Emerging landscape of circHIPK3 and its role in cancer and other diseases (Review).

Circular RNAs (circRNAs) are a special class of recently re‑discovered RNAs, which are covalently closed ring RNA molecules. circRNAs have been reported to possess multiple functions and are considered crucial regulators of several processes, and are therefore gaining increasing attention. In recent years, increasing evidence has shown that circRNAs are implicated in several crucial biological processes via regulation of gene expression, and their dysregulation is also associated with the development of numerous diseases, particularly acting as oncogenic or tumor‑suppressor molecules in cancer. Furthermore, circRNAs are involved in cell proliferation, differentiation, apoptosis, invasion and metastasis. In the present review, the biogenesis and functions of circRNAs are described, with a focus on the most recent research advances and the emerging roles of circular homeodomain‑interacting protein kinase 3 (circHIPK3) in human diseases. The present review may provide novel avenues for research on the roles of circHIPK3 as a clinical diagnostic and prognostic biomarker, as well as highlighting promising therapeutic targets for certain diseases and cancer.

Introduction

Circular RNAs (circRNAs) are endogenous single-stranded non-coding RNAs (ncRNAs) generated from protein-coding genes without caps and tails at 5′ and 3′ ends of their structure and shaped as covalently closed continuous loops (1,2). Due to their circular structure, circRNAs are more stable and resistant to degradation by exonuclease RNase R compared with linear mRNAs (3). circRNAs were once considered a product of mis-splicing or splicing noise of precursor mRNAs (pre-mRNAs) (4). circRNAs are now an increasingly popular subject of study in the field of scientific research, particularly in regard to ncRNAs. Moreover, circRNAs are attracting significant attention as functional regulators, and have an important value in biomedical research, particularly with regard to their clinical potential. circRNAs were first discovered in 1976, in a study of RNA viruses (5). Subsequently, Hsu and Coca-Prados (6) first identified the existence of circRNAs in the cytoplasm of eukaryotic cells using electron microscopy in 1979. In the 21st century, benefiting from the breakthroughs in next generation sequencing technologies and rapid development of bioinformatics, numerous circRNAs have been identified in various organisms (7–9).

Additionally, it has been reported that circRNAs are widely expressed in a variety of living organisms and are evolutionarily conserved amongst different species and often display cell or tissue/developmental-stage-specific expression (10–12). Furthermore, several studies have revealed that circRNAs exhibit aberrant or differential expression in different tissues and disease states, suggesting their important functions in physiological and pathological processes (13–18).

Homeodomain-interacting protein kinase 3 (HIPK3) is a member of the HIPK gene family. circHIPK3 is a circular RNA derived from exon2 of the HIPK3 gene, which is 1,099 nucleotides in length (Fig. 1) (19–21). An increasing number of studies have revealed that circHIPK3 is strongly associated with the occurrence and development of several human diseases, such as osteosarcoma, hepatocellular carcinoma and colorectal cancer (22,23). circHIPK3 has a regulatory role as a modulator of cellular behavior, as well as exhibiting oncogenic or tumor suppressor functions, depending on the specific diseases (24,25). Thus, circHIPK3 may serve as a novel candidate of diagnosis and prognosis for disease biomarkers, as well as a promising therapeutic molecular target. In the present study, the biogenesis and possible functions of circRNAs are discussed, with a focus on recent progress on the study of circHIPK3 and its association with human diseases and cancer. The aim of the present review was to broaden the knowledge on circHIPK3 and aid future studies assessing the regulatory function of circHIPK3 in the development and progression of diseases.

Figure 1.

Schematic diagram of generation of circHIPK3. The circularization of HIPK3 exon 2 forms circHIPK3 (black arrow). Bule arrow represents ‘head-to-tail’ splicing sites of circHIPK3 by Sanger sequencing. circHIPK3, circular homeodomain-interacting protein kinase 3; Chr, chromosome.

Biogenesis of circRNAs

It is generally acknowledged that circRNAs are transcribed from linear pre-mRNAs by RNA polymerase II (RNA Pol II) and formed via back splicing, differing from canonical splicing to form mRNAs (26). According to their genomic origin, circRNAs can be divided into four types: Exonic circRNAs, circular intronic RNAs (ciRNAs), exon-intron circRNAs and tRNA intronic circRNAs (tricRNAs) (1,27,28). Several studies have demonstrated that the biogenesis of circRNAs occurs via four primary models: Lariat-driven circularization path, intron-pairing driven circularization path, RNA-binding protein (RBP)-binding-driven circularization path and intron-splicing driven circularization path (Fig. 2) (29,30). The first model is the lariat-driven circularization path, which requires an upstream 3′ splice site to be joined to a downstream 5′ splice site, resulting in exon skipping to form an RNA lariat consisting of several exons and introns (31). Intron-pairing-driven circularization is the second model of circRNA biogenesis. circRNA formation is dependent on ALU elements or flanking inverted repetitive sequences to promote circularization by base-pairing across different introns (32). Notably, ciRNA biogenesis requires a key motif consisting of both a 7-nt GU-rich element near the 5′ splice site and an 11-nt C-rich element near the branch point site (33). The third model is called RBP-binding driven circularization, as RBP has an important function in initiating circRNA formation via regulation of adjacent splice site (34). Finally, the fourth model is known as intron-splicing-driven circularization; the pre-tRNA is identified and spliced by the tRNA splicing nuclease complex to remove the excised tRNA introns, which then release and ligate the intron termini to form a tRNA and a tricRNA (35,36).

Figure 2.

Four main models of circRNA biogenesis. (A) Intron-pairing-driven circularization: ALU elements or flanking inverted repeats form circRNA by intron pairing and the formation of EIciRNAs or ecircRNAs occurs as introns are removed or retained. (B) Lariat-driven circularization. Upstream 3′ splice site joins with a downstream 5′ splice site, resulting in exon-skipping to form an RNA lariat consisting of multiple exons and introns and leads to formation of EIciRNA, ecircRNA and ciRNA. (C) RBP-binding-driven circularization: RBPs interact with the flanking intronic sequence to form EIciRNA or ecircRNA. (D) Intron-splicing-driven circularization: Pre-tRNAs are synthesized from introns; excised tRNA introns deriving from pre-tRNAs are removed by tRNA splicing enzymes and ligate the released end to form tRNA and tricRNA. This image was originally published in a study by Wen et al (36). circRNA, circular RNA; EIciRNA, exon-intron circRNA; ecircRNA, exonic circRNA; tricRNA, tRNA intronic circRNA; ciRNA, circular intronic RNA; RBP, RNA-binding protein.

Biological functions of circRNAs

To date, the majority of biological functions attributed to circRNAs remain largely incompletely understood. circRNA has a multitude of reported functions, which include serving as a miRNA and protein sponge and transcriptional regulator, and can be translated into protein (Fig. 3).

Figure 3.

Biological functions of circRNAs. circRNAs can (A) sponge miRNAs, (B) act as protein sponges, (C) regulate host gene transcription by interacting with U1snRNPs and then binding to Pol II, (D) compete with canonical pre-mRNA splicing to facilitate alternative splicing and (E) encode proteins or peptides, acting as templates for translation. circRNA, circular RNA; miRNA, microRNA; RBP, RNA-binding protein; Pol II, polymerase II; U1snRNPs, U1 small nuclear ribonucleoproteins.

MicroRNA (miRNA/miR) and protein sponges

circRNAs can bind miRNAs to inhibit their function as competitive endogenous RNAs or miRNA sponges (37). An example of this is circRNA Cdr1as (also known as ciRS-7), which was first reported to function as a sponge of miR-7, containing >70 conserved miR-7 binding sites, and thereby significantly decreasing miR-7 levels when its expression is increased (3,38). Similarly, another established example is circSRY, which is derived from the sex-determining region of the Y chromosome and is composed of 16 binding sites for miR-138 and specifically expressed in the testis (39). Furthermore, numerous studies have demonstrated that circRNAs can function as miRNA sponges. For example, circHIPK3 can regulate cell proliferation by functioning as a sponge of miR-124, inhibiting its expression (20). circNT5E can directly bind miR-422a, acting as a sponge to regulate cell proliferation, migration and invasion in glioblastoma (40). Yang et al (41) has reported that circAmotl1 can bind with c-myc to induce c-myc nuclear translocation and prevent c-myc mRNA degradation, ultimately promoting tumorigenesis.

Studies have shown that circRNAs can also act as a protein or RBP sponge. For example, circMbl, which is derived from the second exon of muscleblind (Mbl), contains the binding sites for the Mbl protein; circMb1 is able to directly bind with Mbl to regulate Mbl expression by competing with conventional pre-mRNA splicing, thereby decreasing the levels of Mbl and in turn affecting the formation of circMbl (26,42). The human antigen R (HuR) protein is an RBP, which is indispensable for promoting the translation of the mRNAs (43).

circPABPN1 has been found to compete with poly(A) binding protein nuclear 1 (PABPN1) mRNA to prevent HuR from binding with PABPN1 mRNA, suppressing its translation (44). circFoxo3, which has recently received increasing attention, has been found to be primarily located in the cytoplasm, where it has been demonstrated to serve as an adaptor bridging p21 and cyclin-dependent kinase 2 (CDK2) (45). Moreover, circFoxo3 can repress cell cycle progression via interaction with p21 and CDK2 to establish a circFoxo3/p21/CDK2 ternary complex inducing cell cycle regulation (45). Additionally, a recent study has revealed that circCcnb1 can interact with both CCNB1 and CDK1 proteins to suppress migration, invasion and proliferation of HTB126 cells (46).

circRNAs as transcriptional regulators

Zhang et al (28) has found that both circRNAs ci-ankrd52 and ci-sirt7 can combine with RNA Pol II in cis, and positively enhance the transcriptional activity of the host genes. Similarly, Li et al (47) has revealed that circEIF3J and circPAIP2 can interact with U1 small nuclear ribonucleic proteins to form a complex, and then bind to Pol II at the promoter region of the host genes to regulate transcription of their host genes. It has been suggested that circRNAs are involved in the regulation of alternative splicing. In 1998, Chao et al (48) reported that the Fmn gene could produce a circRNA via back splicing. In another example, a circRNA from SEPALLATA3 (SEP3) gene regulates splicing of its host SEP3 mRNA via formation of the R-loop, resulting in the suspension of host gene transcription (49). Similar observations have also been attributed to circITCH, which is involved in the regulation of the expression of its host gene (ITCH) indirectly, via sponging its targets miR-1, miR-17 and miR-214 (50).

Translation

As circRNAs lack a 5′-cap and a 3′-end, they were initially shown to not possess protein encoding capacity. However, emerging evidence has indicated that circRNAs may function as a template for translation or synthesis of proteins or peptides (51).

circRNAs were first suggested to possess protein encoding capacity if the sequence contained an internal ribosome entry site (IRES), in a study published in 1995 (52). A subsequent study revealed that circZNF609 could translate proteins in murine myoblasts when driven by IRES in a splicing-dependent and cap-independent manner, which indicated that circRNAs exhibited protein-coding capacity (53). Yang et al (54) demonstrated that circFBXW7 could be translated into a novel 21-kDa functional protein [FBXW7-185 amino acids (aa) and its expression was negatively associated with glioblastoma. Another study reported that circSHPRH contained an open reading frame and encoded a 17-kDa protein (SHPRH-146aa) driven by IRES (55). Furthermore, both circSHPRH and SHPRH-146aa expression was decreased in glioblastoma, thereby suppressing cell proliferation and tumorigenesis (55). In addition, a more recent study by Yang et al (56) demonstrated that N-methyladenosine, the most frequent RNA modification, could promote efficient initiation of protein translation from circRNAs. circPINT, which is derived from exon 2 of long intergenic non-protein coding RNA p53-induced transcript (LINC-PINT), can translate proteins, termed PINT87aa encoded by the circular, but not the linear, form of LINC-PINT (57). Whether these translatable circRNAs serve a physiological function remains to be experimentally investigated and confirmed.

circHIPK3 and human diseases

circHIPK3 and prostate cancer (PC)

PC is a common malignancy of the urinary system and is a leading cause of cancer-associated death in men (58). Cai et al (59) revealed that circHIPK3 expression was upregulated in PC tissues and cells. Overexpression of circHIPK3 accelerated the proliferation and invasiveness of PC cells by sponging miR-338-3p to regulate ADAM17 expression (59). This result provides a potentially novel preventative and therapeutic target for the management of PC. Similarly, Chen et al (60) illustrated that circHIPK3 mediates miR-193a-3p/MCL1 signaling to promote cell proliferation and invasion of PC.

circHIPK3 and lung cancer (LC)

LC is a major health threat and the largest cause of cancer-associated death worldwide (61). Studies have revealed that circHIPK3 exerts oncogenic properties in LC. Yu et al (62) reported that circHIPK3 regulated the expression levels of sphingosine kinase 1, CDK4 and STAT3 by acting as a miR-124 sponge in LC. Recently, Lu et al (63) assessed the clinical significance of circHIPK3 in patients with primary non-small cell LC (NSCLC). Further study (63) demonstrated that circHIPK3 induced cell proliferation and inhibited apoptosis in NSCLC by sponging miR-149, indirectly increasing FOXM1 expression. Similarly, Hong et al (64) confirmed that circHIPK3 promoted NSCLC progression via a circHIPK3/miR-107/brain-derived neurotrophic factor (BDNF) axis, highlighting potential markers for NSCLC screening. A study by Chen et al (65) demonstrated that circHIPK3 functioned as an oncogene, and loss of circHIPK3 significantly impaired cell proliferation, migration and invasion, and induced protective autophagy via a miR-124-3p/STAT3/protein kinase AMP-activated catalytic subunit a2/AMPKa axis in serine/threonine kinase 11-mutant LC cell lines (A549 and H838; Fig. 4). Overall, the aforementioned results highlight the potential prognostic and therapeutic value of circHIPK3 in LC.

Figure 4.

Schematic hypothesis of the regulation of autophagy by circHIPK3. This image was originally published in a study by Chen et al (65). (A) Lung cancer A549 and H838 cells carried a STK11 mutation and lower STK11 copy number and protein expression to silence circHIPK3-induced autophagy, mainly by decreasing pSTAT3 and increasing pPRKAA signaling. (B) H1299 carried wild-type STK11 to silence circHIPK3-induced autophagy, mainly by decreasing STK11-pPRKAA. p, phosphorylated; STK11, serine/threonine kinase 11; PRKAA, protein kinase AMP-activated catalytic subunit α2; circHIPK3, circular RNA homeodomain-interacting protein kinase 3; MIR, microRNA; IL6R, IL-6 receptor.

circHIPK3 and colorectal cancer (CRC)

CRC is the most common gastrointestinal malignant disease, which ranks third in incidence and second in mortality amongst all types of cancer (66). In 2018, a study by Zeng et al (21) was the first study to reveal an association between circHIPK3 and CRC. circHIPK3 was shown to function as an oncogene, resulting in the proliferation, migration and invasion of CRC cells, whilst decreasing apoptosis (21). Furthermore, circHIPK3 expression was upregulated in CRC by sponging miR-7 to sequester and inhibit miR-7 activity, suggesting that circHIPK3 may have value as a prognostic biomarker in CRC (21). Similarly, another study demonstrated that circPIK3 expression was upregulated in CRC cells and further promoted migration, invasion and proliferation of CRC cells by sponging miR-1207-5p, which directly targeted formin-like 2 (FMNL2) (67). These results suggest that circHIPK3 may modulate a miR-1207-5p/FMNL2 axis, highlighting a potentially novel strategy in the management of CRC.

circHIPK3 and gastric cancer (GC)

GC is the leading cause of malignant tumor-associated mortality worldwide and is the most common type of digestive tract cancer, accounting for a third of tumor-associated deaths (68). circHIPK3 has been reported to be involved in GC progression by sponging miR-124 and miR-29b to regulate its target genes collagen type I α1 chain (COL1A1), COL4A1 and CDK6 (69). circHIPK3-knockdown inhibits GC cell proliferation (69). Subsequently, Wei et al (70) confirmed that circHIPK3 was upregulated in GC and associated with clinical stage and grade of GC. Furthermore, circHIPK3-knockdown suppressed the proliferation and migration of GC cells via a circHIPK3/miR-107/BDNF axis. Upregulation of circHIPK3 is associated with a poor prognosis, and thus it may serve as a potential target for GC treatment (70).

circHIPK3 and bladder cancer (BC)

BC is the most common type of tumor of the urinary system and the 9th most frequently diagnosed malignant cancer in the world (71). Recently, Li et al (72) identified thousands of differentially expressed circRNAs between human BC tissues and normal control bladder tissues using RNA sequencing. circHIPK3 is significantly downregulated in BC tissues and cell lines by sponging miR-558 and further suppressing the expression of heparanase. Furthermore, overexpression of circHIPK3 significantly decreased invasion, metastasis and angiogenesis of BC cells, suggesting that circHIPK3 was negatively associated with BC grade (72). circHIPK3 may thus function as a tumor suppressor. Additionally, Xie et al (73) found that circHIPK3 expression was low in BC tissue and its overexpression promoted gemcitabine sensitivity in patients with BC.

circHIPK3 and nasopharyngeal carcinoma (NPC)

NPC is a common malignant tumor in humans, which occurs in the head region (74). In 2018, Ke et al (75) revealed that circHIPK3 expression was higher in NPC tissues and cell lines compared with in normal tissues and cells. circHIPK3 overexpression enhanced tumor cell proliferation, and when circHIPK3 expression was silenced or depleted, proliferation, migration and invasion were significantly decreased in vitro (75). Thus, circHIPK3 seemed to possess an oncogenic role in NPC. Further analyses revealed that circHIPK3 acted as a sponge to negatively regulate miR-4288 expression, which in turn targeted E74-like ETS transcription factor 3 (ELF3), thereby increasing ELF3 expression (75).

circHIPK3 and gallbladder cancer (GBC)

GBC is an aggressive and lethal malignancy of the bile duct, and patients often have a poor prognosis (76). In 2018, Kai et al (77) found that circHIPK3 expression in human GBC cells was higher than that in gallbladder epithelial cells. Apoptosis was induced when circHIPK3 expression was knocked down using a small interfering RNA, which potently inhibited survival and proliferation of established and primary human GBC cells. It was further demonstrated that circHIPK3 acted as a sponge of miR-124, ultimately increasing the expression of miR-124 targets (Rho-associated coiled-coil containing protein kinase 1 and CDK6) and decreasing the activity of miR-124 in GBC cells (77).

circHIPK3 and hepatocellular carcinoma (HCC)

HCC is the 5th leading type of cancer and the most lethal type of carcinoma worldwide (78). circHIPK3 is significantly upregulated in HCC, where it promotes cell proliferation, highlighting its role as an oncogene (79). Chen et al (79) demonstrated that circHIPK3 regulated HCC via a circHIPK3/miR124/aquaporin 3 (AQP3) axis. Notably, circHIPK3 was upregulated in HCC cells and promoted cell proliferation and migration by sponging miR-124 and regulating AQP3 expression (79).

circHIPK3 and osteosarcoma (OS)

OS is the most common type of primary bone cancer, and is more likely to occur in children and adolescents (80). A recent study by Xiao-Long et al (81) revealed that circHIPK3 expression was significantly downregulated in OS cell lines and tissues, and its low expression was associated with a poor prognosis. Functional analysis revealed that downregulated circHIPK3 expression resulted in a shorter OS cell survival time, whereas overexpression of circHIPK3 suppressed proliferation, migration and invasion of OS cells (81). These results suggest that circHIPK3 expression levels may negatively regulate cell behavior and thus that circHIPK3 may be used as a biomarker for OS detection.

circHIPK3 and glioma

Glioma is the most malignant tumor of the adult brain (82). Emerging evidence has revealed that circHIPK3 is associated with glioma, where it functions as an oncogene. For example, circHIPK3 accelerates tumor growth in glioma by sponging miR-124-3p, resulting in upregulation of STAT3 expression (83). Jin et al (84) demonstrated that circHIPK3 overexpression significantly promoted the malignant behaviors of glioma cells, increasing proliferation and invasion by sponging miR-654 via a circHIPK3/miR-654/IGF2BP3insulin-like growth factor 2 mRNA binding protein 3 axis, suggesting circHIPK3 may serve as a potential therapeutic target for the treatment of patients with glioma.

circHIPK3 and epithelial ovarian cancer (EOC)

OC is the most fatal gynecological cancer amongst women and has a death rate of 60% in Asia (85). Teng et al (86) investigated the expression profiles of circRNAs between EOC and normal ovarian tissues using RNA sequencing, revealing that circHIPK3 expression was significantly downregulated in EOC. Moreover, silencing of circHIPK3 promoted the proliferation, migration and invasion of OC cells, suggesting that circHIPK3 may be an important regulator of OC progression, where it exerts a tumor-suppressive function (86).

circHIPK3 and oral squamous cell carcinoma (OSCC)

OSCC is one of the top 10 most common types of cancer of the head and neck worldwide (87). Wang et al (88) analyzed circHIPK3 expression and its clinical significance in OSCC, and its association with miR-124 expression. circHIPK3 expression in OSCC tissues was significantly higher compared with that of the adjacent non-cancerous tissues. Moreover, miR-124 expression in OSCC tissues was significantly lower compared with that in precancerous tissues. Further correlation analysis revealed that circHIPK3 expression negatively regulated miR-124 expression, and silencing of circHIPK3 expression decreased the proliferation of OSCC cells (88). The aforementioned findings suggest that circHIPK3 may contribute to the occurrence and development of OSCC by regulating miR-124 expression.

circHIPK3 and chronic myeloid leukemia (CML)

CML is caused by a reciprocal translocation in chromosomes, and accounts for 15% of reported cases of leukemia (89). Feng et al (90) investigated the expression profile of circHIPK3 in CML, revealing that its expression was significantly upregulated in peripheral blood mononuclear cells and serum samples from CML compared with in healthy normal samples. Further experiments demonstrated that loss-function of circHIPK3 promoted CML progression, indicating that circHIPK3 may serve as a prognostic biomarker (90).

circHIPK3 and age-related cataracts (ARC)

ARC is the leading cause of visual impairment and blindness worldwide (91). Recently, Liu et al (92) reported that circHIPK3 regulated human lens epithelial cell (HLEC) function via a circHIPK3/miR-193a/crystallin αA regulatory network. Furthermore, knockdown of circHIPK3 affected the viability, apoptosis and proliferation of HLECs, suggesting a potential role of circHIPK3 in ARC formation (92). These findings highlight a potentially novel targeted method for the prevention and treatment of ARC.

circHIPK3 and preeclampsia

Preeclampsia, a devastating multisystem syndrome, is becoming an increasingly common disease worldwide, and is associated with a high rate of pregnancy-associated morbidity and mortality (93). Zhang et al (94) first explored the possible role of dysregulated circHIPK3 expression and its potential contribution to the pathogenesis of preeclampsia. It was revealed that circHIPK3 was significantly downregulated in preeclampsia compared with healthy pregnant controls. circHIPK3 silencing inhibited the migration, invasion, proliferation and tube formation capacities of HTR8/SVneo cells, and circHIPK3 overexpression significantly promoted these capacities, excluding proliferation.

circHIPK3 and pancreatic cancer (PCa)

PCa is a malignant tumor of the digestive system with a low probability of incidence (95). circHIPK3 is expressed in pancreatic tissues (96). Liu et al (97) revealed that circHIPK3 expression was upregulated in PCa tissues and was associated with GEM-resistant PCa tissues and cells. Moreover, circHIPK3 exerted its function by enhancing GEM resistance in PCa cells by sponging miR-330-5p, resulting in upregulation of Ras association domain family member 1, ultimately regulating PCa cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT) and apoptosis (97).

circHIPK3 and acute pancreatitis (AP)

AP is a dangerous disease with a high mortality rate (98). Wang et al (99) revealed that circHIPK3 expression was closely associated with inflammation in AP. Silencing its expression inhibited the release of IL-1β and TNF-α (99). Additionally, a recent study demonstrated that circHIPK3 expression was upregulated in the serum of patients compared with AP and in caerulein-stimulated AR42J cells (100). Furthermore, it was revealed that circHIPK3 sponged miR-193a-5p to negatively regulate its expression. Gasdermin D (GSDMD) is a target gene of miR-193a-5p, and is a key gene involved in pyroptosis. Thus, silencing miR-193a-5p reversed the effects of GSDMD. These findings suggest that circHIPK3 may promote pyroptosis and inflammation via regulation of the miR-193a-5p/GSDMD axis in AR42J cells (100).

circHIPK3 and cardiac fibrosis (CF)

CF is a common pathological process that often results in death (101). Ni et al (102) revealed that circHIPK3 promoted the proliferation and migration of cardiac fibroblasts in CF. Furthermore, circHIPK3 expression was markedly increased in CF and heart tissues following treatment with angiotensin II (Ang II). Inhibition of circHIPK3 prevented Ang II-induced CF by sponging miR-29b-3p. The silencing of circHIPK3 effectively reversed miR-29b-3p-induced promotion of CF function and influenced the expression levels of genes targeted by miR-29b-3p (α-smooth muscle actin, COL1A1 and COL3A1), suggesting that circHIPK3 may exhibit potential as a targeted therapy for the management of CF (102).

circHIPK3 and allergic rhinitis (AR)

AR is the most common allergic disease affecting individuals of various demographics worldwide (103). circHIPK3 and long non-coding RNA (lncGAS5) were shown to promote differentiation of T helper 2 cells and aggravate AR via modulating their common target miR-495 (104). Moreover, intranasal administration of circHIPK3/lncGAS5 knockdown lentivirus resulted in a decrease in AR symptoms by downregulating GATA binding protein 3 expression, highlighting a potential therapeutic means for AR management (104).

circHIPK3 and renal cancer (RC)

RC is one of the most common malignant tumors of the urinary system, and the incidence of RC is increasing worldwide (105). Recently, Lai et al (106) revealed that circHIPK3 exerted an oncogenic role, and its expression was upregulated in RC tissues and cells. Additionally, it was shown to promote proliferation and migration, and inhibit the apoptosis of RC cells by competitively binding with miR-485-3p, in-turn indirectly increasing the expression levels of Bcl-2, N-cadherin, vimentin and Ki-67 (106). circHIPK3-knockdown inhibited the proliferation, migration and invasion of RC cells (106). These results provide a promising basis for the molecular-targeted therapy of patients with RC. circHIPK3 may serve as a tumor suppressor in RC progression. Li et al (107) found that the overexpression of circHIPK3 significantly inhibited RC cell invasion and migration in vitro, and it repressed proliferation of RC cells in vitro and in vivo. Additionally, another study by Han et al (108) demonstrated that circHIPK3 promoted clear cell RC cell proliferation and migration by altering miR-5083p/CXCL13 signaling, highlighting a potentially novel target for the molecular treatment of clear cell RC.

circHIPK3 and cervical cancer (CC)

CC is the most common malignancy in women worldwide with >400,000 new cases of CC diagnosed each year (109). Recently, Qian et al (110) investigated the function of circHIPK3 and its clinical application in CC. circHIPK3 functioned as a sponge of miR-338-3p, resulting in upregulation of hypoxia-inducible factor (HIF)-1α expression, and thus promoting CC cell proliferation and EMT, resulting in tumorigenesis (110). miR-338-3p silencing or HIF-1α overexpression rescued circHIPK3-knockdown-mediated inhibition or induction of apoptosis in CC cells (110). These findings may serve as a basis in the search for a promising treatment strategy by highlighting the role of the circHIPK3/miR-338-3p/HIF-1α axis in CC.

circHIPK3 and thyroid cancer (TC)

TC is one of the most common endocrine malignancies globally, and it originates from follicular or parafollicular thyroid cells (111). Recently, Shu et al (112) investigated the effects of circHIPK3 on the proliferation of TC cells and migration of TC. It was revealed that circHIPK3 acted as an oncogenic circRNA in TC, promoting tumorigenesis and invasiveness of TC by sponging miR-338-3p, in turn upregulating the expression of its target gene RAB23. Knockdown of circHIPK3 significantly decreased the migration, invasion and proliferation of TC cells (112). These results suggest that circHIPK3 may serve as a novel biomarker for the diagnosis and prognosis of TC.

circHIPK3 and breast cancer (BRC)

BRC is one of the most common malignant types of cancer amongst women and is the leading cause of cancer-associated death worldwide (113). BRC is a major disease threatening female health, affecting >7% of women in >100 countries (114). Chen et al (115) revealed that circHIPK3 expression was upregulated in BRC, where it facilitated cell proliferation, migration and invasion by targeting miR-193a. Furthermore, overexpression of circHIPK3 enhanced high mobility group box 1/PI3K/AKT signaling, highlighting circHIPK3 as a novel potential therapeutic target for BRC management.

Conclusions and future perspectives

circRNAs have attracted increasing attention over the last decade. In recent years, with the advancement of high throughput RNA sequencing technologies and the rapid development of bioinformatics tools, a large number of circRNAs have been discovered and identified in various organisms. With the efforts of scientists and the application of novel biological methods, the potential role of circRNAs in biological functions is being elucidated. Given the large number of different circRNAs and their potential tissue-specific functions, an in-depth understanding of the complex networks in which they participate and regulate should be developed.

circHIPK3 has been reported to be involved in various human diseases, including different types of cancer. Dysregulation of circHIPK3 has been observed in a range of diseases and cancerous tissues, where it has been shown to exhibit notable effects on cell cycle progression, cell proliferation, apoptosis, invasion and migration in cancer, suggesting that circHIPK3 may possess significant value as a molecular biomarker for the diagnosis, prognosis and monitoring of diseases. The vital physiological and pathological functions of circHIPK3 in diseases are listed in Table I. circHIPK3 has been described as both a tumor suppressor and an oncogene. Currently, due to the technical limitations of available methods, the role of circHIPK3 in cancer and various diseases remains to be further elucidated. miRNA sponging is one of the primary mechanisms by which circHIPK3 exerts its different functions in various diseases. Thus, further studies are required to extensively explore the interaction network of circHIPK3 in cancer and diseases, including the involvement of miRNAs, lncRNAs, mRNAs and protein degrading pathways. Whether there are other regulatory mechanisms or if they possess other functions should be further studied.

Table I.

Functional roles of circHIPK3 in different types of cancer and diseases.

First author, year	Disease	Expression	Functional roles	Target miRs and genes	Refs.
Cai et al, 2019; Chen et al, 2019	Prostate cancer	Up	Proliferation and invasion	miR-338-3p/ADAM17; miR-193a-3p/MCL1	(59,60)
Yu et al, 2018; Lu et al, 2020; Hong et al 2020; Chen et al, 2020	Lung cancer	Up	Viability, proliferation and apoptosis	miR-124/SphK1, STAT3, CDK4; miR-149/FOXM1 miR-107/BDNF miR-124-3p/STAT3, PRKAA, AMPKa	(62–65)
Yan et al, 2020	Colorectal cancer	Up	Proliferation, migration, invasion and apoptosis	miR-1207-5p/FMNL2	(67)
Cheng et al, 2018; Wei et al, 2020	Gastric cancer	Down	Unknown	miR-124, miR-29b/COL1A1, COL4A1, CDK6, WNT1	(69,70)
		Up	Proliferation and migration	miR-107/BDNF TCF4, β-catenin
Li et al, 2017	Bladder cancer	Down	Migration, invasion, angiogenesis and metastasis	miR-558/HPSE, VEGF	(72)
Ke et al, 2019	Nasopharyngeal carcinoma	Up	Proliferation, migration and invasion	miR-4288/ELF3	(75)
Kai et al, 2018	Gallbladder cancer	Up	Viability, proliferation and apoptosis	miR-124/ROCK1, CDK6, miR-29b	(77)
Chen et al, 2018	Hepatocellular carcinoma	Up	Proliferation and migration	miR-124/AQP3	(79)
Xiao-Long et al, 2018	Osteosarcoma	Down	Proliferation, migration and invasion	miR-7/miR-124	(81)
Hu and Zhang, 2019; Jin et al, 2018	Glioma	Up	Proliferation, migration and invasion	miR-654/IGF2BP3, miR-124-3p/STAT3	(83,84)
Teng et al, 2019	Epithelial ovarian cancer	Up	Unknown	Unknown	(86)
Wang et al, 2018	Oral squamous cell carcinoma	Up	Proliferation	miR-124	(88)
Feng et al, 2020	Chronic myeloid leukemia	Up	Unknown	Unknown	(90)
Liu et al, 2018	Age-related cataract	Down	Viability, proliferation and apoptosis	miR-193a/CRYAA	(92)
Zhang et al, 2019)	Preeclampsia	Down	Migration, invasion and proliferation	Unknown	(94)
Liu et al, 2020	Pancreatic cancer	Up	Proliferation, invasion, migration and apoptosis	miR-330-5p/RASSF1	(97)
Wang et al, 2020	Acute pancreatitis	Up	Infiltration	miR-193a-5p/GSDMD	(100)
Ni et al, 2019	Cardiac fibrosis	Up	Proliferation and migration	miR-29b-3p/a-SMA, COL1A1, COL3A1	(102)
Zhu et al, 2020	Allergic rhinitis	Up	Unknown	miR-495	(104)
Lai et al, 2020; Li et al, 2020; Han et al, 2020	Renal cancer	Up	Proliferation and migration	miR-485-3p/Bcl-2, N-cadherin, vimentin, Ki-67, miR-5083P/CXCL13	(106–108)
Qian et al, 2020	Cervical cancer	Up	Proliferation	miR-338-3p/HIF-1α	(110)
Shu et al, 2020	Thyroid cancer	Up	Proliferation, migration and invasion	miR-338-3p/RAB23	(112)
Chen et al, 2020	Breast cancer	Up	Proliferation, migration and invasion	miR-193a/HMGB1/PI3K/AKT	(115)

circHIPK3, circular RNA homeodomain-interacting protein kinase 3; miR, microRNA; CDK, cyclin-dependent kinase; BDNF, brain-derived neurotrophic factor; ROCK1, Rho-associated coiled-coil containing protein kinase 1; ELF3, E74-like ETS transcription factor 3; AQP3, aquaporin 3; IGF2BP3, insulin-like growth factor 2 mRNA binding protein 3; CRYAA, crystallin aA; RASSF1, Ras association domain family member 1; GSDMD, gasdermin D; COL1/3/4A1, collagen type I/III/IV a1 chain; a-SMA, α-smooth muscle actin; HIF-1α, hypoxia-inducible factor 1α; HMGB1, high mobility group box 1; PRKAA, protein kinase AMP-activated catalytic subunit a2; U1snRNPs, U1 small nuclear ribonucleoproteins; IL6R, IL6 receptor; TCF-4, R cell factor 4; HPSE, heparanase; U1snRNPs, U1 small nuclear ribonucleoproteins.

The exact mechanisms by which circHIPK3 regulates pathological processes remain unclear in certain diseases, such as EOC, CML, AR and preeclampsia. Future studies should explore any other potential mechanisms and functions of circHIPK3. To the best of our knowledge, there is no preclinical evidence for the application of circHIPK3 as a target or molecular targeted therapeutic tool for cancer treatment. Based on the findings described in the present review, it may be suggested that circHIPK3 may serve as a predictive biomarker and therapeutic target with clinical promise in the future.