naturally upregulated in bladder cancer tissue and cell lines, is known to aggravate the cell cycle of bladder cancer via MAPK signaling manipulation.Mechanistically, circLRBA sponges miR-19b-3p to enhance citron Rho-interacting serine/threonine kinase (CIT) expression.CIT suppresses the activation of phosphorylated ERK1/2, which is a part of the downstream signaling pathway of MAPK.This leads to an increase in the expression of CDK1 and cyclin D1, while the activity of p53 is suppressed [73].In addition to the MAPK signaling pathway, the Wnt/β-catenin signaling pathway also plays an important role in driving the cell cycle.The evidence indicates that β-catenin induces the expression of c-Myc and cyclin D1, leading to the advancement of the G1 phase [196,197].By utilizing Wnt/β-catenin signaling, circRIMS1 can reinforce cell cycle activity by sponging miR-443-3p [74].By counteracting the inhibitory influence of miR-443-3p on its target, cell division cycle and apoptosis regulator 1 (CCAR1), which is recognized as a co-activator of β-catenin [198].An increase in CCAR1 level thus activates the downstream cascade of the pathway and ultimately upregulates c-Myc, respectively [74].
Several circRNAs were known to directly promote cell cycle-related proteins, regardless of the cellular signaling pathway.For example, hsa_circ_0058063 (circATIC) positively regulates CDK6 by endogenously competing with miR-1485-5p, which inhibits CDK6 mRNA translation.As a result, CDK6 expression is then enhanced due to the downregulation of miR-1485-5p [75].Hsa_circ_0000615 (circZNF609) also sponges miR-1200 to increase its downstream target expression, CDC25B [76].According to the prior study, CDC25B is required to stimulate the G2-M phase transition, and it also regulates checkpoint proteins in response to DNA damage [199].Another example is that circMYLK can upregulate cyclin D3 expression by specifically targeting miR-34a.Once sequestrated by circMYLK, the downstream target of miR-34a, CCND3, can be more readily translated into cyclin D3 [77].Recent research revealed that circGLIS3 can also support cell cycle progression by sponging miR-1273f, which targets S-phase kinase-associated protein (SKP1).The inhibition of miR-1273f leads to the activation of SKP1, which in turn stimulates the production of cyclin D1 and facilitates the transition from the G0/G1 phase to the S phase in the cell cycle [79].
Despite the majority of circRNAs that promote cell cycle progression, a few studies have also shown that some circRNAs have anti-cell cycle properties.Naturally downregulated in bladder cancer cell lines and tissue, circBCRC-3 was found to inhibit cell cycle progression by sponging miR-182-5p, thus upregulating its target expression, p27.The rise in p27 levels hinders the shift from G0/G1 to S phase [80].Another essential signaling pathway involving the cell cycle is PI3K/Akt signaling.Multiple studies have indicated that PI3K/Akt signaling promotes cell cycle activity.To illustrate, Akt promotes the G1 progression by phosphorylating p21, which normally forms complexes with proliferating cell nuclear antigen (PCNA), cyclin, and CDK [200].Phosphorylation of p21 in T145 residue leads to the dissociation of PCNA from the quaternary complex and a reduction in the binding affinity of p21 [200,201].Free PCNA binds to DNA polymerase δ holoenzyme to promote DNA synthesis, while p21 decreases its inhibitory function on CDK2 [202].CircITCH utilizes this signaling network to suppress bladder cancer proliferation by regulating multiple miRNAs, including miR-17 and miR-224.Notably, miR-17 specifically targets p21, while miR-224 specifically targets PTEN mRNA.The overexpression of circITCH thus results in the upregulation of p21 and PTEN, which is considered a key inhibitor of PI3K/Akt signaling [81,203].Hsa_circ_0006117 (circPTPRA) impairs the G0/G1-S phase transition by interacting with insulin-like growth factor 2 binding protein 1 (IGF2BP1), an N 6 -methyladenosine (m 6 A) reader [82].It is shown that IGF2BP1 can identify m 6 A-modified mRNAs and influence the stability and translation of the mRNA it targets [204].Therefore, the interaction with circPTPRA blocks IGF2BP1 from recognizing m 6 A-modified mRNAs, including c-Myc mRNA, eventually suppressing the cell cycle [82].Employing an uncommon molecular mechanism, circNR3C1 targets miR-27a-3p, which further binds to the 5 ′ -UTR of CCND1 to promote cyclin D1 expression.Therefore, the reduction in miR-27a-3p sequestered by circNR3C1 has a detrimental impact on CCND1 translation, decreasing the cyclin D1 level and impeding the cell cycle [83].

Breast Cancer
Hsa_circ_0091074 (circTCONS_00016926) absorbs miR-1297, which is a repressor of transcriptional coactivator with PDZ-binding motif (TAZ).Given that TAZ is a downstream effector of the Hippo signaling pathway.Without the inhibition from miR-1297, TAZ is relieved from repression and induces the protein levels of cyclin D1, CDK4, and CDK6.However, circTCONS_00016926 is usually downregulated in breast cancer tissue and cell lines and does not exhibit cell cycle supportive activity in normal condition [84].Naturally upregulated by the induction of estrogen, circPGR aggravates breast cancer progression by suppressing its target, miR-301a-5p, which partially binds to CDK1, CDK6, and checkpoint kinase 2 (CHEK2) mRNA.Thus, the decrease in miR-301a-5p level mediated by circPGR can lead to the upregulation of the translated products of the abovementioned mRNAs [85].Interestingly, circHMCU was found to hold potential for binding miR-let7 family, which comprises of let-7a-5p, let-7c-5p, and let7-7f-5p.Therefore, their downstream target mRNAs: c-Myc; HMGA2; and cyclin D1, are then prevented from degradation.Furthermore, the expression of other cell cycle regulators, including cyclin B1, cyclin D3, CDK4, and CDK6, is also increased, despite that they are not the direct targets of these miRNAs [86].Cir-cUBE2D2 also contributes to cell cycle progression via sponging miR-512-3p to upregulate the expression of cell division cycle-associated 3 (CDCA3) [87].Similarly, hsa_circ_0136666 (circPRKDC) stimulates the cell cycle by increasing the expression of CDK6.Without the suppression of miR-1299 that is sponged by circPRKDC, CDK6 abundance can flourish [88].Using the same mechanism, hsa_circ_0004676 (circDHTKD1) sequesters miR-377-3p, which targets E2F6 mRNA, thus allowing E2F6 to be translated and further binds to partner of NOB1 homolog (PNO1) promotor to stimulate its expression.PNO1 then induces p53 ubiquitination, impairing its inhibitory effects on the cell cycle [90].CircUBR1 is overexpressed in breast cancer, and it sponges miR-1299 that targets CCND1 mRNA.MiR-1299 is subsequently downregulated, while cyclin D1 is upregulated in the presence of circUBR1 [91].Lastly, hsa_circ_0008039 (circPRKAR1B) supports E2F3 expression via suppressing its inhibitor, miR-432-5p [92].
There are the other circRNAs that mediate the cell cycle through downstream indirect effectors.To illustrate, the high abundance of hsa_circ_0000515 (circRPPH1) decreases the expression of p27, while increases the expression of cyclin D1, and CDK4.Mechanistically, circRPPH1 sponges miR-296-5p, abating the repressive effect on C-X-C motif chemokine ligand 10 (CXCL10) which positively affects the abovementioned cell cycle regulators [93].CircPLK1 competes with miR-4500 and allows insulin-like growth factor (IGF1) mRNA, a target of miR-4500, to be translated.IGF1 later stimulates the upregulation of CDK4 and CDK6, supporting cell cycle activity [98].
Hsa_circ_0001785 (circELP3) decreases PCNA expression and intervenes in cell cycle progression by targeting miR-942.Subsequently, SOCS3 is overexpressed, inhibiting the JAK/STAT signaling pathway [99,205].Surprisingly, circFBXW7 utilizes both miRNA sponging and protein translation mechanisms to inhibit breast cancer.It was shown that the protein encoded from circFBXW7 called FBXW7-185aa can bind to USP28 and suppresses c-Myc activity.Moreover, circFBXW7 itself also sponges miR-197-3p to upregulate the expression of its parental gene, F-box/WD repeat-containing protein 7 (FBXW7), which in turn synergizes the inhibitory effect in repressing c-Myc [100].Another cell cyclesuppressive circRNA, circSETD2, lowers the expression of miR-155-5p by absorbing.This interaction relieves miR-155-5p target, signal peptide CUB domain and EGF like domain containing 2 (SCUBE2), from suppression.SCUBE2 then exerts its inhibitory function on CDK4 and cyclin D1, forestalling the G0/G1 to S phase transition [101].

Colon Cancer
Hsa_circ_0008231 (circNBPF11) enhances colon cancer proliferation via PI3K/Akt signaling by endogenously competing with miR-338-3p.Without miR-338-3p-mediated repression, ETS proto-oncogene 1 (ETS1) expression is then increased and triggers phosphorylation of the upstream players of PI3K/Akt signaling, such as PI3K and Akt.Therefore, the upregulation of cyclin D1 is then followed [114].Another study reported that circCTIC1 employs a different approach to modulate tumor-initiating cells in colon cancer.CircCTIC1 interacts with bromodomain PHD finger transcription factor (BPTF), one of the crucial partners of nuclear remodeling factor (NURF) complex, to mediate the localization into the nucleus.NURF complex binds to c-Myc promotor and thus increases c-Myc expression, promoting self-renewal capacity [115].In the other way, circCSPP1 positively regulates Rho-associated coiled-coil containing protein kinase 1 (ROCK1) abundance through miR-431 inhibition.ROCK1 further promotes cyclin D1 and CDK4 expression, which, in turn, phosphorylate Rb to allow the G0/G1-S phase transition [116].
On the other hand, circRNAs that act against cell cycle are, indeed, found to be downregulated in gastric cancer tissue and cell lines.To begin with, hsa_circ_0006470 (circMFN2) promotes p53 inducible protein 11 (TP53I11) by sponging miR-1234.The upregulation of TP53I11 prevents Akt phosphorylation and leads to the inhibition of the PI3K/Akt signaling pathway.Furthermore, TP53I11 also stimulates FOXO1 synthesis to suppress the activity of CDK2 [133].As with circEVI5, it sequesters miR-4793-3p to relieve FOXO1 expression, followed by the encoding of p21 and p27 [134].

Glioma
Hsa_circ_0001495 (circCCNB1) can be induced by a transcription factor, eukaryotic translation initiation factor 4A3 (EIF4A3).CircCCNB1 employs multiple mechanisms for modulating glioma aggressiveness.It recruits HuR, an RNA-binding protein that functions as a stabilizer of CCND1 mRNA.Moreover, circCCNB1 simultaneously sponges miR-516b-5p to prevent miRNA-mediated degradation of CCND1, resulting in an increased cyclin D1 protein level [135].Utilizing only miRNA sponge capability, hsa_circ_0001982 (circRNF111) sequesters miR-1205, which is an inhibitor of E2F1 mRNA.Due to the lack of miR-1205 presence, E2F1 is freed from repression and participates in the S phase transition [132].Nonetheless, hsa_circ_0012129 (circB4GALT2) and hsa_circ_0030018 (circPOSTN) can also promote the progression of glioma without the direct control of cell cycle-related proteins.CircB4GALT2 upregulates TGIF2 expression through sponging miR-761.Subsequently, TGIF2 boosts the abundance of CDK2 and CDK4 to proceed to the S phase [136].In a similar manner, circPOSTN absorbs miR-1297 to increase RAB21 level, which then facilitates the elevation of cyclin D1 and PCNA [137].
DNA damage in gliomas can induce circCDR1as, which serves as a protein sponge to attract p53.The interaction prevents p53 from establishing a complex with MDM2, its negative regulator [138].MDM2 blocks transcriptional activation and subjects p53 for degradation mediated by ubiquitination [207].Consequently, p53 and its downstream effector p21 are then increased, forestalling the cell cycle of glioma cells [138].

Hepatocellular Carcinoma
The majority of circRNA involving cell cycle activity in hepatocellular carcinoma is upregulated in both tumor tissue and cell lines.In addition, most of them are classified as cell cycle supporters.To begin with, hsa_circ_0036412 (circETFA) manipulates the Hedgehog signaling network through binding to ELAV like RNA-binding protein 1 (ELAVL1), an RNA-binding protein.ELAVL1 stabilizes GLI2 mRNA and increases protein levels [139].GLI2 is an essential regulator in the Hedgehog signaling pathway.A previous study showed that downregulation of GLI2 negatively affects hepatocellular carcinoma proliferation due to the increase in p21 and p27 expression [208].High GLI2 abundance mediated by circETFA then stimulates cyclin D1.In addition, circETFA utilizes miRNA sponge capability to synergistically enhance GLI2 production by sponging its suppressor, miR-579-3p [139].
Hsa_circ_0091581 (circGPC3) efficiently promotes hepatocellular carcinoma proliferation by establishing a positive feedback loop.To illustrate, miR-526b, which is a repressor of c-Myc mRNA, is sponged by circGPC3, thus upregulating c-Myc translation.The increase in c-Myc further stimulates circGPC3 production and cell cycle progression [140].Hsa_circ_0000519 (circRPPH1) facilitates the G0/G1 to S phase transition through sponging miR-1296.Identified as one of the targets of miR-1296, E2F7 becomes upregulated when overexpressed with cirRPPH1.Interestingly, cyclin D1 and cyclin E1 were also found to be elevated, even though they are not direct targets to miR-1296 [96].Another example, circROBO1 absorbs miR-130a-5p, which inhibits CCNT2 mRNA translation.This results in the reduction of miR-130a-5p, followed by the elevation of cyclin T2 level and allows the cell cycle to proceed to the M phase [142].CircMMP9 acts via the miR-149/CCND2 axis to support cell cycle.Upon the downregulation of miR-149 by circMMP9, cyclin D2 expression is then increased [143].Hsa_circ_101555 elevates CDCA3 expression by sponging its inhibitor, miR-145-5p.In the absence of miR-145-5p, CDCA3 abundance is thus more evident [144].CircZNF83 also participates in cell proliferation via modulating indirect downstream targets.MiR-324-5p, a suppressor of CDK16 and a target of circZNF83, is then downregulated, allowing the expression of CDK16 to thrive.Moreover, circZNF83 relies on the JAK/STAT pathway to simultaneously aggravate cancer behavior, as the phosphorylated JAK2 and STAT3 were found to be increased.Nonetheless, the expression of the other cell cycle regulators has not been examined [145].Lastly, circSLC7A11 endogenously silences miR-330-3p, which targets CDK1 mRNA, resulting in the downregulation of miR-330-3p and the upregulation of cyclin D1 expression, respectively.In addition, an increase in cyclin B1 level can be observed in circSLC7A11-enriched condition [146].
As previously mentioned, circGPC3 greatly supports cell cycle activity.A recent study showed that the other circular transcript of circGPC3, hsa_circ_0091579, can also contribute to cell cycle progression.Mechanistically, hsa_circ_0091579 sponges miR-1287 to inhibit miR-1287-mediated mRNA degradation on pyruvate dehydrogenase kinase 2 (PDK2) mRNA.An elevated PDK2 level positively influences cyclin D1 expression [141].Similarly, hsa_circ_0005397 (circRHOT1), which is originally overexpressed in hepatocellular carcinoma, also sequesters miR-326 to upregulate PDK2.Indeed, an increase in cyclin D1 abundance can be detected, along with a decrease in p21 expression [147].Hsa_circ_0000517, the other circular transcript of circRPPH1, promotes the transition of the cell cycle to the S phase by sponging miR-326.After circRNA-mediated sequestration, miR-326 level is then declined, which leads to the upregulation of its target, SMAD6.Cyclin D1 expression is subsequently upregulated under the influence of SMAD6 [97].
CircVAMP3 participates in anti-cell cycle activity as it features protein binding capability and acts against cell proliferation.Mechanistically, circVAMP3 directly binds to cell cycle-associated protein 1 (CAPRIN1) to block the interaction with G3BP stress granule assembly factor 1 (G3BP1).Without the complex resulting from the association between CAPRIN1 and G3PB1, the activation of c-Myc is restrained [148].Another example, circLARP4, absorbs miR-761 to restore RUNX3.Thus, RUNX3 expression is elevated during miR-761 depletion and then positively influences p53 and p21 expression, inhibiting the cell cycle [149].As well as hsa_circ_ 0000204 (circWDR37), which acts as cell cycle-suppressive circRNA.Through sponging miR-191, circWDR37 can upregulate KLF6 expression, which further inhibits cyclin D1, cyclin D2, and c-Myc [150].

Leukemia
As previously described, some circRNAs can be synthesized from fused genes in cancer, such as F-circBA1, which resulted from the fusion of BCR and ABL gene.A study indicated the cell cycle supportive role of F-circBA1 as it aggravates the transition of the G2 to M phase in chronic myeloid leukemia.F-circBA1 binds to miR-148b-3p which suppresses CDC25B mRNA translation, thus upregulating CDC25B abundance [28].Hsa_circ_0005774 (circCDK1) sponges miR-192-5p to increase the expression of uncoordinated 51-like kinase 1 (ULK1).The report showed that ULK1 is a positive regulator of cyclin D1 and PCNA because these proteins are increased in the presence of ULK1 [151].As well as hsa_circ_0094100 (circSFMBT2), it increases the upregulation of cyclin D1 and PCNA through the miR-217/ATP1B1 axis.The decline of miR-217 mediated by circSFMBT2 results in the elevation of ATPase Na + /K + -transporting subunit beta 1 (ATP1B1), which further stimulates cyclin D1 and PCNA [152].In addition, circNFIX was found to upregulate the expression of cyclin D1.By sponging miR-876-3p, circNFIX can increase the level of tripartite motif containing 31 (TRIM31), which then activates the synthesis of cyclin D1 [153].

Lung Cancer
EGFR stimulation can lead to the synthesis of hsa_circ_0000190 (circCNIH4), an upregulated circRNA in non-small-cell lung cancer (NSCLC).CircCNIH4 inhibits miR-142-5p to further restore CDK6 expression.In addition, circCNIH4 also takes advantage of the MAPK signaling pathway by increasing the phosphorylation of MEK1/2 and ERK1/2.Therefore, the downstream targets of the pathway, such as CDK1, CDK4, and phosphorylated Rb, are upregulated [154].Another circRNA that modulates cell signaling to facilitate cell cycle progression is hsa_circ_0014235 (circS100A2).MiR-146b-5p naturally interferes with the translation of Yes-associated protein (YAP) mRNA, which is classified as one of the key regulators in Hippo signaling [155].Previous studies reported that YAP is involved in the activation of E2F, CDK2, CDK4, and CDK6 [209].The increase in YAP mediated by the circS100A2/miR-146b-5p axis thus facilitates the production of CDK4 [155].Moreover, circS100A2 can also utilize the miRNA sponge function to bind miR-520a-5p, which is a suppressor of CDK4 [156].Taken together, the evidence indicates that circS100A2 can effectively upregulate CDK4 expression.
Many circRNAs also modulate lung cancer through the production of indirect effectors.For example, circTP63 sponges miR-873-3p to stimulate the expression of FOXM1, thus further activating the activity and expression of cyclin B1 [165].Another example, circFOXM1, upregulates cyclin D1 and cyclin E1 levels through the miR-614/FAM83D axis.Upon suppression by circFOXM1, miR-614 is then declined, which facilitates the expression of FAM83D, a positive regulator of cyclin D1 and cyclin E1 [166].A similar path of action can also be found in hsa_circ_0046263 (circP4HB), which binds to miR-940 to prevent repressive function in NOVA alternative splicing regulator 2 (NOVA2).Next, NOVA2 triggers the abundance of cyclin D1 and PCNA [167].As well as hsa_circ_0072088 (circZFR), which facilitates the expression of NOVA2 through sponging miR-377-5p.An increase in cyclin D1 and PCNA is then followed [104].

Melanoma
Hsa_circ_0082835 (circEZH2) sponges miR-429, which inhibits its parental gene expression, EZH2.With a lower miR-429 level, EZH2 is relieved from repression and further activates Wnt5a and β-catenin, which are important components in the Wnt/β-catenin signaling network.Indeed, downstream cell cycle regulators, including cyclin D1 and cyclin E1, are then upregulated [171].Similarly, hsa_circ_0062270 (circCDC45) mediates melanoma phenotype by modulating its parental gene product, CDC45, and functions as a protein sponge as well.EIF4A3, an RNA-binding protein, is recruited to bind to circCDC45 and assist CDC45 mRNA stabilization.This results in an increase in CDC45 protein levels and promotes cell cycle [172].

Multiple Myeloma
CircPSAP promotes the cell cycle through the miR-331-3p/histone deacetylase 4 (HDAC4) axis.The suppression of miR-331-3p mediated by circPSAP leads to the upregulation of HDAC4, which further stimulates cyclin D1 expression to drive the transition to the S phase [173].
As it is downregulated in multiple myeloma, circMYBL2 exerts its anti-cancer effect by facilitating the complex formation of cyclin F and its parental gene product, MYBL2.This prevents the phosphorylation of MYBL2, a transcriptional regulator of several oncogenes, thus inactivating MYBL2 and impeding cell cycle progression [174].

Oral Squamous Cell Carcinoma
Hsa_circ_0000745 (circSPECC1) combines both protein binding and miRNA sponge function to upregulate cyclin D1.To illustrate, circSPECC1 recruits HuR to assist CCND1 mRNA stabilization.Moreover, it absorbs miR-488, which suppresses CCND1 translation.Therefore, circSPECC1 can efficiently promote cyclin D1 abundance [175].Another example is circOSBPL10, a downregulated circRNA that also acts against cell cycle by downregulating miR-299-3p.Without the repression from miR-299-3p, its target, CDK6, can be overexpressed.Due to its downregulated status in oral squamous cell carcinoma tissue and cell lines, cell cycle supportive function of circOSBPL10 is usually disabled [176].
Utilizing the same approach as circSPECC1, circYAP also features protein binding capability to ameliorate oral squamous cell carcinoma aggression.CDK4 is recruited to the binding site located within circYAP.This interaction prevents complex formation between CDK4 and cyclin D1 and impairs nucleus translocation.Thus, cyclin D1 expression in the nucleus is diminished, including other regulators such as PCNA, c-Myc, and Rb [177].

Ovarian Cancer
Using a similar mode of action to circCNNB1 in glioma, circE2F2 serves as a protein sponge to recruit HuR to the binding site.HuR subsequently promotes E2F2 mRNA stabilization and therefore increases E2F2 protein level [182].The other circRNA that supports the cell cycle in ovarian cancer is hsa_circ_0000714 (circAARS).The study reported that circAARS was found to be upregulated in paclitaxel-resistant ovarian tissue and cell lines.Through absorbing miR-370-3p, circAARS can mediate RAB17 expression, which further stimulates CDK6 and Rb, aggravating cancer behavior [183].

Pancreatic Ductal Adenocarcinoma
CircNEIL3 exerts its cell cycle supportive role by sponging miR-432-5p which, in turn, targets adenosine deaminase acting on RNA 1 (ADAR1).ADAR1 induces adenosine-toinosine (A-to-I) editing of GLI family zinc finger 1 (GLI1) and performs a positive feedback loop to stimulate the production of circNEIL3 [184].As with GLI2, which was previously mentioned, GLI1 is also considered a downstream important key in the Hedgehog pathway [211].The evidence reported that GLI1 depletion led to the downregulation of many cell cycle regulators [212].Therefore, the upregulation of ADAR1-induced GLI1 results in a surge of cyclin D1, cyclin E1, CDK2, CDK4, and CDK6 [184].
CircPVRL3 represses several cell cycle regulators by relying on the transactivation between the JAK/STAT and PI3K/Akt pathways [185].To illustrate, the expression of Akt can be abolished by silencing STAT3 or JAK2 [213].Another study showed that trans-signaling of the JAK/STAT pathway mediated by IL-6 also activates both the PI3K/AKT and MAPK networks, indicating the importance of JAK/STAT signaling to the PI3K/Akt pathway [214].CircPVRL3 absorbs miR-194-5p, which is a repressor of suppressor of cytokine signaling 2 (SOCS2), an inhibitor of JAK/STAT.The high expression of SOCS2 is then mediated to inactivate the pathway, negatively affecting PI3K/Akt signaling in the process.Thus, many regulators driving the cell cycle, such as cyclin D1, cyclin E1, CDK2, and CDK4, are declined, whereas p21 is increased instead [185].

Prostate Cancer
Few studies were conducted to examine the role of circRNA and cell cycle-related proteins.For instance, hsa_circ_0057558 (circSLC39A10) was demonstrated to boost c-Myc, cyclin B1, and cyclin D1 expression via inhibiting miR-206 activity.Ubiquitin specific peptidase (USP33) is identified as a target of miR-206, and its function is to deubiquitinate c-Myc, thus allowing c-Myc to escape degradation and to upregulate the abovementioned proteins [186].However, circHMGCS1 employs different mechanisms for enhancing cell cycle.By sponging miR-205-5p, its downstream target, Erb-B2 receptor tyrosine kinase 3 (ErBB3), is then upregulated.ErBB3 promotes phosphorylation of Akt and PI3K to activate the PI3K/Akt signaling pathway, resulting in an increase in cyclin D1 and CDK4 [187].Directly bound to CCND1 mRNA, miR-195 can impede its translation into cyclin D1.However, miR-195 is usually repressed by circDPP4 in prostate cancer cell lines, thus facilitating cyclin D1 expression [188].Lastly, circDPP4 functions as a sponge to attract miR-195, a repressor of CCND1.The reduction in miR-195 level is then mediated, followed by the elevation of cyclin D1, respectively [188].

Thyroid Cancer
Functioning as a protein recruiter, circEIF3I attracts AU-rich element RNA-binding factor 1 (AUF1) to the binding site.AUF1 is then occupied and cannot be used to trigger CCND1 mRNA degradation.Subsequently, cyclin D1 is significantly increased [189].CircPRKCI and hsa_circ_0000644 (circKIAA1199) were identified to share the same target E2F3, yet they mediate through different miRNAs.CircPRKCI binds to miR-335 while circKIAA1199 sponges miR-1205 [190,191].
CircHACE1 exhibits an anti-cell cycle in thyroid cancer cells through the miR-346/ TFC2L1 axis.The overexpression of circHACE1 leads to a reduction in miR-346 levels and an increase in TFC2L1, respectively.TFC2L1 then downregulated cyclin B1 and PCNA expression, therefore impeding the cell cycle [192].

Other Cancers
In laryngeal carcinoma, a naturally overexpressed circMYLK aggravates cancer cell proliferation by sponging miR-195.Consequently, CCND1 mRNA, a target of miR-195, is free from its repressor and can be translated into cyclin D1 [78].As found upregulated in nasopharyngeal carcinoma, circCAMSAP1 manages to reinforce the cancer phenotype through bizarre function.Rather than recruiting to miRNA or protein, circCAMSAP1 directly binds and manipulates serpin family H member 1 (SERPINH1) mRNA, enhancing stabilization.High expression of SERPINH1 prevents the ubiquitination and degradation of c-Myc.Moreover, the positive feedback loop can also be stimulated by the complex formation of c-Myc and splicing factor 10 (SRSF10), resulting in the upregulation of circ-CAMSAP1 [193].CircFAM114A2 acts against cell cycle activity in urothelial carcinoma by sponging miR-222-3p and miR-146a-5p.Both miRNAs target negative cell cycle regulators.MiR-222-3p suppresses p27 translation, whereas miR-146a-5p targets p21.Thus, the overexpression of circFAM114A2 leads to the expression of p27 and p21 [194].

Conclusions and Future Perspectives
Cancer is a global health issue and is considered life threatening.An aberrant expression of cell cycle regulators combined with a modulation of cellular signaling is one of the key driving factors that aggravates cancer behavior.Emerging research indicated that circRNAs might play an important role in regulating cancer aggressiveness since they are most likely to be dysregulated in cancer tissues and cell lines.CircRNAs can serve as either cell cycle supporters or cell cycle inhibitors, depending on the expression status, miRNA targets, mRNA targets, or protein targets.Most circRNAs have been reported to serve as miRNA sponges.The mounting evidence suggests that they might also hold other molecular mechanisms such as protein sponge, protein translation, mRNA sponge, and guiding A-to-I editing [215].However, many studies have only identified a brief correlation between circRNAs and cell cycle activity, without examining whether circRNAs indeed cause the altered expression of cell cycle regulators.
Due to the advancement of bioinformatics tools and high-throughput RNA sequencing that have been rapidly developing, the identification of novel modes of circRNA-mediated gene regulation has thus gained more attention.A recent study demonstrated that circRNA-miRNA interactions can be predicted using a combination of deep learning and algorithms called KGDCMI.RNA characteristics in the form of digitalized data can be retrieved from algorithms before constructing a possible interaction network.Lastly, the calculation of the final predicted score will be made.The prediction accuracy was considerably high compared to that of the existing model, indicating the effectiveness of KGDCMI [216].Other than predicting circRNA-miRNA interactions, many bioinformatics tools have also been recently developed for the prediction of circRNA-protein interactions in recent years.Recently, circRNA regulator identification tool (CRIT) has utilized multiple datasets such as gene alteration, clinical significance, gene ontology (GO) similarity, and transcriptome data collected from twelve cancer types.All the data are subjected to being characterized and clustered using non-negative matrix factorization (NMF), resulting in 73 predicted candidates and 17 known candidates [217].Therefore, CRIT might be another efficient tool for predicting circRNA-protein interactions, as it revealed both novel and known regulators.These recent bioinformatics tools are undoubtedly useful for the future discovery of circRNA modulating cell cycle regulation in cancers.
In addition to the growing trend in establishing prediction tools, many molecular techniques have also been developed, especially for the study of circRNA-protein interaction.Employing RNA immunoprecipitation (RIP) might be effective in revealing RBPs, but it would require a suitable antibody.Thus, electrophoretic mobility shift assays (EMSAs) are more appropriate for determining the interaction between circRNAs and candidate proteins.Basically, both circRNA and RBPs are incubated in the mixture before being subjected to electrophoresis.Free circRNA tends to migrate faster than circRNA-bearing RBPs [15].Nonetheless, disadvantages persist because binding circRNAs to RBPs necessitates a stable condition during gel run, and large circRNAs may not be suitable for this approach [218].In addition, these interactions may not be physiologically present in the cells.Although these methods have their limitations, they may help us learn more about how circRNAs and their RBPs play a role in cell cycle dysregulation.Moreover, it could reveal the possibility of discovering biomarkers and therapeutic targets.
Given that circRNAs are abnormally expressed in each organ or cancer tissue, measuring their quantity would be a promising diagnosis.Reports suggest that the aggressiveness of the tumor influences the expression of some circRNAs.However, there are still some limitations, as it is common to find circRNAs in chunks and in extremely low abundance, which can complicate the process of identifying the specific one.Moreover, investigating the significance of circRNAs from biological samples, especially blood and plasma, is also considered a long procedure and may lead to incomplete identification [219,220].Therefore, huge developments and research are required before utilizing circRNAs as a biomarker for disease diagnosis in clinical practice.

Figure 1 .
Figure1.CircRNA biogenesis and its functions.CircRNA is a product of backsplicing, which begins with the joining of the downstream splice-donor site and the upstream splice-acceptor site, forming a circular loop-like structure.Alu or RNA-binding proteins (RBPs) can stimulate this interaction.The current circular loop-like structure, EIcircRNA, can also be generated via an exon-skipping event, and it might proceed through an internal splicing event to eliminate the intron, resulting in an ecircRNA.Moreover, canonical splicing can generate the other type of circRNA, ciRNA, which is entirely composed of introns.CircRNAs might be imported to the cytoplasm, where they primarily function.Mostly, circRNAs possess the ability to bind to miRNAs to regulate gene expression.CircRNA was recently found to be a template for protein translation or to establish an interaction with proteins.It can act like a protein sponge, which might later facilitate or inhibit the interaction between two different proteins.Utilizing protein sponge activity, some proteins avoid ubiquitinmediated degradation by binding to circRNAs.Remarkably, some circRNAs have also been discovered to regulate their parental genes through various mechanisms, such as directly binding to the promotor or recruiting proteins to mediate gene expression.

Figure 1 .
Figure1.CircRNA biogenesis and its functions.CircRNA is a product of backsplicing, which begins with the joining of the downstream splice-donor site and the upstream splice-acceptor site, forming a circular loop-like structure.Alu or RNA-binding proteins (RBPs) can stimulate this interaction.The current circular loop-like structure, EIcircRNA, can also be generated via an exon-skipping event, and it might proceed through an internal splicing event to eliminate the intron, resulting in an ecircRNA.Moreover, canonical splicing can generate the other type of circRNA, ciRNA, which is entirely composed of introns.CircRNAs might be imported to the cytoplasm, where they primarily function.Mostly, circRNAs possess the ability to bind to miRNAs to regulate gene expression.CircRNA was recently found to be a template for protein translation or to establish an interaction with proteins.It can act like a protein sponge, which might later facilitate or inhibit the interaction between two different proteins.Utilizing protein sponge activity, some proteins avoid ubiquitin-mediated degradation by binding to circRNAs.Remarkably, some circRNAs have also been discovered to regulate their parental genes through various mechanisms, such as directly binding to the promotor or recruiting proteins to mediate gene expression.

Figure 2 .
Figure 2. Oncogenic circRNAs and their path of action through various cell cycle regulators in bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer,

Figure 2 .
Figure2.Oncogenic circRNAs and their path of action through various cell cycle regulators in bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, hepatocellular carcinoma, laryngeal cancer, leukemia, lung cancer, melanoma, multiple myeloma, nasopharyngeal carcinoma, oral squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic ductal adenocarcinoma, and prostate cancer.

Figure 3 .
Figure 3.Tumor-suppressing circRNAs and their path of action through various cell cycle regulators in bladder cancer, breast cancer, gastric cancer, glioma, hepatocellular carcinoma, lung cancer, multiple myeloma, oral squamous cell carcinoma, pancreatic ductal adenocarcinoma, thyroid cancer, and urothelial carcinoma.

Figure 3 .
Figure 3. Tumor-suppressing circRNAs and their path of action through various cell cycle regulators in bladder cancer, breast cancer, gastric cancer, glioma, hepatocellular carcinoma, lung cancer, multiple myeloma, oral squamous cell carcinoma, pancreatic ductal adenocarcinoma, thyroid cancer, and urothelial carcinoma.

Table 1 .
CircRNAs and their functions in modulating cell cycle regulators throughout different cancers.