Deregulated circRNAs in Epithelial Ovarian Cancer With Activity in Preclinical In Vivo Models: Identification of Targets and New Modalities for Therapeutic Intervention

ULRICH H WEIDLE; FABIAN BIRZELE

doi:10.21873/cgp.20442

. 2024 May 3;21(3):213–237. doi: 10.21873/cgp.20442

Deregulated circRNAs in Epithelial Ovarian Cancer With Activity in Preclinical In Vivo Models: Identification of Targets and New Modalities for Therapeutic Intervention

ULRICH H WEIDLE ¹, FABIAN BIRZELE ²

PMCID: PMC11059596 PMID: 38670587

Abstract

Epithelial ovarian cancer (EOC) is associated with a dismal prognosis due to development of resistance to chemotherapy and metastasis in the peritoneal cavity and distant organs. In order to identify new targets and treatment modalities we searched the literature for up- and and down-regulated circRNAs with efficacy in preclinical EOC-related in vivo systems. Our search yielded circRNAs falling into the following categories: cisplatin and paclitaxel resistance, transmembrane receptors, secreted factors, transcription factors, RNA splicing and processing factors, RAS pathway-related components, proteolysis and cell-cycle regulation, signaling-related proteins, and circRNAs regulating proteins in additional categories. These findings can be potentially translated by validation and manipulation of the corresponding targets, inhibition of circRNAs with antisense oligonucleotides (ASO), small interfering RNAs (siRNA) or small hairpin RNA (shRNA) or by reconstituting their activity.

Keywords: Inhibition and reconstitution of circ RNA, small hairpin RNA (shRNA), small interfering RNA (siRNA), target validation, xenograft models, review

The incidence of ovarian cancer (OC) in the USA is 22,000 cases per year and 14,000 deaths, and 29,000 deaths in Europe (1). The vast majority are epithelial ovarian cancers (EOC). This type of tumor is typically treated with a combination of surgery and chemotherapy, which often includes cisplatin (DDP) and paclitaxel (PTX). An exciting development was the treatment of homologous recombination-deficient ovarian tumors with breast cancer antigen (BRCA) mutations or deletions with poly-ADP-ribose polymerase (PARP) inhibitors (2). Three PARP inhibitors (olaparib, rucaparib and niraparib) have been approved for the treatment of OCs in different clinical settings. In addition, anti-angiogenic therapy with Bevacizumab was approved (3). Nevertheless, recurrence due to resistance mechanisms is commonly observed and significantly impairs the therapeutic benefit of treatment (4). Epithelial ovarian cancer (EOC) gains a growth advantage due to interactions with fat cells, mesothelial cells, and cancer-associated fibroblasts. These interactions enhance the activation of pathways that support its growth (5-7). Also, its dissemination in ascites fluid and formation of nodules in the peritoneum are a unique mechanism of metastasis hampering therapeutic intervention (8,9). Immunotherapy with checkpoint inhibitors such as Pembrolizumab has shown limited success (10). Diverse mechanisms of immune escape in a tumor-location specific manner have been observed (11). Taken together, there is a tremendous medical need for identification of new targets and modalities for treatment of OC. Therefore, we searched the literature for circular RNAs (circRNAs) that are up- or down-regulated in EOC and upon their modulation exhibit efficacy in preclinical in vivo models of EOC.

Circular RNA in Cancer

circRNA can be generated during mRNA processing by intra-molecular mRNA pairing followed by circularization, RNA-binding protein-mediated and lariat-driven circularization (12). Physiologically, circRNAs are involved in a plethora of cellular functions (13). In cancer, circRNAs can exert oncogenic as well as tumor-suppressive functions modulating proliferation, angiogenesis, migration, and metastasis (14-17). In addition, circRNAs can act as scaffolds or sponges for proteins, regulate transcription, interact with RNAs, modulate translation and, in some cases, they can encode proteins (18). Another important issue is their impact on regulation of inter-cell interactions and orchestration of the tumor micro-environment through their exosome-mediated transmission (19). Recently, circRNAs have been engineered for protein production (20). The function of circRNAs in EOC as biomarkers, prognostic markers and as targets for therapy have been summarized in several recent reviews (21-23). Here, we focus on circRNAs which exhibit in vivo activity in EOC-related preclinical models. The identified targets can be either inhibited or reconstituted with small molecules or antibody-derived entities and the corresponding circRNAs can be reconstituted or inhibited with ASO, siRNA or shRNA or by intervention with clustered regularly interspaced short palindromic repeats/CRISPR associated enzymes (CRISPR-CAS) (24,25).

CircRNAs Deregulated in EOC

Circular RNAs and cisplatin (DDP) resistance.

Circ sorting nexin 12 (Snx12) up-regulates solute carrier family 7 member 11 (SCL7A11). circSnx12 (Figure 1) was up-regulated in EOC tissues and cells resistant to DDP (26). circSnx12 confers DDP-resistance in SKOV3 and A2780 EOC cells by inducing ferroptosis resistance (26). miR-194-5p was sponged by circSnx12 resulting in up-regulation of SCL7A11. The SLC superfamily includes 458 proteins, which transport a variety of substances across cell membranes (27). Knockdown of circSnx12 rendered DDP-resistant cells sensitive to DDP in vitro (SKOV3 and A2780) and in vivo (SKOV3) after subcutaneous (s.c.) implantation into nude mice (26). Transmembrane protein SLC7A11 is a key component of the glutamate antiporter system which is involved in glutathione (GSH) synthesis and resistance to ferroptosis (28). Inhibition of ferroptosis is a common phenomenon in EOC. Ferroptosis is associated with lipid peroxidation, iron accumulation and GSH deprivation (29). DDP resistance is a major challenge in the treatment of EOC (30,31).

Circ integrin β6 (ITGB6) stabilizes fibroblast growth factor 9 (FGF9). Elevated levels of circITGB6 (Figure 1) correlated with DDP chemoresistance and poor prognosis in EOC patients (32). circITGB6 induced chemoresistance of ID8 OC cells in nude mice after intraperitoneal injection in a tumor micro-environment (TME)-dependent manner (32). circITGB6 induced macrophage polarization towards the M2 phenotype (32). circITGB6 interacted with insulin-growth factor binding protein 2 (IGFBP2) directly, forming a ternary complex with FGF9. M2 macrophages have been shown to play a role in the progression and chemoresistance of EOC (33). Macrophage-based evaluation of therapy options for EOC are under investigation (34). It has been shown that FGF9 promotes DDP resistance in colorectal cancer patients by activation of wingless-related integration site (WNT)/β catenin signaling (35). In lung cancer, interaction between FGF9 and fibroblast growth factor receptor 1 (FGFR1) promotes proliferation, epithelial-mesenchymal transition (EMT), M2 polarization and liver metastasis (36).

Circ0063804 up-regulates clusterin (CLU). High expression of circ006384 (Figure 1) indicated poor prognosis in EOC patients (37). In OVCAR3 cells, silencing of circ006384 inhibited proliferation and DDP-resistance and induced apoptosis (37). circ006384 sponged miR-1276 and up-regulated CLU. circ006384 silencing inhibited growth of OVCAR3 xenografts after s.c. implantation into nude mice (37). CLU is a chaperone involved in the protein folding pathway with oncogenic and cytoprotective effects similar to heat-shock proteins (38-40). Custirsen (OGX-011), a second-generation antisense inhibitor of CLU has been evaluated in prostate cancer, hepatocellular carcinoma and lung cancer patients, but did not reach the expected clinical endpoints (41,42).

Circ0067934 up-regulates inorganic pyrophosphatase PPA1. circ0067934 (Figure 1) was found to be over-expressed in EOC samples and was associated with advanced tumor stages and lymph node metastasis (43). Down-regulation of circ0067934 reduced DDP resistance of cell line A2780/DDP in vitro and in xenografts in nude mice (43). circ0067934 sponged miR-545-3p and up-regulated PPA1. Up-regulation of PPA1 also enhanced proliferation, invasion and reduced pro-apoptotic JUN-kinase (JNK) signaling in A2780 cells (43). It was shown that the role of PPA1 in energy metabolism is to promote progression of malignant tumors (44). PPA1-mediated dephosphorylation was found to positively regulate the activity of yes-associated protein 2 (YAP2), promoting survival and DDP-resistance of EOC cells (45). YAP2, which is an effector of the HIPPO pathway, functions as an EOC oncogene (46). Dephosphorylated YAP was shown to be involved in the pathogenesis of EOC (47).

Circ lysophosphatic acid receptor 3 (circLARP3) up-regulates pyruvate dehydrogenase kinase1 (PDK1). circLARP3 (Figure 1) was up-regulated in DDP-resistant EOC tissues and cell lines (48). Knockdown of circLARP3 enhanced DDP-sensitivity of SKOV3/DDP and A2780/DDP cells in vitro and of SKOV3/DDP xenografts after s.c. injection into nude mice (48). circLARP3 sponged miR-634 and up-regulated PDK1. The latter was shown to be involved in promotion of proliferation, migration, glycolysis, and inhibition of apoptosis of EOC cell lines. It was demonstrated that PDK1 plays an oncogenic and prognostic role in progression and metastasis of EOC (49). Perturbation of PDK1 modulates growth, angiogenesis, and metabolic pathways in EOC xenografts (50). It was also found that PDK1 can contribute to DDP-resistance in EOC through activation of the epidermal growth factor receptor (EGFR) pathway (51).

Circ homeodomain-interacting protein kinase 2 (circHIPK2) up-regulates chromatin target of PRMT1 (CHTOP). circHIPK2 (Figure 1) was up-regulated in EOC patients and associated with DDP-resistance (52). In SKOV3/DDP and A2789/DDP EOC cells, knockdown of circHIPK2 inhibited proliferation, migration, invasion, cell-cycle progression, increased apoptosis, reversed DDP resistance in vitro and restrained tumor growth and DDP-resistance in A2780/DDP xenografts after s.c. implantation into nude mice. circHIPK2 sponged miR-338-3p and up-regulated CHTOP. The latter functions in the regulation of gene transcription and mRNA transport (53) and is involved in the chemoresistance of EOC (54). CHTOP binds to arginine methyltransferases PRMT1 and PRMT5 promoting methylation of arginine residues (54). Its knockdown inhibited stemness, invasion and metastasis and enhanced DDP-induced apoptosis in EOC cells (55).

circ0026123 up-regulates Ras-related protein RAB1A. The expression of circ0026123 (Figure 1) was found to be elevated in DDP-resistant EOC tumors and cells (56). Down-regulation of circ0026123 inhibited EOC cell growth, angiogenesis, migration, and invasion and interfered with DDP resistance (56). circ0026123 inhibition decreased EOC growth in nude mice and enhanced cytotoxicity of DDP (56). miR-655-3p was sponged by circ0026123 resulting in up-regulation of RAB1A. It was shown previously that miR-655-3p inhibits proliferation and migration of EOC cells by targeting RAB1A (57). RAB GTPases are coordinators of vesicle trafficking in normal and cancer cells (58,59). They can act as oncogenes as well as tumor suppressors. RAB-mediated membrane delivery can shift normal cell behavior towards malignancy (59). In EOC, deregulation of GTPases of the RAS superfamily is commonly observed (60).

Circ cerebellar degenerated-related protein 1 antisense (circCDR1as) down-regulates protein phosphatase 1 regulatory subunit 12B (PPP1R12B). Down-regulation of circCDR1as in EOC was associated with DDP- resistance (61). circCDR1 (Figure 1) suppressed DDP-resistance in SKOV/DDP and HO8910/DDP cells in vitro and inhibited DDP-chemoresistance in nude mice after s.c. administration. circCDR1as sponged miR-1299, up-regulated PPP1R12B and inhibited AKT/mammalian target of rapamycin (mTOR) signaling (61). PPP1R12B contains a terminal leucine zipper and is involved in dimerization and protein-protein interaction (62). In colon cancer, PPP1R12B promotes proliferation, migration, inhibits apoptosis and up-regulates phosphatidyl-inosite-3-kinase (PI3K)/AKT signaling (63,64).

CircRNAs and Paclitaxel (PTX) Resistance

Circ0006404 and circ0000735 up-regulate P-glycoprotein (P-GP). circ0006404 and circ0000735 (Figure 2) were suppressed in PTX-treated SKOV3 cells and regulated response to PTX in vitro and in xenograft models (65). PTX resistance is a major problem in the treatment of EOC (66,67). Both sponged miR-346 and miR-526, resulting in up-regulation of Dickkopf 3 and 4 (DKK3,4) and P-GP. DKK proteins are antagonists of WNT signaling through interactions with LDL receptor related protein 5 and 6 (LRP5 and LRP6) (68). P-GP, also known as ABC subfamily B member 1 (ABCC1) and multidrug resistance protein 1 (MDR1), is an ATP-binding efflux protein, which is involved in resistance against several chemotherapeutic agents (69). It is a member of a family of ABC transporters of more than 40 proteins, which in addition to P-GP includes multi-drug resistance protein (MRP) and breast cancer resistance protein (BCRP) (70).

CircSET domain bifurcated histone lysine methyltransferase 1 (circSETDB1) up-regulates P-glycoprotein (P-GP). circSETDB1 (Figure 2) was highly expressed in PTX-resistant EOC (71). Knockdown of SETDB1 inhibited proliferation, half-maximal inhibitory concentration of PTX, cell-cycle progression and induced apoptosis in PTX-resistant EOC cells. In nude mice, knockdown of circSETDB1 enhanced PTX sensitivity of xenografts. circSETDB1 sponged miR-508-3p and up-regulated P-GP (72).

Circ transportin 3 (circTNPO3) up-regulates never in mitosis (NIMA) related kinase 2 (NEK2). circTNPO3 (Figure 2) was found to be over-expressed in EOC and associated with PTX resistance (73). Downregulation of circTNPO3 rendered PTX resistant cell lines derived from SKOV3 and Hey1-8 cells more sensitive to PTX. In nude mice, knockdown of circTNPO3 enhanced the anti-tumor effect of PTX in EOC xenografts. circTNPO3 sponged miR-1299 and up-regulated NEK2. The latter is involved in mitotic processes, such as centrosome duplication and separation, microtubule stabilization, kinetochore attachment and spindle assembly checkpoint (74). NEK2 expression correlated with rapid relapse and poor outcome in several types of cancer and its therapeutic potential is under investigation (75). In EOC, NEK2 is over-expressed, promotes proliferation and migration and is associated with drug resistance (76,77).

Circ Cadherin EGF LAG seven-pass G-type receptor 1 (circCELSR1) up-regulates salt-induced kinase 2 (SIK2). circCELSR1 (Figure 2) was up-regulated in PTX-resistant EOC and cell lines (78). In PTX-resistant EOC cell lines, knockdown of circCELSR1 enhanced PTX-sensitivity as well as cell apoptosis and repressed cell viability, colony formation and cell-cycle progression. circCELSR1 silencing impeded PTX-resistance in EOC xenografts in nude mice. SIK2 was up-regulated by sponging of miR-149-5p by circCELSR1. Three SIKs have been identified, which loosely resemble AMP-activated protein kinase (AMPK) (79). They can promote oncogenic as well as tumor-suppressive functions (80). In EOC, SIK2 functions as a centrosome kinase, which is required for bipolar mitotic spindle cell formation (81). SIK2 has been shown to promote EOC motility by phosphorylation of myosin-light chain kinase (MYLK) (82). It also enhances synthesis of fatty acids and cholesterol and promotes tumor growth through PI3K/AKT signaling in EOC (83). Structure-based design of selective SIK inhibitors is an ongoing effort (84).

Circ nuclear receptor interacting protein 1 (circNRIP1) up-regulates homeobox C8 (HOXC8). circNRIP1 (Figure 2) was highly expressed in PTX-resistant EOC and cell lines (85). Silencing of circNRIP1 in PTX-resistant SKOV3 and A2780 cells repressed PTX-resistance in vitro and of SKOV3/PTX xenografts in nude mice after s.c. implantation. circNRIP1 sponged miR-211-5p and up-regulated HOXC8. The latter belongs to a family of at least 39 HOX genes in mammals, which act as transcription factors and contribute to the hallmarks of cancer (86,87). HOX genes play an important role in serous OC (88). HOXC8 is associated with poor prognosis in EOC (89).

Circ0061140 up-regulates chromobox 2 (CBX2). circ0061140 (Figure 2) was up-regulated in PTX-resistant EOC tissues and cells such as SKOV3 and HeyA8 cells (90). In nude mice, knockdown of circ0061140 inhibited tumor growth and PTX resistance of SKOV3 xenografts after s.c. implantation. circ0061140 sponged miR-136 and up-regulated CBX2. The latter is part of the polycomb group complex (PcG), which silences genes by remodeling of chromatin and is involved in renewal of cancer stem cells (91-93). CBX2 has prognostic value and therapeutic potential for EOC (94). CBX2 has been identified as a driver of anoikis escape and dissemination of EOC (94).

Circ cadherin EGF LAG seven pass G-type receptor 1 (CELSR1) up-regulates forkhead box 2 (FOXR2). circCELSR1 (Figure 2) was highly expressed in EOC and correlated with PTX resistance (95). Silencing of circCELSR1 enhanced PTX-induced cytotoxicity in SKOV3/PTX and HeyA-8/PTX cells. circCELSR1 knockdown increased the anti-tumor effect of PTX in SKOV3/PTX xenografts after s.c. implantation into nude mice. mir-1252 was sponged by circCELSR1 resulting in up-regulation of FOXR2. The latter is part of the forkhead family of transcription factors, which comprises 43 members (96) and exhibits oncogenic function (97). FOXR2 promotes metastasis and growth of EOC by stimulating angiogenesis and activating hedgehog signaling (98). FOXR2 also is involved in DDP resistance of EOC (99).

Circ ankyrin repeat domain protein 17 (circANKRD17) stabilizes FOXR2. circANKRD17 (Figure 2) was highly expressed in EOC and correlated with PTX resistance (100). Knockdown of circANKRD17 decreased PTX-resistance, decreased cell viability and induced apoptosis in vitro and in EOC xenografts. circANKRD17 interacted with fused in sarcoma (FUS), which bound to FOXR2, resulting in its stabilization. FUS, also known as heterogeneous nuclear ribonucleoprotein (hnRNP), represents a subunit of a complex involved in maturation of pre-mRNA with a C-terminus, which binds to RNA (101,102).

Circ exocyst complex component 6B (circEXOC6B) is down-regulated and leads to inhibition of forkhead box protein O3 (FOXO3). circEXOC6B (Figure 2) was down-regulated in EOC samples (103). circEXOC6B suppressed proliferation and motility and decreased PTX resistance in EOC cells in vitro and in xenografts in nude mice. circEXOC6B sponged miR-376c-3p leading to down-regulation of FOXO3. The latter is a member of the FOXO transcription factors, which play a role in response to antitumor drugs (104,105). FOXO3 is expressed in ovarian tissues and acts as an apoptosis initiator in granulosa cells in chickens (106). FOXO3 has been shown to inhibit proliferation, invasiveness, and the tumorigenic potential of cancer cells (107).

CircRNAs Targeting Transmembrane Receptors and Secreted Proteins

Circ0013958 up-regulates PlexinB2 (PLXNB2). circ0013958 (Figure 3) was up-regulated in EOC tissues and cells (108). Its knockdown inhibited proliferation, invasion and promoted apoptosis of SKOV3 and CAOV3 OC cells in vitro. Xenograft growth of SKOV3 cells was hampered by knockdown of circ0013958 in nude mice after s.c. implantation. circ0013958 sponged miR-637 and up-regulated PLXNB2. The latter is member of a family of nine transmembrane receptors, which interact with at least 20 members of semaphorins as ligands (109,110). Plexins B family members are involved in neural development, axon growth guidance, as well as the modulation of the cytoskeletal and adhesive machinery. In cancer, they have been shown to be involved in adhesion, proliferation, motility, invasion, and angiogenesis (110,111). PLXNB2 binds to semaphorins 4C and 4D, activates AKT and extracellular signal-regulated kinase 1,2 (ERK1/2) signaling and promotes proliferation of EOC cells (112,113).

Circ0025033 up-regulates solute carrier 1A5 (SLC1A5). circ0025033 (Figure 3) was up-regulated in EOC and positively regulated viability, DNA synthesis in SKOV3 and A2780 EOC cells (114). Knockdown of circ0025033 inhibited growth of A2780 EOC xenografts after s.c. implantation into nude mice. In addition, it acted as a mediator of angiogenesis. It sponged miR-370-3p and up-regulated SLC1A5, also known as alanine, serine, cysteine transporter 2 (ASCT2), which is also involved in glutamine transport and plays a role in proliferation, migration, invasion, angiogenesis, and apoptosis of cancer cells and is associated with a poor prognosis (115,116). SLC1A5 acts as a promoter of EOC (117).

Circ kinesin family member 4A (circKIF4A) up-regulates junctional adhesion molecule 3 (JAM3). circKIF4A (Figure 3) was highly expressed in EOC tissues (118). Its knockdown inhibited proliferation and invasion of SKOV3 and CAO3 EOC cells in vitro. Intra-tumoral injected si-circ KIF4A inhibited growth of SKOV3 xenografts in nude mice and i.v. injected si-circ KIF4A decreased lung metastases of tail-vein injected SKOV3 cells. circKIF4A acted as a sponge for miR-127 and up-regulated JAM3. JAMs are adhesion molecules of the immuno-globulin superfamily, which are connected to the cytoskeleton by interaction with PDZ-domain containing scaffold proteins recruiting and assembling signaling complexes (119,120). JAMs are involved in angiogenesis and can exert pro- and anti-tumoral functions (121,122). In a murine model of EOC, JAM3 has been shown to play a key role in the development of tumors (123). High expression of JAM-A is associated with poor survival in patients with EOC (124).

Circ Wolf-Hirschhorn syndrome candidate 1 (circWHSC1) up-regulates mucin1 (MUC1) and human telomerase reverse transcriptase (hTERT). circWHSC1 (Figure 3) was found to be over-expressed in EOC tissues (125). It promoted viability, invasion, and migration of OVCAR3 and CAOV3 EOC cell lines. Exosomal circWHSC1 increased s.c. growth of CAOV3 xenografts after i.p. injection and peritoneal dissemination into nude mice. circWHSC1 sponged miR-45 and -1185 and up-regulated MUC1 and hTERT. MUC1, a transmembrane glycoprotein, promotes metastasis and progression in EOC (126) and regulates AKT signaling by up-regulation of EGFR expression in OC cells (127). hTERT is involved in proliferation and metastasis and inhibits apoptosis of EOC cells (128).

Circ004712 up-regulates frizzled 4 (FZD4). circ004712 (Figure 3) was aberrantly over-expressed in EOC tissues and cells (129). Down-regulation of circ004712 inhibits proliferation, attenuated migration and invasion and stimulated apoptosis in SKOV3 and OVCAR3 EOC cells in vitro. Knockdown of circ004712 blocked growth of SKOV3 xenografts after s.c. injection into nude mice. circ004712 sponged miR-331-3p resulting in up-regulation of FZD4. The latter plays a role in WNT signaling in EOC (130).

Circ0061140 up-regulates leucine zipper and EF-hand transmembrane protein 1 (LETM1). circ0061140 (Figure 3) was notably up-regulated in EOC and cell lines (131). Knockdown of circ0061140 suppressed proliferation, migration, invasion and angiogenesis-promoting activity and triggered apoptosis in EOC cell lines in vitro. Knockdown of circ0061140 inhibited growth of EOC-related xenografts in nude mice. circ0061140 sponged miR-761 and up-regulated LETM1. The latter is located in the inner mitochondrial membrane, acts as protein Ca-exchange protein and is required for mitochondrial homeostasis and cellular viability (132,133). In EOC, LETM1 has been identified as a promoter of tumorigenesis and metastasis (134).

Circ E3 ubiquitin ligase itchy homolog (circITCH) up-regulates cadherin-1 (CADH1). circITCH (Figure 3) was down-regulated in EOC. It inhibited proliferation, invasion, glycolysis and promoted apoptosis of A2780 and OVCAR3 EOC cells (135). circITCH suppressed proliferation, invasion, and glycolysis of A2780 and OVCAR3 OC cells in vitro. Over-expression of circITCH repressed the growth of SKOV3 xenografts after s.c. implantation into nude mice. circITCH sponged miR-106a resulting in increased levels of miR-106a and reduced levels of CDH1 (135). Expression of CDH1 in EOC is a controversial issue because increased levels (136,137) as well as decreased levels of CDH1 have been associated with progression of EOC (138-141).

CircRAS homology family member C (circRHOC) up-regulates vascular endothelial growth factor A (VEGFA). circRHOC (Figure 3) was over-expressed in EOC (142). In A2780 and CAOV3 EOC cells, circRHOC increased viability, migration, and invasion. Down-regulation of circ RHOC attenuated dissemination of A2780 EOC cells after i.p. injection into nude mice. circRHOC functioned as a sponge for miR-302e and up-regulated VEGFA.

Circ histone lysine methyltransferase 2L (circ ASH2L) up-regulates VEGFA. circASH2L (Figure 3) was up-regulated in EOC tissues and cell lines (143). circASH2L enhanced proliferation and invasion in SKOV3 EOC cells by sponging miR-665 and up-regulating VEGFA. Knockdown of circASH2L in SKOV3 cells inhibited growth, angiogenesis, and lymphangiogenesis after s.c. implantation into nude mice. VEGFA also up-regulated kinase domain insert receptor (KDR), also known as VEGFR2 (144) and Fms related receptor tyrosine kinase 4 (FLT4), which binds VEGFC and VEGFD (145). Angiogenesis plays an important role in generation and progression of EOC (146). Therefore, anti-angiogenic approaches play an important role in the treatment of EOC (147). Bevacizumab, which neutralizes VEGFA has been approved for treatment of EOC in various clinical scenarios (148).

Circ0001445 up-regulates secreted frizzled-related protein 1 (SFRP1). Expression of circ0001445 (Figure 3) was decreased in EOC (149). It blocked proliferation and migration and promoted apoptosis in SKOV3 and HO8910 EOC cells. Over-expression of circ0001445 in HO8910 EOC cells inhibited tumorigenesis and i.p. metastasis in nude mice. circ0001445 sponged miR-576-5p and up-regulated SFRP1. The latter is a member of a family of five proteins, which bind to WNT ligands or to frizzled receptors with the consequence of interfering with WNT signaling (150,151). In EOC, it was shown that SFRP1 inhibits proliferation, migration, and invasion, and WNT/β-catenin signaling (152). Methylation-associated silencing of SFRP1 was observed in high-grade serous ovarian carcinoma (153).

CircRNAs Targeting Transcription Factors

Circ0061140 up-regulates forkhead box M1 (FOXM1). circ0061140 (Figure 4) was up-regulated in EOC and cell lines (154). Knockdown of circ0061140 suppressed proliferation and invasion of A2780 and SKOV3 OC cell lines and inhibited growth of SKOV3 xenografts after s.c. implantation into nude mice. circ0061140 sponged miR-370 and up-regulated transcription factor FOXM1. The latter is frequently over-expressed in cancer (155). In EOC, FOXM1 is involved in proliferation, invasion and metastasis, genomic instability, cancer stem cell (CSC) maintenance, cellular metabolism, and chemo-resistance (156). Peritoneal spread and migration is mediated by expression of FOXM1 (157,158). Small molecules targeting the FOXM1 DNA binding domain exhibit antitumor activity in EOC (159,160).

Circ cysteine-rich motor neuron protein 1 (circCRIM1) up-regulates CRIM1 and zinc finger E-box binding homeobox 2 (ZEB2). circCRIM1 (Figure 4) was over-expressed in EOC (161). Its knockdown inhibited cell viability, migration, invasion and promoted apoptosis in CAOV3 and OVCAR3 EOC cells. circCRIM increased growth of CAOV3 xenografts after s.c. implantation into nude mice. circCRIM1 sponged miR-145-5p resulting in up-regulation of CRIM1 and, in addition, it sponged miR-383-5p leading to up-regulation of ZEB2. CRIM1 regulates processing of bone morphogenetic protein (BMP) preprotein into mature protein and delivery of BMPs to the cell surface (162). It stimulates capillary formation, angiogenesis and EMT (162,163). ZEB2, together with other transcription factors, such as SLUG, SNAIL, TWIST and ZEB1 acts as a mediator EMT (164). ZEB2 is highly expressed in EOC and correlates with poor prognosis (165). In EOC, ZEB2 has been shown to act as a repressor of E-cadherin (166).

Circular RNA protein tyrosine kinase 2 (circPTK2) up-regulates chromosomal helicase DNA binding protein CHD1L and forkhead-box C1 (FOXC1). circPTK2 (Figure 4) was over-expressed in EOC and positively affected migration, invasion, angiogenesis and EMT in SKOV3 and OVCAR3 cells (167). OVCAR3 cells transfected with circPTK2 showed increased tumor growth after s.c. implantation into nude mice. circPTK2 expression was positively correlated with CDH1L mRNA and interacted with miR-639 resulting in up-regulation of FOXC1. CDH1L acts as an oncogene promoting unleashed proliferation, inhibition of apoptosis by binding to apoptotic nuclear receptor protein NUR77 and activation of AKT signaling (168). CDH1L is over-expressed in EOC and promotes its invasiveness and metastasis by regulation of methionyl aminopeptidase 2 (169,170). The forkhead family of transcription factors plays an important role in ovarian function (171). FOXC1 is involved in cancer cell proliferation, migration, angiogenesis, and cancer stem cell maintenance and is a potential target for therapy (172).

CircRNAs Up-regulating RNA Binding and Splicing Proteins

Circ0007841 up-regulates Mex-3 RNA binding family member C (MEX3C). circ0007841 (Figure 4) was highly expressed in EOC and promoted proliferation, invasion, and migration in SKOV3 and OVCAR3 EOC cells (173). Knockdown of circ0007841 in SKOV3 EOC cells suppressed tumor growth after s.c. implantation into nude mice. The underlying mechanism implicated sponging of miR-151-3p and up-regulation of RNA binding protein MEX3C. RNA binding proteins have been implicated in human cancer and other diseases by diverse mechanisms, such as mRNA splicing, polyadenylation, translation, regulation of its stability and subcellular localization (174,175). MEX3C contains two RNA binding domains and a RING-finger domain and constitutes an RNA binding ubiquitin ligase (176). MEX3C has been shown to promote lipid metabolism to support bladder tumorigenesis by activation of the JNK pathway (177). In addition, MEX3B has been shown to mediate decay of SOCS3 mRNA promoting Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling and facilitating hepatocellular carcinoma metastasis (178).

Circ0025033 up-regulates Sm-like protein 4 (LSM4). circ0025033 (Figure 4) was up-regulated in EOC and its knockdown blocked colony formation, migration, invasion, and glycolysis of EOC cells (179). In nude mice, circ0025033 knockdown inhibited growth of EOC xenografts after s.c. implantation. circ0025033 sponged miR-184 resulting in over-expression of ribonucleoprotein LMS4. The latter is a member of an RNA binding protein family with 14 members (180). LMS4 binds to the 3´UTR of small nuclear RNA U6snRNA (181,182).

Circ0001756 up-regulates insulin growth factor 2 mRNA binding protein (IGF2BP2). circ0001756 (Figure 4) was up-regulated in EOC and its knockdown in SKOV7 and A2780 EOC cells inhibited proliferation, invasion, EMT and tumor growth of SKOV3 xenografts after tail vein injection (183). circ0001756 was shown to bind and promote expression of IGF2BP2 to interact with RAS-associated protein 5A (RAB5A) and to activate EGFR/mitogen-activated protein kinase (MAPK) signaling (183). IGF2BP2 has been identified as a post-transcriptional driver and as an oncogene in human cancer (184,185). RAB5A mediates cell proliferation by APPL1 related epidermal growth factor signaling in EOC (186). IGF2BP2 has been shown to promote aggressiveness and stemness of EOC by ERB-B2 receptor tyrosine kinase 4(ERBB4)/PI3K/AKT signaling (187).

Circbasonuclin 2 (circBCN2) up-regulates La ribonucleoprotein 4 (LARP4). circBCN2 (Figure 4) was found to be down-regulated in EOC (188). Its over-expression decreased proliferation, migration, invasion of EOC cells in vitro and inhibited growth of EOC xenografts in nude mice. circBCN2 sponges miR-223-3p resulting in up-regulation of RNA binding protein LARP4. It is member of a family of proteins with a conserved 90 aa signature sequence, which are deregulated in cancer and can exert an oncogenic or tumor-suppressive function (189,190). It has been shown that LARP4 inhibits motility of EOC cells (191,192).

CircRNAs Targeting RAS Pathway-related Proteins

Circ0061140 up-regulates RAS-related protein 1A (RAB1A). circ0061140 (Figure 4) was up-regulated in EOC tissues and cells and its down-regulation impeded proliferation, migration, invasion, EMT and angiogenesis capability of EOC cells in vitro and in nude mice (193). It sponged miR-361-5p and up-regulated RAB1A. The latter is a small GTPase, which is involved in vesicular trafficking between the endoplasmic reticulum and the Golgi apparatus (194). RAB1A was shown to mediate proliferation and migration of colorectal cancer (195).

Circ itchy homolog E3 ubiquitin protein ligase (circITCH) up-regulates RAS p21 protein activator 1 (RASA1). circITCH (Figure 4) was down-regulated in EOC tissues and cell lines (196). It inhibited cell viability, motility, wound-healing, and invasion of EOC cell lines and tumor growth of EOC xenografts in nude mice. circITCH sponged miR-145 and up-regulated RASA1, which is also known as RAS-GTPase activating protein (RAS-GAP). RASA1 acts as a GAP with dual specificity that enhances and accelerates GTPase activity of RAS and ras-related protein (RAP) (197). RASA1 is composed of several domains, such as src homology regions 2 and 3 (SH2, SH3), a pleckstrin domain (PH), a phospho-lipid binding domain (C2) and a GTPase activating domain (GAP) (197). In cancer, RASA1 is involved in cell growth, proliferation, and apoptosis (197).

Circ ceramide synthase (circ CERS6) up-regulates RAS-association domain family member 8 (RASSF8). circ CERS6 (Figure 4) was markedly reduced in EOC tissues and cell lines (198). circCERS6 inhibited proliferation, migration, invasion and EMT of EOC cells. circCERS6 over-expression in EOC cells blocked tumor growth in nude mice. circCERS6 sponged miR-630 and up-regulated RASSF8. The latter belongs to a protein family of ten members (199). RASSF8 acts as a tumor suppressor by maintaining adherents junctions and plays a role in epithelial migration and suppression of WNT and nuclear factor ĸB (NFĸB) signaling (200). RASSF8 is in involved in regulation of the cell-cycle and apoptosis (201,202). RASSF8 has been shown to be involved in proliferation and migration of EOC (203).

circRNAs Targeting Ubiquitinylation and Cell-cycle Related Proteins

Circ0015756 and circ0021573 up-regulate cullin 4B (CUL4B). circ0015756 (Figure 5) was up-regulated in EOC tissues and cells (204). Knockdown of 0015756 inhibited proliferation, migration, and invasion in OC90 and SKOV3 EOC cells. Depletion of circ0015756 hindered growth of SKOV3 xenografts in nude mice. The underlying mechanism involved binding of miR-942-5p to circ0015756 and subsequent up-regulation of CUL4B (204). circ0021573 was also over-expressed in EOC tissues and its inhibition impeded cell proliferation, migration and invasion, and induced apoptosis of EOC cells in vitro and diminished growth of EOC-related xenografts in nude mice (205). circ0021573 sponged miR-936 and also up-regulated CUL4B. The latter is a scaffold protein that participates in the formation of the E3 ubiquitin ligase complex (206). CUL4B is over-expressed in a variety of tumors and can affect the cell-cycle, promoter methylation, histone deacetylation, and DNA damage and repair, resulting in context-dependent oncogenic and tumor-suppressive properties (207,208). It is well documented that ubiquitinylation can have pro-tumoral as well as tumor-suppressive effects such as degradation of p53 (209,210). CUL4B is up-regulated in EOC and correlates with poor prognosis and induces expression of cyclin-dependent kinase 2 (CDK2) and cyclin D (211).

Circ basonuclin 2 (circBCN2) up-regulates F box and WD repeat domain containing 7 (FBXW7). circBCN2 (Figure 5) was down-regulated in EOC patients and decreased expression correlated with poor prognosis (212). It inhibited cell growth, proliferation, migration, invasion, and cell-cycle progression in SKOV3 and HO-8910 OC cells. circBCN2 sponged miR-223-3p and up-regulated FBXW7. Over-expression of circBCN2 in SKOV3 EOC cells suppressed lung metastasis after tail vein injection into nude mice. FBXW7, a member of the F-box protein family, is a component of the Skp, F-box containing complex (SCF). This complex, an E3 ubiquitin ligase, regulates substrate specificity, ubiquitinates proteins and triggers their degradation in the proteasome. It acts as a tumor suppressor by ubiquitinylation of substrates such as the transcription factors c-MYC and JUN and cyclin E and induces myeloid leukemia cell differentiation protein 1 (MCL1), receptor tyrosine kinase NOTCH1 and mTOR (213,214). FBXW7 is aberrantly expressed in several types of cancer (213,214). In EOC, FBW7 has been shown to suppress N6-methyladenosine binding protein YTHDF2 (215).

Circ0072995 up-regulates cyclin-dependent kinase 6 (CDK6). circ0072995 (Figure 5) was up-regulated in EOC tissues and cell lines (216). High expression of circ0072995 correlated with pathological grading. Its knockdown suppressed proliferation, migration, and induced apoptosis of HO8910 and A2780 EOC cancer cells. Down-regulation of circ0072995 inhibited tumor growth of HO8910 xenografts after s.c. implantation into nude mice. It sponged miR-147 resulting in up-regulation of CDK6. Targeting of CDK4 and CDK6, which are critical mediators of S-phase entry, has led to approved drugs for treatment of hormone receptor positive breast cancer (217). CDK6 also exerts kinase-independent functions as a chromatin-bound co-factor by inducing genes involved in angiogenesis, cell-cycle inhibition, stem cell activation and activation of the immune response (218). CDK6 has been shown to contribute to progression of EOC and to protect EOC cells from DDP-induced cell death (219,220). Furthermore, it has been shown that CDK4/6 inhibition promotes immune infiltration in EOC and synergizes with programmed death (PD)-blockade (221).

Circ phosphoglycerate mutase1 (circPGAM1) up-regulates cell division 5-like (CDC5L). circPGAM1 (Figure 5) was up-regulated in EOC tissues and its silencing resulted in inhibition of proliferation, migration, and invasion, and promoted apoptosis in CAOV3 and OVCAR3 EOC cells (222). In OVCAR3 and CAVOV3 xenografts, circPGAM1 stimulated tumor growth after s.c. implantation into nude mice. circPGAM1 sponged miR-542-3p and up-regulated CDC5L. The latter interacted with the promoter of pseudopodium enriched atypical kinase 1 (PEAK1) and increased its expression. PEAK1 activated ERK1/2 and JAK2 signaling pathways. CDC5L functions as a cell-cycle regulator at G2/M transition and is involved in pre-mRNA splicing and DNA damage repair (223). Depletion of CDC5L was shown to inhibit mitotic progression and mitotic catastrophe (224). PEAK1 has intrinsic tyrosine kinase activity and, in addition, exhibits scaffolding functions. It promotes proliferation and motility and is involved in regulation of actin cytoskeleton and focal adhesions and represents a potential target for anti-cancer drugs (225,226).

circRNAs Targeting Kinases and Phosphatases

CircSET domain bifurcated histone lysine methyltransferase 1 (circSETDB1) up-regulates mitogen-activated protein kinase kinase kinase 3 (MAP3K3). circSETDB1 (Figure 5) was up-regulated in EOC tissues and cell lines (227). Silencing of circSETDB1 repressed proliferation, invasion and migration, and induced apoptosis in A2780 and SKOV3 EOC cell lines. CircSETDB1 depletion inhibited tumor formation and metastases of i.p. injected SKOV3 cells in nude mice. circ SETB1 sponged miR-129-3p and up-regulated MAP3K3, a kinase, which activates ERK1/2, c-jun terminal kinase (JNK) and mitogen-activated protein kinase p38 (228). MAP3K3 over-expression was associated with poor survival in EOC patients (229). MAP3K3 promotes growth of EOC through activation of NFĸB signaling (230). MAP3K3 also confers resistance to apoptosis in EOC cells through stimulation of NFĸB (231).

Circ0000471 up-regulates dual-specificity phosphatase 5 (DUSP5). circ0000471 (Figure 5) was found down-regulated in EOC tissues and cell lines (232). Over-expression of circ0000471 blocked proliferation, migration and invasion, and triggered apoptosis in EOC cells. Its mechanism of action involves sponging of miR-135b-5p and down-regulating DUSP5. Over-expression of circ0000471 inhibited EOC-derived xenografts in nude mice. DUSP5 is a member of dual-specificity phosphatases, which inactivate different mitogen-activated kinases (MAPK), such as ERKs, JNK and p38 (233). DUSP5 has been shown to suppress EOC progression by inhibiting interleukin 33 (IL33) signaling (234).

circRNAs Targeting Components of Signaling Systems

Circ0002711 up-regulates Rho-associated protein kinase 1 (ROCK1). The level of circ0002711 (Figure 6) was up-regulated in EOC tissues (235). Knockdown of circ0002711 inhibited cell proliferation and aerobic glycolysis in SKOV3 and OV90 EOC cells. Decreased expression of circ0002711 mediated inhibition of SKOV3 xenografts after s.c. implantation. circ0002711 sponged miR-1244 and up-regulated the Ser-Thr kinase ROCK1. The latter is a downstream effector of GTPases RHOA and RHOC and is frequently deregulated in cancer. It mediates cytoskeleton contractability, migration, survival, and proliferation of tumor cells (236,237). For cancer, a ROCK1 inhibitor has not yet being approved due the narrow therapeutic window, whereas four different ROCK1 inhibitors have been approved for other diseases (237). It has been shown that ROCK1 promotes proliferation, invasion, and migration of EOC cells (238,239).

Circ0007874 up-regulates suppressor of cytokine signaling 3 (SOCS3). circ0007874 (Figure 5) was decreased in EOC cell lines (240). It suppressed growth and migration of A2780 and SKOV3 EOC cell lines. Over-expression of circ0007874 inhibited growth of A2780 EOC cells in nude mice after s.c. implantation. It sponged miR-760 and up-regulated SOCS3. The latter is a member of a family of eight proteins, , each characterized by varying N-termini, an SH2 domain that binds to proteins phosphorylated by tyrosine kinases, and a C-terminus responsible for recruiting E3 ligases and ubiquitin signaling molecules (241). SOCS3 is induced by cytokines which activate STAT3 via JAK2 and inhibits this pathway by a variety of mechanisms (242). SOCS3 suppresses progression of EOC by blockade of the JAK/STAT signaling pathway (243). Reduced expression of SOCS3 predicts poor outcome in EOC (244).

Circ neuroblast differentiation associated gene (circAHNAK) induces eukaryotic initiation factor 2B subunit ε (EIF2B5). circAHNAK (Figure 6) was decreased in patients with EOC (245). Expression of circAHNAK in EOC cells promoted apoptosis and inhibited cell proliferation, migration, invasion, EMT and JAK2/STAT signaling. circAHNAK retarded growth of EOC xenografts in nude mice. It sponged miR-28 and up-regulated EIF2B5, a component of EIF2B, which is composed of five subunits (246). The mechanism through which EIF2B suppresses JAK2/STAT signaling is not yet resolved. Low expression of EIF2B5 predicts a poor prognosis in EOC (247). Inactivation of EIF2B5 by promoter methylation mediated metastasis of EOC cell lines (248).

Circ attractin-like1 (circ ATRNL1) up-regulates mothers of decapentapledgic homolog 4 (SMAD4). circATRNL1 (Figure 6) was down-regulated in the tissues of EOC patients and suppressed proliferation, migration, invasion in SKOV3 and CAOV3 EOC cells and inhibited angiogenesis (249). In an i.p. xenograft model, circATRNL1 suppressed abdominal metastasis of SKOV3 and CAOV3 EOC cells. circATRNL1 bound miR-378 and up-regulated SMAD4. miR-378 activated AKT via targeting transcription factor SMAD4. SMADs transduce extracellular signaling to the nucleus and SMAD4 is activated by transforming growth factor β (TGFβ) and related ligands and induces cell-cycle arrest, apoptosis, and suppression of cancer development (250-252). It was independently demonstrated that SMAD4 inhibited proliferation of EOC cells (253).

circRNAs Targeting Additional Categories of Proteins

Circ keratin 7 (circ KRT7) up-regulates collagen 1A1 (COL1A1). circKRT7 (Figure 6) was highly expressed in EOC tissues (254). Down-regulation of circKRT7 suppressed proliferation and invasion of ES2 and SKOV3 EOC cells. Inhibition of circKRT7 decreased growth of ES2 xenografts in nude mice. circKRT7 sponged miR-29a-3p and up-regulated COLA1, a major component of type I collagen, which is the main structural component of the extracellular matrix. Collagen is composed of a triple helix with two identical α1 chains and an additional α2 chain that differs slightly in its chemical composition. The ECM plays an important role in cancer genesis and progression (255). COL1A1 was elevated in ascites from EOC patients in comparison to normal peritoneal fluids (256). COL1A1 was mainly derived from fibroblasts and bound to β1 integrin, activating AKT signaling and promoting migration and invasion (256). The extension of understanding of the functions of the extracellular matrix (ECM) will enable the design of new therapeutics for the treatment of cancer (257). Furthermore, it was shown that COL1A1 was involved in DDP resistance of EOC (258).

Circ ATPase plasma membrane Ca²⁺ transporter 4 (ATP2B4) up-regulates sterol regulatory element-binding factor 1 (SREBF1). circATP2B4 (Figure 6) was up-regulated in EOC tissue samples and positively correlated with disease progression (259). circATP2B4 targets EOC cells as well as tumor-associated macrophages. EOCs releasing circATP2B4 in extracellular vesicles (EV) enhance migration, invasion and EMT of SKOV3 and A2780 EOC cells. circATP2B4 was highly expressed in EVs from EOC cells and could be transferred into macrophages resulting in their polarization into protumoral M2 macrophages. SKOV3 cells mixed with conditional macrophages stimulated with EVs from A2780 cells exhibited significantly increased tumor weight and peritoneal metastases after i.p. injection into nude mice in comparison to the corresponding control group. It was shown that circATP2B4 sponges miR-532-3p and up-regulated SREBF1 resulting in activation of SREBF1/PI3K/AKT signaling and macrophage polarization. SREBF1 mediates lipogenesis, activates PI3K-AKT-mTOR signaling and suppresses ferroptosis (260). In EOC, SREBF1 is required for tumor growth (261) and targeting of lipogenesis is an important topic for treatment of EOC (262). A correlation between high level of M2 macrophages and low survival in EOC patients has been noted, therefore preclinical evaluation of macrophage-targeted therapies for EOC are under evaluation (263).

Circ0015756 up-regulates phosphoserine aminotransferase 1 (PSAT1). circ0015756 (Figure 6) was highly expressed in EOC tissues and cells (264). Knockdown of circ0015756 suppressed growth, migration, and invasion of EOC cell in vitro and impeded growth of EOC xenografts in nude mice. circ0015756 acted as a sponge for miR-145-5p and up-regulated PSAT1, which is involved in serine biosynthesis and functions as a pro-proliferative and pro-survival factor (265). In cancer, PSAT1 provides anabolic support of tumor cells, stimulating proliferation, survival, autophagy, migration, invasion and non-enzymatically regulates the IGF1 pathway and nuclear PKM2 to promote EMT and metastasis (266). In EOC, PSAT1 is markedly over-expressed and correlates with lymph node metastasis, distant metastasis, and presence of ascites (267). Its inhibition decreases growth of EOC cells, induces apoptosis and cell-cycle arrest (267). PSAT1 increases the proportion of GSH and reduced nicotinamide dinucleotide phosphate (NADPH) in EOC cells, increasing oxidative stress tolerance (267).

Circ pleckstrin homology domain family M member 3 (circPLEKHM3) up-regulates breast cancer antigen 1 (BRCA1). Down-regulation of circPLEKHM3 (Figure 6) was associated with a poor prognosis in patients with EOC (268). circPLEKM3 repressed proliferation, migration and EMT of A2780 and OV90 EOC cells in vitro and in vivo of corresponding xenografts after s.c. implantation. circPLEKHM3 was shown to bind to miR-9 and to suppress its activity. BRCA1, DNAJ heat shock family (Hsp40), member B6 (DNAJB6) and Krueppel-like transcription factor 4 (KLF4) were identified as targets of miR-9. It was shown that circPLEKHM3 inactivates AKT1 and WNT/β catenin signaling. BRCA1 is part of a complex that repairs double-strand breaks and regulates DNA repair, transcription, and cell-cycle regulation in response to DNA damage and is frequently inactivated in EOC (269,270). DNAJB6 interacts with hsp70 chaperones, inhibits WNT and NFĸB signaling and negatively regulates tumor growth and metastasis (271). The other target of circPLEKHM3, KLF4, has been shown to be down-regulated in EOC and its over-expression caused EOC proliferation, migration, and invasion by inhibiting TGFβ induced EMT (272).

Circ0007444 up-regulates phosphatase and tensin homolog (PTEN). Low expression of circ0007444 (Figure 6) predicted poor prognosis in patients with EOC (273). circ0007444 inhibited proliferation, migration, invasion and promoted apoptosis of SKOV3 and OVCAR3 EOC cells in vitro and suppressed growth of OVCAR3 xenografts after s.c. implantation into nude mice. circ0007444 sponged miR-570-3p and up-regulated PTEN. The latter acts as a tumor suppressor by dephosphorylating phosphatidylinositol-3,4,5 triphosphate and other phosphoinositides and inhibiting PI3K/AKT/mTOR signaling (274). PTEN also acts as a scaffold protein both in the nucleus and the cytoplasm through a phosphatase-independent function acting as a chromosomal stability controller (275). In EOC, PTEN is inactivated in 5-7% of the tumors (276).

Circ cadherin RGF LAG seven pass-G-type receptor 1 (circCELSR1) up-regulates bromodomain-containing protein 4 (BRD4). circCELSR1 (Figure 6) was over-expressed in EOC cancer cells (277). Its knockdown inhibited proliferation, migration and promoted apoptosis in SKOV3 and A2780 EOC cells. In nude mice, knockdown of circCELSR1 suppressed growth and metastasis of SKOV3 cells injected into the abdominal cavity of nude mice. BRD4 was up-regulated due to sponging of miR-598 by circCELSR1. BRD4 is a member of the bromodomain and extraterminal protein family (BET) with two tandem bromodomains, which can bind to acetylated histones and other proteins and activate oncogenic proteins by interaction with RNA polymerase II (278,279). Several BET inhibitors, which mimic the acetyl moiety occluding the acetyl binding site pocket unique to the BET family of proteins, have been designed (278,279). In EOC, cyclin E1 (CCNE1) and BRD4 amplification are associated with poor outcomes in patients (280). BRD4 amplification facilitates oncogenic gene expression in EOC and confers sensitivity to BET inhibitors (281). BRD4 inhibition has been shown to be synthetically lethal together with PARP inhibition through induction of homologous recombination deficiency (282). BET inhibition also has been shown to resensitize EOC cells to approved anticancer agents such as DDP and PARP inhibitors (283).

Circ0026123 up-regulates enhancer of zeste homolog 2 (EZH2). circ0026123 (Figure 6) was significantly increased in EOC in comparison to adjacent normal tissues (284). Silencing of circ0026123 inhibited proliferation, migration, and CSC differentiation markers in SKOV3 cells. Down-regulation of circ0026123 suppressed tumor growth of SKOV3 cells after s.c. implantation into nude mice. All of these effects are based on sponging miR-124-3p by circ0026123 and subsequent up-regulation of EZH2. The latter is the catalytic subunit of the polycomb repressive complex (PRC2), which mediates repression of target genes by trimethylation of Lys 27 in histone 3 (285). EZH2 is involved in cancer cell proliferation, invasion, metastasis, angiogenesis, and resistance to chemotherapy (286). In EOC, EZH2 is over-expressed, promotes proliferation, inhibits apoptosis, and enhances angiogenesis. Currently, multiple inhibitors targeting EZH2 are undergoing clinical trials (287,288).

Technical Issues

Searching the literature, we identified up- and down-regulated EOC-related circRNAs and their corresponding targets. Only circRNAs which exhibit activity in EOC-related xenograft models in nude mice were selected. The corresponding targets can be validated with respect to their priority for drug development by further in vitro and in vivo experiments. According to the target class identified, up-regulated targets can be inhibited with small molecules, antibody-derived moieties, or proteolysis-targeting chimeras (PROTACS) (289,290). Down-regulated targets can be up-regulated by gene transfer or small molecules (291). The latter are often associated with specificity issues and target deconvolution is necessary.

Up-regulated circRNAs can be inhibited with ASO, siRNA or shRNA and down-regulated circRNAs can be reconstituted by gene transfer (292,293). However, several technical hurdles have to be tackled. These issues are not discussed in further details in this review. Among the issues are pharmacokinetic and pharmacodynamic aspects of the corresponding agents, immunogenicity, specificity, and delivery (15-17). The optimization process depends on the specific approach and the clinical scenario to be pursued. Lipid derived nanoparticles (LNPs) are frequently used for delivery of corresponding inhibitors of circRNA or circRNAs for reconstitution experiments. They consist of variations of basically four compounds: a cationic or ionizable lipid, cholesterol, a helper lipid and a polyethylene glycol lipid (294). Conjugation of siRNA with N-acetyl galactosamine (GalNAc) resulted in liver transfer (295) and functionalization of siRNA with antibodies has enabled transfer to endothelial cells and tumor cells (296). Four siRNAs for different indications have been approved now including Patisiran for treatment of transerytrin-mediated amyloidosis as the first one (297).

Concluding Remarks

We identified up- and down-regulated circRNAs with efficacy in EOC-related preclinical in vivo systems. The vast majority act by sponging miRNAs. They can be assigned to the following categories according to the targets they regulate: DDP- and PTX-resistance, transmembrane receptors and secreted factors, transcription factors, RNA binding and processing factors, RAS pathway-related factors, ubiquitinylation- and cell-cycle proteins, signaling-related components, and targets that fit into additional categories.

Figure 1 and Figure 2 show that resistance to DDP and PTX can be mediated by a variety of targets, which complicates the treatment of chemo-resistance, one of the major problems of the treatment of EOC. PLXND2, SCL1A5, JAM3, FZD4 and SFRP1 and corresponding circRNAs were identified as potential targets for treatment of EOC (Figure 3). The role of transcription factors, RNA splicing and processing related proteins and components of the RAS-related signaling system as targets of circRNAs are outlined in Figure 4. The significance of ubiquitinylation, proteolysis and cell-cycle proteins is highlighted in Figure 5. PSAT-1 and SREBF-1 were identified as targets for interference with metabolism and lipogenesis of EOC (Figure 6). EZH2 and BRD4 have emerged as targets for interference with epigenetic mechanisms and induction of macrophage polarization as a strategy for treatment of EOC (Figure 6). Reconstitution of activity of tumor suppressor genes, such as BRCA1 and PTEN might be of therapeutic benefit in patients with EOC (Figure 6).

Since circRNAs exhibit a unique splice junction, elimination of circRNAs with the CRISPR-CAS technology might be a new mode of therapeutic intervention (24,25). Also, investigations on the representation of individual circRNAs will pave the way for identification of circRNAs with a dominant role in EOC. The role of defined circRNA in cancer-related networks, the issue of synthetic lethality of inhibition of circRNAs together with other targets should be examined in more detail. Demonstration of activity of circRNA modulating agents in patient-derived xenograft models (PDX) would increase the confidence for this approach with respect to clinical translation.

Conflicts of Interest

FB is and UHW was an employee of Roche.

Authors’ Contributions

FB and UHW contributed equally to all aspects of the paper.

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PERMALINK

Deregulated circRNAs in Epithelial Ovarian Cancer With Activity in Preclinical In Vivo Models: Identification of Targets and New Modalities for Therapeutic Intervention

ULRICH H WEIDLE

FABIAN BIRZELE

Abstract

Circular RNA in Cancer

CircRNAs Deregulated in EOC

CircRNAs and Paclitaxel (PTX) Resistance

CircRNAs Targeting Transmembrane Receptors and Secreted Proteins

CircRNAs Targeting Transcription Factors

CircRNAs Up-regulating RNA Binding and Splicing Proteins

CircRNAs Targeting RAS Pathway-related Proteins

circRNAs Targeting Ubiquitinylation and Cell-cycle Related Proteins

circRNAs Targeting Kinases and Phosphatases

circRNAs Targeting Components of Signaling Systems

circRNAs Targeting Additional Categories of Proteins

Technical Issues

Concluding Remarks

Conflicts of Interest

Authors’ Contributions

References

ACTIONS

PERMALINK

RESOURCES

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PERMALINK

Deregulated circRNAs in Epithelial Ovarian Cancer With Activity in Preclinical In Vivo Models: Identification of Targets and New Modalities for Therapeutic Intervention

ULRICH H WEIDLE

FABIAN BIRZELE

Abstract

Circular RNA in Cancer

CircRNAs Deregulated in EOC

CircRNAs and Paclitaxel (PTX) Resistance

CircRNAs Targeting Transmembrane Receptors and Secreted Proteins

CircRNAs Targeting Transcription Factors

CircRNAs Up-regulating RNA Binding and Splicing Proteins

CircRNAs Targeting RAS Pathway-related Proteins

circRNAs Targeting Ubiquitinylation and Cell-cycle Related Proteins

circRNAs Targeting Kinases and Phosphatases

circRNAs Targeting Components of Signaling Systems

circRNAs Targeting Additional Categories of Proteins

Technical Issues

Concluding Remarks

Conflicts of Interest

Authors’ Contributions

References

ACTIONS

PERMALINK

RESOURCES

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