Next Article in Journal
Characteristic of Concurrent Uterine Lipoleiomyoma and Hemangioma by Algorithm of Candidate Biomarkers for Uterine Mesenchymal Tumor
Next Article in Special Issue
N6-methyladenosine Modification of Noncoding RNAs: Mechanisms and Clinical Applications in Cancer
Previous Article in Journal
Associations between Bone Mineral Density and Longitudinal Changes of Vertebral Bone Marrow and Paraspinal Muscle Composition Assessed Using MR-Based Proton Density Fat Fraction and T2* Maps in Patients with and without Osteoporosis
Previous Article in Special Issue
Increased Expression of Pyroptosis in Leukocytes of Patients with Kawasaki Disease
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Diagnostics
Volume 12
Issue 10
10.3390/diagnostics12102469
diagnostics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Diagnostic and Therapeutic Role of Circular RNA HIPK3 in Human Diseases

by
Yanfei Feng
1,†,
Zitong Yang
2,†,
Bodong Lv
3,* and
Xin Xu
4,*
1
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
2
Department of Urology, The Fourth Affiliated Hospital, Zhejiang University; Hangzhou 322000, China
3
Department of Urology, The Second Affiliated Hospital, Zhejiang University; Hangzhou 310009, China
4
Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Diagnostics 2022, 12(10), 2469; https://doi.org/10.3390/diagnostics12102469
Submission received: 14 September 2022 / Revised: 5 October 2022 / Accepted: 9 October 2022 / Published: 12 October 2022
(This article belongs to the Special Issue The Diagnostic and Therapeutic Value of RNAs in Human Diseases)
Browse Figures
Review Reports Versions Notes

Abstract

:
Circular RNAs (circRNAs) are a class of noncoding RNAs with closed-loop of single-stranded RNA structure. Although most of the circRNAs do not directly encode proteins, emerging evidence suggests that circRNAs play a pivotal and complex role in multiple biological processes by regulating gene expression. As one of the most popular circRNAs, circular homeodomain-interacting protein kinase 3 (circHIPK3) has frequently gained the interest of researchers in recent years. Accumulating studies have demonstrated the significant impacts on the occurrence and development of multiple human diseases including cancers, cardiovascular diseases, diabetes mellitus, inflammatory diseases, and others. The present review aims to provide a detailed description of the functions of circHIPK3 and comprehensively overview the diagnostic and therapeutic value of circHIPK3 in these certain diseases.

1. Introduction

During the past few decades, an enormous number of studies have outlined the complex regulatory networks of various RNAs in multiple human diseases [1]. Generally, according to whether they encode proteins or not, RNAs are divided into two types—protein-encoding messenger RNAs (mRNAs) and noncoding RNAs. Noncoding RNAs, as the name indicates, cannot directly encode proteins, yet account for approximately 98% of the total transcriptome and play a pivotal role in gene expression [2]. In recent years, the understanding of noncoding RNAs has gradually deepened, with the development of sequencing technologies and bioinformatics [3], notably insights into the mechanisms of different noncoding RNAs in cell biology.
Circular RNAs (circRNAs), one of the hottest noncoding RNAs currently studied, exist in the form of a continuous closed loop. Initially, they were mistaken as meaningless byproducts of RNA splicing. Nonetheless, recent studies have shown that their significance is underestimated. First, advanced sequencing and bioinformatics tools have uncovered the fact that circRNAs are endogenously abundant [4]. Distinguished with linear RNAs, circRNAs have a more conservative and stable structure, with neither a 5′ cap nor a 3′ poly A tail, making these molecules more tolerable to degradation by exonucleases [5]. Evidence indicates that the majority of circRNAs are present in the cytoplasm of eukaryotic cells. Moreover, the widespread but discrepant expression of circRNAs in various organs and cells suggests that they may participate in multiple crucial physiological and pathological processes [6,7].
Actually, the regulatory functions of circRNAs in gene expression are diverse and complicated. In most cases, circRNAs bind specific microRNAs (miRNA) and act as competitive endogenous RNAs (ceRNAs) or so-called “miRNA sponges” [8]. In addition, circRNAs have the opposite abilities to act as miRNA reservoirs, stabling and activating some other miRNAs. Furthermore, circRNAs are reported to bear relevance to gene expression both upstream and downstream in three aspects. First, it has been reported that circRNAs may correlate with RNA polymerases to regulate the transcription complex. Second, another regulation pattern called “back-splicing” can be initiated by circRNAs to inhibit linear splicing. Third, circRNAs can interact with RNA-binding proteins (RBPs) to act as protein antagonists [9]. Counterintuitively, although it is conventionally believed that circRNAs are not equipped with encoding capabilities, some studies have illustrated that certain circRNAs might encode proteins if internal ribosome entry sites (IRESs) exist in their structures [10].
Circular homeodomain-interacting protein kinase 3 (circHIPK3), which originates from the second exon of the HIPK3 gene, is an eye-catching molecule among all the circRNAs [11]. Plenty of studies have demonstrated the biogenesis of circHIPK3 and its vital roles in the progression of multiple human diseases, including cancers, cardiovascular diseases, inflammatory diseases, diabetes mellitus, etc. [12,13]. This review aims to provide a more detailed description of the functions of circHIPK3 and a more comprehensive overview of its diagnostic and therapeutic values in some of the aforementioned diseases.

2. Biogenesis of circHIPK3

The HIPK3 gene is an important member of the nuclear kinases HIPK family, in addition to HIPK1, HIPK2, and HIPK4 [14], located on chromosome 11p13 of humans. The results of genomic sequencing reveal that circHIPK3 consists of exon 2 with 1099bq flanked on both sides by two long introns with highly complementary Alu repeats, which are considered as the key elements in the process of intron-pairing driven circularization [11,15]. The circularization of circHIPK3 was reported to be dependent on the canonical spliceosome mechanisms in HeLa cells, and the flanking introns could mediate the efficiency of circularization [16]. A study on Drosophila revealed that the biogenesis of some circRNAs, including circHIPK3, could be co-modulated by cis-acting elements and trans-acting splicing factors such as heterogeneous nuclear ribonucleoproteins (hnRNPs) and SR proteins [17]. Intriguingly, scientists illustrated that double-stranded RNA (dsRNA)-specific adenosine deaminase (ADAR) enzymes also play an important role in circRNA formation [18]. The regulation of circRNA production is complicated. Although the regulatory networks of the biogenesis of circRNAs have not been fully elucidated [19], it can be determined that circRNAs, including circHIPK3, are ubiquitous in a variety of tissues including brain, heart, lung, etc. [20]. Figure 1 depicts the biogenesis of circHIPK3.

3. The Role of circHIPK3 in Human Cancers

Accumulating studies have substantiated that the dysregulation of circHIPK3 contributes to multiple processes in the carcinogenesis and progression of various human cancers [21]. Not only does this molecule play a pivotal role in the proliferation, migration, invasion, and drug resistance of tumor cells, but also it has the potential to act as a biomarker in early diagnosis and prognosis [22], considering that in most cases, circHIPK3 is a tumor promoter by sponging miRNAs. Table 1 displays the expression status, the regulatory targets, and the associated functions of circHIPK3 in human cancers.

3.1. Lung Cancer (LC)

As one of the most life-threatening human malignancies, lung cancer has been a global challenge during the past years [23]. Several published reports have provided us some novel clues of the occurrence and progression of LC mediated by overexpressed circHIPK3. Yu and colleagues elucidated that enriching circHIPK3 facilitated the expression of sphingosine kinase 1 (SphK1), cyclin-dependent kinase 4 (CDK4), and signal transducer and activator of transcription 3 (STAT3) through impeding miR-124 in lung cancer cells, and accelerating LC cell growth [24]. Chen et al. also illustrated another signaling pathway mediated by circHIPK3/miR-124-3p. STAT3 was reported to be the downstream target of miR-124-3p in this case [25]. Lu and others explored another miRNA which was involved in the carcinogenesis and progression of nonsmall-cell lung cancer (NSCLC) mediated by circHIPK3. Their research revealed that circHIPK3 negatively regulated miR-149, promoting forkhead box M1 (FOXM1) expression. Eventually, cell proliferation was triggered when apoptosis was blocked [26]. MiR-107 was introduced by Hong and colleagues indicating that circHIPK3 downregulated miR-107, reversing its inhibitive effect on brain-derived neurotrophic factor (BDNF), which facilitated NSCLC progression [27]. However, Zhao et al. observed a lower expression level of circHIPK3 in LC specimens compared with surrounding nontumor tissues. Moreover, patients with lower circHIPK3 were more likely to have larger tumor size, more advanced TNM stage, and more lymph node infiltration. Further experiments on gefitinb-resistant cell line revealed that low circHIPK3 contributed to gefitinib resistance [28].

3.2. Hepatocellular Carcinoma (HCC)

HCC is a common malignancy with high recurrence and mortality rate around the world [23]. An augmented level of circHIPK3 in HCC was validated in several studies. Chen and colleagues observed that the increased level of circHIPK3 was positively associated with Aquaporin 3 (AQP3) expression in HCC specimens. Mechanistically, miR-124 was considered as an intermediate link between circHIPK3 and AQP3. Intriguingly, the aberrant expression of circHIPK3 was closely correlated with several clinical parameters such as tumor stage, the amount of HBV–DNA copy and the existence of liver cirrhosis in patients with HCC [29]. MiR-124 was also confirmed as the target of circHIPK3 in other studies. Yu et al. observed that the upregulation of circHIPK3 was associated with depletion of miR-124 and miR-506. Pyruvate dehydrogenase kinase 2 (PDK2) was reported to be the downstream target of miR-124 or miR-506. The circHIPK3-miR-124/miR506-PDK2 signaling gave rise to carcinogenesis and progression of HCC cells [30]. Hu and others demonstrated the expression of miR-124-3p and miR-4524-5p was inhibited by circHIPK3, promoting multidrug-resistant protein 4 (MRP4) expression. Although their findings suggested MRP4 was not directly involved in occurrence and progression of HCC, MRP4 itself was proved to be aberrantly overexpressed in multiple cancers [31]. Another miRNA involved in the association between circHIP3 and HCC was miR-338-3p introduced by Li et al. Similarly, circHIPK3 served as the sponge of miR-338-3p, hindering zinc finger E-box binding homeobox 2 (ZEB2) expression. This signaling eventually led to epithelial–mesenchymal transition (EMT) and HCC metastasis [32].

3.3. Esophageal Squamous Cell Carcinoma (ESCC)

ESCC is a malignancy of the digestive system which severely affects quality of life [23]. Yao et al. reported that an elevated level of circHIKP3 in ESCC cells remarkably absorbed miR-599 expression and significantly stimulated c-MYC expression, leading to cell growth and metastasis [33]. Yao and colleagues validated that miR-124 functioned as the sponged miRNA in this case and serine/threonine kinase 3 (AKT3) was enhanced under the modulation of circHIPK3, which further triggered ESCC cell growth and metastasis [34].

3.4. Gastric Cancer (GC)

The incidence of GC has been gradually escalating during the past decades [23]. Most of the emerging studies demonstrated an overexpression of circHIPK3 in GC cells. Cheng et al. discovered that circHIPK3 was even higher in metastatic GC cells. They further unveiled the underlying mechanisms that circHIPK3 suppressed the expression of miR-29b and miR-124, enhancing GC cell replication. Furthermore, this signaling pathway was considered to be a prognostic factor of GC [35]. Wei et al. elucidated the connections between circHIPK3 (level, stage, grade) and the prognosis of GC. Knocking down circHIPK3 significantly extenuated GC progression by upregulating miR-107 and then depleted brain-derived neurotrophic factor (BDNF) [36]. Another miRNA introduced by Li and others was miR-876-5p. Their research showed that circHIPK3 sponged miR-876-5p, reversing its inhibitive effects on phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), an oncogene proved to exist in multiple tumors, including GC [37]. A study conducted by Jin et al. illustrated that circHIPK3 contributed to metastatic disease of GC by downregulating miR-653-5p and miR-338-3p. Neuropilin 1 (NRP1) was determined as the inhibited target downstream of these two molecules and its depletion stimulated extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways [38]. Yang et al. observed another regulatory pathway in which circHIPK3 suppressed miR-637, rescuing the function of serine/threonine kinase 1 (AKT1) sabotaged by miR-637 and then enhancing GC cell progressive activities [39]. Liu and colleagues observed that silencing circHIPK3 decreased GC cell proliferation and migration. The Wnt/β-catenin pathway was considered as the intermediate factor of this process [40]. However, Ghasemi and colleagues arrived at a contrary conclusion, that a dramatically decreased level of circHIPK3 in GC was proved to be associated with patient age and clinical stage [41]. The conflicting conclusions drawn by different scientists made the role of circHIPK3 in GC more complicated.

3.5. Colorectal Cancer (CRC)

CRC is another most common gastrointestinal cancer which hugely affects quality of life [23]. A study organized by Zeng et al. clarified that an augmented level of circHIPK3 in CRC cells blocked miR-7 expression and then contributed not only to the activation of cell proliferation and metastasis, but also inhibits cell apoptosis [42]. Yan et al. also discovered an increase in circHIPK3 level in CRC cells. Another miRNA was introduced by them, miR-1207-5p, which was negatively regulated by circHIPK3 and whose inhibitive effects on formin-like 2 (FMNL2) were relieved. This signaling pathway consequently resulted in CRC cell replication and metastasis [43]. Zhang et al. explored the oxaliplatin-resistant mechanisms of CRC and demonstrated that circHIPK3 acted as the sponge of miR-637 to enhance STAT3 expression, triggering Bcl-2/beclin1 afterward, and as a result detecting decreased autophagy. Additionally, they observed connections between an elevated level of circHIPK3 and clinical indicators of poor prognosis [44].

3.6. Prostate Cancer (PCa)

The incidence of PCa ranks first in men [23], in which an unregulated level of circHIPK3 was validated in several studies. In the research of Chen et al., circHIPK3 was identified as a crucial factor of prognosis. Via sponging miR-193a-3p, circHIPK3 promoted myeloid cell leukemia 1 (MCL1) expression, and activated PCa cell growth and tumor progression [45]. Cai and colleagues demonstrated that the enrichment of circHIPK3 stimulated the proliferation and invasion of PCa cells by impeding miR-338-3p and strengthening a disintegrin and metalloproteinases 17 (ADAM17) expression [46]. Another study by Liu et al. identified other downstream molecules of miR-338-3p as Cdc2 and Cdc25B and this signaling pathway modulated by circHIPK3 led to acceleration of G2/M transition and the proliferation of PCa cells [47]. Liu and others uncovered another pathway mediated by circHIPK3 in which circHIPK3 downregulated miR-448 to activate metadherin (MTDH), thus accelerating PCa cell proliferation and metastasis [48]. Tang et al. identified an overexpression of exosomal circHIPK3 in PCa, which suppressed exosomal miR-212 and relieved its negative modulation on B-cell-specific MMLV insertion site-1 (BMI-1), consequently activating cell growth and metastasis [49].

3.7. Renal Cell Carcinoma (RCC)

RCC is one of the urinary cancers with high prevalence [23]. Lai and colleagues detected that an elevated expression of circHIPK3 in RCC cells blocked the function performed by miR-485-3p on several molecules related to EMT and cell death. For example, the overexpression of clever caspase-3, Bax, and E-Cadherin was hampered and the decrease in Vimentin, N-Cadherin, and Bcl-2 was reversed [50]. Han et al. verified that by hindering expression of miR-508-3p, the increased level of circHIPK3 boosted RCC cell viability. The downstream target of miR-5083p was determined as chemokine ligand 13 (CXCL13), whose activation was also validated to be associated with several cancers [51]. Omata and others discovered an upstream regulator of circHIPK3 as adenosine deaminase acting on RNA 1 (ADAR1), which could inhibit circHIPK3 and then activate miR -381-3p, so as to block the translation process of MRP4 protein, a factor which was clarified to be related with drug resistance [52]. On the contrary, Li et al. elaborated that circHIPK3 was sharply diminished in RCC cells, and that lifting circHIPK3 expression repressed the invasiveness of RCC cells by hampering miR-637 [53].

3.8. Bladder Cancer

Bladder cancer is another frequently diagnosed cancer of the urinary system [23]. Compared with other malignancies, circHIPK3 tended to be downregulated in bladder cancer cells. Li et al. showed that circHIPK3 expression was negatively associated with clinical stage, invasiveness, and lymph node infiltration in bladder cancer patients. Mechanistically, circHIPK3 sponged miR-558 to hinder heparanase (HPSE) expression, reducing the development of bladder cancer cells [54]. Xie and colleagues clarified the prognostic value of circHIPK3 in bladder cancer and illustrated that an elevated expression of circHIPK3 enhanced the response to gemcitabine chemotherapy [55]. Remarkably, the analysis conducted by Okholm et al. demonstrated that circHIPK3 was rigidly related with aggressiveness in nonmuscle-invasive bladder cancer, further highlighting the prognostic role of circHIPK3 in bladder cancer [56].

3.9. Breast Cancer

Breast cancer has created onerous economic and social burden owing to its high prevalence in females [23]. Qi and colleagues along with Luo et al. detected an aberrantly elevated expression of circHIPK3 in breast cancer. The downstream target of circHIPK3 was considered to be miR-326, and the depletion of miR-326 mediated by circHIPK3 resulted in cell replication, migration, and invasion of breast cancer [57,58]. Shi et al. demonstrated that an upregulated circHIPK3 targeted miR-124-3p to boost MTDH expression, facilitating angiogenic activities of breast cancer cells [59]. Chen et al. identified miR-193a as another target of circHIPK3. Further, the signaling pathway went downstream to high mobility group box-1 (HMGB1)/phosphoinositide-3-kinase (PI3K)/AKT and the proliferative and metastatic abilities of breast cancer cells were enhanced as a consequence [60]. Zhang et al. offered deep insight into the mechanisms of trastuzumab resistance in breast cancer and discovered that exosomal circHIPK3 was capable of lowering the sensitivity of breast cancer cells to trastuzumab [61]. A study managed by Ni and colleagues revealed another phenomenon of chemoresistance in which circHIKP3 overexpression suppressed miR-1286 to enhance hexokinase 2 (HK2) expression and decreased the response to paclitaxel treatment in breast cancer cells [62].

3.10. Ovarian Cancer (OC)

OC is not uncommon in the female genital system [23]. Liu et al. uncovered that circHIPK3 expression was hugely increased in OC tissues and cell lines, which was considered to correlate with unfavorable outcomes of OC [63] as well. However, Teng and colleagues detected a reduction in circHIPK3 level in OC cells. CircHIPK3 depletion was validated to stimulate cell growth, invasion, and migration, on the one hand, and, on the other, prevent cell death. A number of miRNAs, such as miR-10a, miR-106a, and miR-148b, were assumed to be modulated in this process, but exactly which miRNAs were inhibited remained elusive [64].

3.11. Cervical Cancer (CC)

Cervical cancer, one of the most common genital cancers in postmenopausal women, usually causes poor outcomes [23]. Wu and colleagues observed a dramatically upregulated status of circHIPK3 in CC cells. The miRNA sponged by circHIPK3 was reported to be miR-485-3p, and its depletion accelerated fibroblast growth factor 2 (FGF2) expression, strengthening the tumorigenic and progressive abilities of CC cells [65]. Qian et al. validated miR-338-3p as another molecule inhibited by circHIPK3. Accordingly, hypoxia-inducible factor-1alpha (HIF-1α) activated and triggered EMT to stimulate CC cell proliferation, migration, and invasion [66].

3.12. Osteosarcoma

Osteosarcoma is a type of severe disease frequently diagnosed in youngsters [23]. Huang and colleagues demonstrated an augmented expression of circHIPK3 in osteosarcoma cells, which downregulated miR-637, relieved its negative regulation on STAT3, and caused osteosarcoma cell metastasis [67]. Similarly, Wen et al. introduced another signaling pathway in which circHIPK3 mediated osteosarcoma progression by decreasing miR-637 to facilitate histone deacetylase 4 (HDAC4) expression [68]. However, Ma et al. observed a strikingly decreased level of circHIPK3 in osteosarcoma cells and specimens, which correlated with an advanced stage, distant metastasis, and unfavorable prognosis. While a higher circHIPK3 expression dramatically declined aggressiveness of tumor cells [69], the contradictory conclusions obtained by these studies requires further exploration.

3.13. Glioma

With unfavorable prognosis, glioma is one of the most malignant tumors in the central nervous system [23]. Emerging published reports clarified an increased level of circHIPK3 in glioma cells. Jin et al. validated that circHIPK3 promoted insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) expression by blocking miR-654, which expanded the proliferative and metastatic capabilities of glioma cells [70]. Hu and colleagues demonstrated that a high expression level of circHIPK3 significantly suppressed miR-124-3p to rescue its negative effects on STAT3. This pathway had a promotive influence on tumorigenesis and progression of glioma cells [71]. Another target of circHIPK3/miR-124 interaction determined by Liu et al. was cyclin D2 (CCND2), which again spurred the development of glioma [72]. CircHIPK3 was also considered to be inextricably bound with temozolomide treatment of glioma, and two signaling pathways were introduced by scientists. One study of Han et al. verified that exosomal circHIPK3 reduced the sensitivity to temozolomide treatment via absorbing the effect of miR-421 and triggering zinc finger of the cerebellum 5 (ZIC5) expression [73]. The other study conducted by Yin and colleagues identified miR-524-5p as the direct target of circHIPK3 and kinesin family member 2A (KIF2A) the downstream molecule [74].

3.14. Oral Squamous Cell Carcinoma (OSCC)

OSCC is a particularly severe malignant tumor with poor outcomes that occurs in the regions of head and neck [23]. Bi et al. uncovered the enhanced expression of circHIPK3 in OSCC and clarified its further target molecule as miR-381-3p. Yes-associated protein1 (YAP1) was determined to be the downstream factor whose upregulation stimulated the carcinogenesis and progression of OSCC cells [75]. Similarly, the findings of Jiang et al. suggested that miR-637 was negatively modulated by augmented circHIPK3, triggering nuclear protein 1 (NUPR1) and PI3K/AKT pathway to activate OSCC cell growth and metastasis [76].

3.15. Leukemia

The incidence of leukemia has been increasing during the past years [23]. Feng et al. found that circHIPK3 was enormously overexpressed in the blood cells and serum of chronic myeloid leukemia (CML), suggesting a worse outcome [77]. Similarly, Gaffo and colleagues detected an abnormally increased expression of circHIPK3 in acute lymphoblastic leukemia (ALL) cells, which provided novel findings in this issue [78].

3.16. Other Cancers

Apart from those mentioned, there have been connections between circHIPK3 and other cancers including nasopharyngeal cancer (NPC), pancreatic cancer, thyroid cancer, gallbladder cancer (GBC), melanoma, and glioblastoma. Ke et al. revealed an augmented expression of circHIPK3 in NPC and a dramatically declined miR4288 expression. Mechanistically, circHIPK3 blocked miR4288 in order to boost the expression of E74-like ETS transcription factor 3 (ELF3), and promote NPC cell growth [79]. In terms of pancreatic cancer, Liu and colleagues demonstrated that the overexpression of circHIPK3 remarkably downregulated miR-330-5p-activated RAS-association domain family 1 (RASSF1) expression, stimulating the carcinogenesis and progression and becoming immune to gemcitabine therapy of pancreatic cancer cells [80]. Shu et al. showed an aberrantly increased circHIPK3 level in thyroid cancer cells and identified miR- 338-3p as the downstream sponged factor. Ras-like in rat brain 23 (RAB23) was enhanced under the modulation of circHIPK3, which contributed to tumorigenesis and progression of thyroid cancer cells [81]. Regarding GBC, circHIPK3 expression was found significantly higher in GBC cells by Kai and colleagues. MiR-124 was considered to be sharply suppressed by circHIPK3, escalating the expression of rho-associated protein kinase 1 (ROCK1) and cyclin-dependent kinase 6 (CDK6), which caused the accelerated growth of GBC cells [82]. Zhu et al. observed that circHIPK3 was remarkably overexpressed in melanoma cells and the downstream target molecule was confirmed to be miR-215-5p, the depletion of which significantly triggered Yin Yang 1 (YY1) expression and thereby expedited cell growth and mitigated cell death of melanoma [83]. Stella and colleagues discovered correlations between the reduction in circHIPK3 in serum extracellular vesicle and the prognosis of glioblastoma and suggested that circHIPK3 could possibly serve as a promising biomarker [84].

4. The Role of circHIPK3 in Cardiovascular Disease

Cardiovascular disease, a global health burden, is a class of disease that seriously affects quality of life and survival [85]. A genomic analysis verified the profile of circRNAs in the human heart and showed that the expression of circHIPK3 ranked third in healthy hearts [86]. A few studies explored the possible functions of circHIPK3 in the biology of cardiomyocytes after myocardial infarction (MI). Si et al. revealed circHIPK3 was strikingly expressed in fetal mice and silencing circHIPK3 significantly impeded proliferation of cardiomyocytes. Additionally, circHIPK3 was validated to accelerate angiogenic activities by enhancing the abilities to proliferate and form tubular structure of vessel endothelial cells. Furthermore, circHIPK3 might alleviate cardiac fibrosis by stabilizing and activating Notch1 intracellular domain (N1ICD), and then stimulate functions of endothelia cells by sponging miR-33a to facilitate connective tissue growth factor (CTGF) expression [87]. Wang and colleagues demonstrated that exosomal circHIPK3 of hypoxic cardiomyocytes dramatically expedited the proliferative and migrative abilities of cardiac endothelial cells, which was considered to be possibly conducive to minimizing the infarction region. Mechanistically, circHIPK3 depleted miR-29a and thereby promoted VEGFA expression [88]. However, Wu et al. obtained an opposite conclusion that knocking down circHIPK3 in MI cell models remarkably suppressed miR-93-5p expression to deactivate Rac1/PI3K/AKT signaling pathway, shrinking infarction area and protecting cardiomyocytes [89]. Concerning cardiac fibrosis, Liu et al. observed the level of circHIPK3 in cardiac fibroblasts was conspicuously raised under low oxygen circumstances. Overexpressed circHIPK3 strengthened TGF-β2 signaling pathway by hampering miR-152-3p so as to accelerate the process of fibrosis [90]. Liu et al. along with Ni and colleagues also demonstrated that silencing circHIPK3 contributed to retard cardio fibrosis triggered by angiotensin II [91,92]. Ni and colleagues further discovered the miRNA sponged by circHIPK3 as miR-29b-3p in their study [92]. CircHIPK3 was validated to be associated with ischemia-reperfusion (IR) injury of cardiomyocytes as well. Bai et al. found that by negatively regulating miR-124-3p, circHIPK3 overexpression decreased proliferation and stimulated death of cardiomyocytes in IR models [93]. Cheng and colleagues observed that under high-glucose conditions, circHIPK3 was downregulated by overexpressed miR-29a, and this interaction went downstream to AKT3/PIK3R3 pathway, enhancing the anti-apoptosis of cardiomyocytes and preventing cardiomyocytes from IR injury [94]. Some other studies focused on the role of circHIPK3 in hypoxia-reoxygenation (HR) injury of cardiomyocytes. Qiu et al. clarified that augmented circHIPK3 notably triggered autophagy and cell death of cardiomyocytes suffering HR injury. They also identified miR-20b-5p/autophagy-related 7 (ATG7) pathway modulated by circHIPK3 involved in IR injury of cardiomyocytes [95]. Exosomal circHIPK3 was considered by Wang et al. to have the potential to diminish oxidative injury of cardiac microvascular endothelial cells by abolishing miR-29a and thereby promoting expression of insulin-like growth factor-1 (IGF-1) [96]. Additionally, some studies reported new findings of circHIPK3 in pathophysiology of other cardiovascular diseases. For example, Wei et al. validated that circHIPK3 declined in atherosclerosis models and its overexpression showed pro-autophagy effects through sponging miR-190b, thereby relieving ATG7 [97]. Similarly, Zhang et al. enhanced the expression of circHIPK3 in atherosclerosis models and observed miR-106a-5p was negatively modulated when mitofusin 2 (MFN2) was stimulated. Intriguingly, calcium content was dramatically diminished in vascular smooth muscle cells (VSMC) [98]. Kang et al. knocked down circHIPK3 in VSMC and proliferative activities were consequently extenuated. Mechanistically, circHIPK3 hampered miR-637 expression and silenced CDK6 expression in VSMC [99]. Fan and colleagues illustrated that silencing circHIPK3 was able to mitigate myocarditis in mice and cell models caused by lipopolysaccharide [100]. Deng et al. verified that circHIPK3 could possibly be detrimental to patients with heart failure because it enhanced the function of adrenaline in the long term [101]. Xu et al. demonstrated that knocking down circHIPK3 in cardiac hypertrophy models preconditioned by transverse aortic constriction (TAC) and angiotensin II could improve the heart functions because it blocked miR-185-3p [102].

5. The Role of circHIPK3 in Diabetes Mellitus (DM) and Its Complications

DM is a major worldwide health issue caused by multiple elements such as genes, environment, and epigenetic factors [103]. Rezaeinejad et al. discovered that circHIPK3 level was highly elevated in Type 2 DM and circHIPK3 was associated with HbA1c, fasting blood glucose, etc. [104]. Liu and colleagues detected an overexpressed circHIPK3 in the kidney specimens of diabetic nephropathy mice and cell models. Mechanistically, circHIPK3 impeded miR-185 function and facilitated expression of cyclin D1, proliferating cell nuclear antigen (PCNA), TGF-β1, collagen Ⅰ, and fibronectin, and compounded diabetic nephropathy [105]. Wang et al. silenced aberrantly overexpressed circHIPK3 in diabetic cardiomyopathy models and found that the fibrosis of cardiomyocytes sharply decreased. Further, they identified miR-29b-3p as the target of circHIPK3 and Col1a1 as well as Col3a1, the downstream molecules [106]. CircHIPK3 was also reported by Cai et al. to be involved in hyperglycemia and insulin insensitivity via hampering miR-192-5p and stimulating transcription factor forkhead box O1 (FOXO1) [107]. Wang and colleagues clarified that overexpressed circHIPK3 silenced miR-124, escalating the degree of neuropathic pain induced by DM in mice [108]. Shan et al. verified that highly expressed circHIPK3 in retinal vascular silenced miR-30a-3p and strengthened the functions of vascular endothelial growth factor-C, Frizzled-4 (FZD4), and WNT2, aggravating the damage to vascular endothelial cells [109]. Wang et al. found an aberrantly elevated exosomal circHIPK3 in aortic endothelial cells of mice, strongly downregulating miR-106a-5p and stimulating expression of forkhead box O1 (Foxo1), which as a consequence expedited proliferation of vascular smooth muscle cells under high-glucose circumstances [110]. On the other hand, despite the harmful overexpression of circHIPK3 as mentioned above, several studies found the opposite answers. For instance, Cao et al. described a diminished level of circHIPK3 in the endothelial cells of the umbilical vein and primary aortic in human DM. CircHIPK3 depletion exacerbated the injury of endothelial cells by targeting miR-124 [111]. Zhuang et al. observed that the enhancement of circHIPK3 expression was capable of extenuating DM-induced renal tubular epithelial cell injury by decreasing miR-326 or miR-487a-3p to boost Sirtuin 1 (SIRT1) function [112]. Jiang et al. revealed that upregulation of circHIPK3 exerted its anti-apoptotic functions on cardiomyocytes by negatively mediating PTEN in diabetic cardiomyopathy [113].

6. The Role of circHIPK3 in Inflammatory Diseases

The pathophysiological mechanisms of different inflammatory diseases vary considerably. CircHIPK3 was confirmed to play a pivotal role in the occurrence of inflammation in a few human diseases. Wu et al. discovered that circHIPK3 level was remarkably lifted in cartilage specimens of human osteoarthritis, negatively targeting miR-124 and stimulating SRY-box transcription factor 8 (SOX8) expression. Consequently, the proliferation of chondrocytes was notably promoted in osteoarthritis [114]. Li et al. observed a similar signaling pathway but reached a different conclusion. Mechanistically, circHIPK3 originating from extracellular vesicles alleviated chondrocyte damage by blocking miR-124-3p to enrich the expression of myosin heavy-chain 9 (MYH9) [115]. In gouty arthritis, Lian and colleagues elucidated that circHIPK3 was enriched in mononuclear cells of synovial fluid, which strikingly repressed miR-561 and miR-192, and thereby facilitated pro-inflammatory functions of toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) [116]. Zhu et al. demonstrated that circHIPK3 expression obviously escalated along with lncGAS5 in allergic rhinitis mice models. Through silencing miR-495, the two molecules sparked Th2 differentiation and resulted in deterioration of allergic rhinitis [117]. In spinal cord injury (SCI), Yin et al. found that circHIPK3 was sharply diminished in SCI cell models and circHIPK3 overexpression attenuated inflammation and neuron death by downregulating miR-382-5p and then strengthened dual specificity phosphatase 1 (DUSP1) expression [118].

7. The Role of circHIPK3 in Other Human Diseases

7.1. Asthma

Airway remodeling plays an essential role in the occurrence and development of asthma [119]. Lin et al. detected an augmented expression of circHIPK3 in airway smooth muscle cells (ASMCs). In this condition, miR-326 was proved to be inhibited by circHIPK3 and its downstream factor stromal interaction molecule 1 (STIM1) was activated. As a consequence, proliferation and migration of ASMCs was accelerated, whereas apoptosis was retarded under this modulation [120]. Jiang and colleagues revealed another signaling pathway induced by circHIPK3 in which miR-375, as the target factor, was silenced by circHIPK3 and then the expression of matrix metallopeptidase 16 (MMP-16) was upregulated, resulting in escalation of proliferation and migration in ASMCs [121].

7.2. Osteoporosis

Osteoporosis is an age-related disease which seriously affects daily movement of the elderly [122]. Liang et al. showed that circHIPK3 decreased in osteoporosis models, and that enhancing expression of circHIPK3 significantly abolished miR-124 and prevented human osteoblasts from apoptosis caused by hydrogen peroxide [123]. Similarly, Zhu and colleagues reported that circHIPK3 overexpression had protective effects on osteoblasts injured by dexamethasone, in which miR-124 also participated [124].

7.3. Cataract

Cataract is a common disease of ophthalmology that has become a global burden in the past decades [125]. Cui et al. along with Liu et al. validated that circHIPK3 level declined in human lens epithelium cells (HLECs) and overexpressed circHIPK3 preserved the viability of HLECs. Mechanistically, the former verified that circHIPK3 overexpression absorbed miR-221-3p and stimulated PI3K/AKT pathway, whilst the latter demonstrated that elevated circHIPK3 diminished miR-193a and expedited alpha A crystallin (CRYAA) expression [126,127].

8. Conclusions

In parallel with the rapid advancement of RNA-sequencing and bioinformatics tools, scientists have gained deeper understanding of the specific roles that circRNAs play in human diseases. During the past decade, this has been particularly demonstrated in the gradually clarified biogenesis and expression of circRNAs in various organs and tissues, and the huge amount of circRNAs identified. Still, their regulatory network is rather complicated.
circHIPK3, a member of the circRNA family, has grabbed increasing attention from scientists. Accumulating studies are now trying to set forth the pathophysiological effects of circHIPK3 in a wide range of human diseases, including multiple malignancies, cardiovascular diseases, DM, inflammatory diseases, and others. Emerging evidence demonstrates that circHIPK3, the same as other circRNAs, mainly acts as the so-called “miRNA sponge”, and that the circHIPK3/miRNA/protein regulatory network is the basic modulation mode of circHIPK3. Figure 2 highlights the miRNAs that can be sponged by circHIPK3.
After comprehensively reviewing published reports, we summarized and integrated the role of circHIPK3 in human diseases. In the new concept of early diagnosis and early treatment of human cancers, the exploration of novel tumor biomarkers is of great importance. CircHIPK3 would be an ideal choice because it is abnormally expressed in an enormous range of different tumor cells. In other human diseases, as mentioned above, circHIPK3 can serve as the biomarker used for early warning of pathophysiological changes and prediction of prognosis. With the development of RNA detection technologies, we are optimistic that the detection of circHIPK3 will be applied in clinical practice. More importantly, the vast majority of preclinical experiments demonstrate the landscape of circHIPK3/miRNA/protein regulatory networks in a variety of human diseases. It has been verified that circHIPK3 plays a significant role in cell biology, not only in tumors but also in other diseases. Therefore, we reasonably predict that drugs targeting circHIPK3 may have a promising clinical application prospect and will further promote the individualized and precise treatment of human diseases in the future.
At the same time we noticed that some issues in this area still need further exploration. For instance, more efforts ought to be devoted to improving and enriching the regulatory mechanisms of circHIPK3, because contradictory conclusions have been reached by several similar studies regarding the expression and functions of circHIPK3 in diseases such as GC, osteosarcoma, and MI.
In conclusion, circHIPK3, despite its pending issues, has the potential to become a diagnostic biomarker and therapeutic target in clinical practice in the days to come.

Author Contributions

Z.Y. and X.X., conception of the study; Y.F. and Z.Y., manuscript drafting; B.L. and X.X., manuscript revision; Y.F. and Z.Y. contributed equally to this work. X.X. and B.L. are the co-corresponding authors. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82172597), Zhejiang Provincial Natural Science Foundation (LY22H160027), and Beijing Bethune Charitable Foundation.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Cooper, T.A.; Wan, L.; Dreyfuss, G. RNA and disease. Cell 2009, 136, 777–793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Boley, N.; Stoiber, M.H.; Booth, B.W.; Wan, K.H.; Hoskins, R.A.; Bickel, P.J.; Celniker, S.E.; Brown, J.B. Genome-guided transcript assembly by integrative analysis of RNA sequence data. Nat. Biotechnol. 2014, 32, 341–346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Ozsolak, F.; Milos, P.M. RNA sequencing: Advances, challenges and opportunities. Nat. Rev. Genet. 2011, 12, 87–98. [Google Scholar] [CrossRef] [PubMed]
  4. Jeck, W.R.; Sharpless, N.E. Detecting and characterizing circular RNAs. Nat. Biotechnol. 2014, 32, 453–461. [Google Scholar] [CrossRef]
  5. Memczak, S.; Jens, M.; Elefsinioti, A.; Torti, F.; Krueger, J.; Rybak, A.; Maier, L.; Mackowiak, S.D.; Gregersen, L.H.; Munschauer, M.; et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013, 495, 333–338. [Google Scholar] [CrossRef] [PubMed]
  6. Lee, E.C.S.; Elhassan, S.A.M.; Lim, G.P.L.; Kok, W.H.; Tan, S.W.; Leong, E.N.; Tan, S.H.; Chan, E.W.L.; Bhattamisra, S.K.; Rajendran, R.; et al. The roles of circular RNAs in human development and diseases. Biomed. Pharmacother. 2019, 111, 198–208. [Google Scholar] [CrossRef] [PubMed]
  7. Lei, K.; Bai, H.; Wei, Z.; Xie, C.; Wang, J.; Li, J.; Chen, Q. The mechanism and function of circular RNAs in human diseases. Exp. Cell Res. 2018, 368, 147–158. [Google Scholar] [CrossRef]
  8. Shao, Q.; Huang, Y.; Zhang, C.; Gao, X.; Gao, S. Emerging landscape of circHIPK3 and its role in cancer and other diseases. Mol. Med. Rep. 2021, 23, 409. [Google Scholar] [CrossRef]
  9. Chen, X.; Yang, T.; Wang, W.; Xi, W.; Zhang, T.; Li, Q.; Yang, A.; Wang, T. Circular RNAs in immune responses and immune diseases. Theranostics 2019, 9, 588–607. [Google Scholar] [CrossRef]
  10. Xie, Y.; Yuan, X.; Zhou, W.; Kosiba, A.A.; Shi, H.; Gu, J.; Qin, Z. The circular RNA HIPK3 (circHIPK3) and its regulation in cancer progression: Review. Life Sci. 2020, 254, 117252. [Google Scholar] [CrossRef]
  11. Zheng, Q.; Bao, C.; Guo, W.; Li, S.; Chen, J.; Chen, B.; Luo, Y.; Lyu, D.; Li, Y.; Shi, G.; et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat. Commun. 2016, 7, 11215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Wen, J.; Liao, J.; Liang, J.; Chen, X.-P.; Zhang, B.; Chu, L. Circular RNA HIPK3: A Key Circular RNA in a Variety of Human Cancers. Front. Oncol. 2020, 10, 773. [Google Scholar] [CrossRef] [PubMed]
  13. Zhou, J.; Wang, B.; Bin, X.; Xie, C.; Li, B.; Liu, O.; Tang, Z. CircHIPK3: Key Player in Pathophysiology and Potential Diagnostic and Therapeutic Tool. Front. Med. 2021, 8, 615417. [Google Scholar] [CrossRef] [PubMed]
  14. Zhang, Y.; Liu, Q.; Liao, Q. CircHIPK3: A promising cancer-related circular RNA. Am. J. Transl. Res. 2020, 12, 6694–6704. [Google Scholar] [PubMed]
  15. Jeck, W.R.; Sorrentino, J.A.; Wang, K.; Slevin, M.K.; Burd, C.E.; Liu, J.; Marzluff, W.F.; Sharpless, N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats. Rna 2013, 19, 141–157. [Google Scholar] [CrossRef] [Green Version]
  16. Starke, S.; Jost, I.; Rossbach, O.; Schneider, T.; Schreiner, S.; Hung, L.-H.; Bindereif, A. Exon Circularization Requires Canonical Splice Signals. Cell Rep. 2015, 10, 103–111. [Google Scholar] [CrossRef] [Green Version]
  17. Kramer, M.C.; Liang, D.; Tatomer, D.C.; Gold, B.; March, Z.M.; Cherry, S.; Wilusz, J.E. Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev. 2015, 29, 2168–2182. [Google Scholar] [CrossRef] [Green Version]
  18. Ivanov, A.; Memczak, S.; Wyler, E.; Torti, F.; Porath, H.T.; Orejuela, M.R.; Piechotta, M.; Levanon, E.Y.; Landthaler, M.; Dieterich, C.; et al. Analysis of Intron Sequences Reveals Hallmarks of Circular RNA Biogenesis in Animals. Cell Rep. 2015, 10, 170–177. [Google Scholar] [CrossRef] [Green Version]
  19. Kristensen, L.S.; Andersen, M.S.; Stagsted, L.V.W.; Ebbesen, K.K.; Hansen, T.B.; Kjems, J. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 2019, 20, 675–691. [Google Scholar] [CrossRef]
  20. Zhang, L.; Wang, Y.; Yu, F.; Li, X.; Gao, H.; Li, P. CircHIPK3 Plays Vital Roles in Cardiovascular Disease. Front. Cardiovasc. Med. 2021, 8, 733248. [Google Scholar] [CrossRef]
  21. Fu, Y.; Sun, H. Biogenesis, cellular effects, and biomarker value of circHIPK3. Cancer Cell Int. 2021, 21, 256. [Google Scholar] [CrossRef] [PubMed]
  22. Wenzhe, G.; Jiahao, X.; Cheng, P.; Hongwei, Z.; Xiao, Y. Circular RNA HIPK3 is a Prognostic and Clinicopathological Predictor in Malignant Tumor Patients. J. Cancer 2020, 11, 4230–4239. [Google Scholar] [CrossRef] [PubMed]
  23. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef] [PubMed]
  24. Yu, H.; Chen, Y.; Jiang, P. Circular RNA HIPK3 exerts oncogenic properties through suppression of miR-124 in lung cancer. Biochem. Biophys. Res. Commun. 2018, 506, 455–462. [Google Scholar] [CrossRef] [PubMed]
  25. Chen, X.; Mao, R.; Su, W.; Yang, X.; Geng, Q.; Guo, C.; Wang, Z.; Wang, J.; Kresty, L.A.; Beer, D.G.; et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer. Autophagy 2020, 16, 659–671. [Google Scholar] [CrossRef] [PubMed]
  26. Lu, H.; Han, X.; Ren, J.; Ren, K.; Li, Z.; Sun, Z. Circular RNA HIPK3 induces cell proliferation and inhibits apoptosis in non-small cell lung cancer through sponging miR-149. Cancer Biol. Ther. 2020, 21, 113–121. [Google Scholar] [CrossRef]
  27. Hong, W.; Zhang, Y.; Ding, J.; Yang, Q.; Xie, H.; Gao, X. circHIPK3 Acts as Competing Endogenous RNA and Promotes Non-Small-Cell Lung Cancer Progression through the miR-107/BDNF Signaling Pathway. BioMed Res. Int. 2020, 2020, 6075902. [Google Scholar] [CrossRef]
  28. Zhao, Y.; Zhang, C.; Tang, H.; Wu, X.; Qi, Q. Mechanism of RNA circHIPK3 Involved in Resistance of Lung Cancer Cells to Gefitinib. BioMed Res. Int. 2022, 2022, 4541918. [Google Scholar] [CrossRef]
  29. Chen, G.; Shi, Y.; Liu, M.; Sun, J. circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma. Cell Death Dis. 2018, 9, 175. [Google Scholar] [CrossRef] [Green Version]
  30. Yu, Q.; Chen, W.; Li, Y.; He, J.; Wang, Y.; Yang, S.; Zhou, J. The novel circular RNA HIPK3 accelerates the proliferation and invasion of hepatocellular carcinoma cells by sponging the micro RNA-124 or micro RNA-506/pyruvate dehydrogenase kinase 2 axis. Bioengineered 2022, 13, 4717–4729. [Google Scholar] [CrossRef]
  31. Hu, H.; Wang, Y.; Qin, Z.; Sun, W.; Chen, Y.; Wang, J.; Wang, Y.; Nie, J.; Chen, L.; Cai, S.; et al. Regulation of MRP4 Expression by circHIPK3 via Sponging miR-124-3p/miR-4524-5p in Hepatocellular Carcinoma. Biomedicines 2021, 9, 497. [Google Scholar] [CrossRef] [PubMed]
  32. Li, W.; Xue, H.; Li, Y.; Li, P.; Ma, F.; Liu, M.; Kong, S. HIPK3 Circular RNA Promotes Metastases of HCC Through Sponging miR-338-3p to Induce ZEB2 Expression. Dig. Dis. Sci. 2021, 66, 3439–3447. [Google Scholar] [CrossRef] [PubMed]
  33. Ba, Y.; Liu, Y.; Li, C.; Zhu, Y.; Xing, W. HIPK3 Promotes Growth and Metastasis of Esophageal Squamous Cell Carcinoma via Regulation of miR-599/c-MYC Axis. Onco Targets Ther. 2020, 13, 1967–1978. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Yao, D.; Lin, S.; Chen, S.; Wang, Z. circHIPK3 regulates cell proliferation and migration by sponging microRNA-124 and regulating serine/threonine kinase 3 expression in esophageal squamous cell carcinoma. Bioengineered 2022, 13, 9767–9780. [Google Scholar] [CrossRef] [PubMed]
  35. Cheng, J.; Zhuo, H.; Xu, M.; Wang, L.; Xu, H.; Peng, J.; Hou, J.; Lin, L.; Cai, J. Regulatory network of circRNA-miRNA-mRNA contributes to the histological classification and disease progression in gastric cancer. J. Transl. Med. 2018, 16, 216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Wei, J.; Xu, H.; Wei, W.; Wang, Z.; Zhang, Q.; De, W.; Shu, Y. circHIPK3 Promotes Cell Proliferation and Migration of Gastric Cancer by Sponging miR-107 and Regulating BDNF Expression. OncoTargets Ther. 2020, 13, 1613–1624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Li, Q.; Tian, Y.; Liang, Y.; Li, C. CircHIPK3/miR-876-5p/PIK3R1 axis regulates regulation proliferation, migration, invasion, and glutaminolysis in gastric cancer cells. Cancer Cell Int. 2020, 20, 391. [Google Scholar] [CrossRef]
  38. Jin, Y.; Che, X.; Qu, X.; Li, X.; Lu, W.; Wu, J.; Wang, Y.; Hou, K.; Li, C.; Zhang, X.; et al. CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment. Front. Oncol. 2020, 10, 1612. [Google Scholar] [CrossRef]
  39. Yang, D.; Hu, Z.; Zhang, Y.; Zhang, X.; Xu, J.; Fu, H.; Zhu, Z.; Feng, D.; Cai, Q. CircHIPK3 Promotes the Tumorigenesis and Development of Gastric Cancer Through miR-637/AKT1 Pathway. Front. Oncol. 2021, 11, 637761. [Google Scholar] [CrossRef]
  40. Liu, W.G.; Xu, Q. Upregulation of circHIPK3 promotes the progression of gastric cancer via Wnt/beta-catenin pathway and indicates a poor prognosis. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 7905–7912. [Google Scholar]
  41. Ghasemi, S.; Emadi-Baygi, M.; Nikpour, P. Down-regulation of circular RNA ITCH and circHIPK3 in gastric cancer tissues. Turk. J. Med. Sci. 2019, 49, 687–695. [Google Scholar] [CrossRef] [PubMed]
  42. Zeng, K.; Chen, X.; Xu, M.; Liu, X.; Hu, X.; Xu, T.; Sun, H.; Pan, Y.; He, B.; Wang, S. CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis. 2018, 9, 417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Yan, Y.; Su, M.; Qin, B. CircHIPK3 promotes colorectal cancer cells proliferation and metastasis via modulating of miR-1207-5p/FMNL2 signal. Biochem. Biophys. Res. Commun. 2020, 524, 839–846. [Google Scholar] [CrossRef] [PubMed]
  44. Zhang, Y.; Li, C.; Liu, X.; Wang, Y.; Zhao, R.; Yang, Y.; Zheng, X.; Zhang, Y.; Zhang, X. circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637. eBioMedicine 2019, 48, 277–288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Chen, D.; Lu, X.; Yang, F.; Xing, N. Circular RNA circHIPK3 promotes cell proliferation and invasion of prostate cancer by sponging miR-193a-3p and regulating MCL1 expression. Cancer Manag. Res. 2019, 11, 1415–1423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Cai, C.; Zhi, Y.; Wang, K.; Zhang, P.; Ji, Z.; Xie, C.; Sun, F. CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p. OncoTargets Ther. 2019, 12, 3363–3372. [Google Scholar] [CrossRef] [Green Version]
  47. Liu, F.; Fan, Y.; Ou, L.; Li, T.; Fan, J.; Duan, L.; Yang, J.; Luo, C.; Wu, X. CircHIPK3 Facilitates the G2/M Transition in Prostate Cancer Cells by Sponging miR-338-3p. Onco Targets Ther. 2020, 13, 4545–4558. [Google Scholar] [CrossRef]
  48. Liu, D.C.; Song, L.L.; Li, X.Z.; Liang, Q.; Zhang, Z.G.; Han, C.H. Circular RNA circHIPK3 modulates prostate cancer progression via targeting miR-448/MTDH signaling. Clin. Transl. Oncol. 2021, 23, 2497–2506. [Google Scholar] [CrossRef]
  49. Tang, Y.; Liu, J.; Li, X.; Wang, W. Exosomal circRNA HIPK3 knockdown inhibited cell proliferation and metastasis in prostate cancer by regulating miR-212/BMI-1 pathway. J. Biosci. 2021, 46, 69. [Google Scholar] [CrossRef]
  50. Lai, J.; Xin, J.; Fu, C.; Zhang, W. CircHIPK3 promotes proliferation and metastasis and inhibits apoptosis of renal cancer cells by inhibiting MiR-485-3p. Cancer Cell Int. 2020, 20, 248. [Google Scholar] [CrossRef]
  51. Han, B.; Shaolong, E.; Luan, L.; Li, N.; Liu, X. CircHIPK3 Promotes Clear Cell Renal Cell Carcinoma (ccRCC) Cells Proliferation and Metastasis via Altering of miR-508-3p/CXCL13 Signal. OncoTargets Ther. 2020, 13, 6051–6062. [Google Scholar] [CrossRef] [PubMed]
  52. Omata, Y.; Okawa, M.; Haraguchi, M.; Tsuruta, A.; Matsunaga, N.; Koyanagi, S.; Ohdo, S. RNA editing enzyme ADAR1 controls miR-381-3p-mediated expression of multidrug resistance protein MRP4 via regulation of circRNA in human renal cells. J. Biol. Chem. 2022, 298, 102184. [Google Scholar] [CrossRef] [PubMed]
  53. Li, H.; Heng, B.; Ouyang, P.; Xie, X.; Zhang, T.; Chen, G.; Chen, Z.; Cheang, K.; Lai, C. Comprehensive profiling of circRNAs and the tumor suppressor function of circHIPK3 in clear cell renal carcinoma. J. Mol. Histol. 2020, 51, 317–327. [Google Scholar] [CrossRef] [PubMed]
  54. Li, Y.; Zheng, F.; Xiao, X.; Xie, F.; Tao, D.; Huang, C.; Liu, D.; Wang, M.; Wang, L.; Zeng, F.; et al. CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep. 2017, 18, 1646–1659. [Google Scholar] [CrossRef] [PubMed]
  55. Xie, F.; Zhao, N.; Zhang, H.; Xie, D. Circular RNA CircHIPK3 Promotes Gemcitabine Sensitivity in Bladder Cancer. J. Cancer 2020, 11, 1907–1912. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Okholm, T.L.H.; Nielsen, M.; Hamilton, M.P.; Christensen, L.-L.; Vang, S.; Hedegaard, J.; Hansen, T.; Kjems, J.; Dyrskjøt, L.; Pedersen, J.S. Circular RNA expression is abundant and correlated to aggressiveness in early-stage bladder cancer. NPJ Genom. Med. 2017, 2, 36. [Google Scholar] [CrossRef] [Green Version]
  57. Qi, L.; Sun, B.; Yang, B.; Lu, S. circHIPK3 (hsa_circ_0000284) Promotes Proliferation, Migration and Invasion of Breast Cancer Cells via miR-326. OncoTargets Ther. 2021, 14, 3671–3685. [Google Scholar] [CrossRef] [PubMed]
  58. Luo, N.; Liu, S.; Li, X.; Hu, Y.; Zhang, K. Circular RNA circHIPK3 promotes breast cancer progression via sponging MiR-326. Cell Cycle 2021, 20, 1320–1333. [Google Scholar] [CrossRef]
  59. Shi, P.; Liu, Y.; Yang, H.; Hu, B. Breast cancer derived exosomes promoted angiogenesis of endothelial cells in microenvironment via circHIPK3/miR-124-3p/MTDH axis. Cell Signal 2022, 95, 110338. [Google Scholar] [CrossRef]
  60. Chen, Z.G.; Zhao, H.J.; Lin, L.; Liu, J.B.; Bai, J.Z.; Wang, G.S. Circular RNA CirCHIPK3 promotes cell proliferation and invasion of breast cancer by sponging miR-193a/HMGB1/PI3K/AKT axis. Thorac Cancer 2020, 11, 2660–2671. [Google Scholar] [CrossRef] [PubMed]
  61. Zhang, H.; Yan, C.; Wang, Y. Exosome-mediated transfer of circHIPK3 promotes trastuzumab chemoresistance in breast cancer. J. Drug Target 2021, 29, 1004–1015. [Google Scholar] [CrossRef] [PubMed]
  62. Ni, J.; Xi, X.; Xiao, S.; Xiao, X. Silencing of circHIPK3 Sensitizes Paclitaxel-Resistant Breast Cancer Cells to Chemotherapy by Regulating HK2 Through Targeting miR-1286. Cancer Manag. Res. 2021, 13, 5573–5585. [Google Scholar] [CrossRef]
  63. Liu, N.; Zhang, J.; Zhang, L.-Y.; Wang, L. CircHIPK3 is upregulated and predicts a poor prognosis in epithelial ovarian cancer. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 3713–3718. [Google Scholar]
  64. Teng, F.; Xu, J.; Zhang, M.; Liu, S.; Gu, Y.; Wang, X.; Ni, J.; Qian, B.; Shen, R.; Jia, X. Comprehensive circular RNA expression profiles and the tumor-suppressive function of circHIPK3 in ovarian cancer. Int. J. Biochem. Cell Biol. 2019, 112, 8–17. [Google Scholar] [CrossRef] [PubMed]
  65. Wu, S.; Liu, S.; Song, H.; Xia, J. Circular RNA HIPK3 plays a carcinogenic role in cervical cancer progression via regulating miR-485-3p/FGF2 axis. J. Investig. Med. 2021, 69, 768–774. [Google Scholar] [CrossRef]
  66. Qian, W.; Huang, T.; Feng, W. Circular RNA HIPK3 Promotes EMT of Cervical Cancer Through Sponging miR-338-3p to Up-Regulate HIF-1α. Cancer Manag. Res. 2020, 12, 177–187. [Google Scholar] [CrossRef] [Green Version]
  67. Huang, Z.; Yuan, C.; Gu, H.; Cheng, X.; Zhou, K.; Xu, J.; Yin, X.; Xia, J. Circular RNA circHIPK3 Promotes Cell Metastasis through miR-637/STAT3 Axis in Osteosarcoma. BioMed Res. Int. 2020, 2020, 2727060. [Google Scholar] [CrossRef]
  68. Wen, Y.; Li, B.; He, M.; Teng, S.; Sun, Y.; Wang, G. circHIPK3 promotes proliferation and migration and invasion via regulation of miR637/HDAC4 signaling in osteosarcoma cells. Oncol. Rep. 2021, 45, 169–179. [Google Scholar] [CrossRef] [PubMed]
  69. Xiao-Long, M.; Kun-Peng, Z.; Chun-Lin, Z. Circular RNA circ_HIPK3 is down-regulated and suppresses cell proliferation, migration and invasion in osteosarcoma. J. Cancer 2018, 9, 1856–1862. [Google Scholar] [CrossRef]
  70. Jin, P.; Huang, Y.; Zhu, P.; Zou, Y.; Shao, T.; Wang, O. CircRNA circHIPK3 serves as a prognostic marker to promote glioma progression by regulating miR-654/IGF2BP3 signaling. Biochem. Biophys. Res. Commun. 2018, 503, 1570–1574. [Google Scholar] [CrossRef] [PubMed]
  71. Hu, D.; Zhang, Y. Circular RNA HIPK3 promotes glioma progression by binding to miR-124-3p. Gene 2019, 690, 81–89. [Google Scholar] [CrossRef] [PubMed]
  72. Liu, Z.; Guo, S.; Sun, H.; Bai, Y.; Song, Z.; Liu, X. Circular RNA CircHIPK3 Elevates CCND2 Expression and Promotes Cell Proliferation and Invasion Through miR-124 in Glioma. Front. Genet. 2020, 11, 1013. [Google Scholar] [CrossRef] [PubMed]
  73. Han, C.; Wang, S.; Wang, H.; Zhang, J. Exosomal circ-HIPK3 Facilitates Tumor Progression and Temozolomide Resistance by Regulating miR-421/ZIC5 Axis in Glioma. Cancer Biother Radiopharm. 2021, 36, 537–548. [Google Scholar] [CrossRef] [PubMed]
  74. Yin, H.; Cui, X. Knockdown of circHIPK3 Facilitates Temozolomide Sensitivity in Glioma by Regulating Cellular Behaviors Through miR-524-5p/KIF2A-Mediated PI3K/AKT Pathway. Cancer Biother. Radiopharm. 2021, 36, 556–567. [Google Scholar] [CrossRef]
  75. Bi, L.; Zhang, C.; Yao, Y.; He, Z. Circ-HIPK3 regulates YAP1 expression by sponging miR-381-3p to promote oral squamous cell carcinoma development. J. Biosci. 2021, 46, 20. [Google Scholar] [CrossRef]
  76. Jiang, W.; Zhang, C.; Zhang, X.; Sun, L.; Li, J.; Zuo, J. CircRNA HIPK3 promotes the progression of oral squamous cell carcinoma through upregulation of the NUPR1/PI3K/AKT pathway by sponging miR-637. Ann. Transl. Med. 2021, 9, 860. [Google Scholar] [CrossRef]
  77. Feng, X.Q.; Nie, S.M.; Huang, J.X.; Li, T.L.; Zhou, J.J.; Wang, W.; Zhuang, L.K.; Meng, F.J. Circular RNA circHIPK3 serves as a prognostic marker to promote chronic myeloid leukemia progression. Neoplasma 2020, 67, 171–177. [Google Scholar] [CrossRef] [PubMed]
  78. Gaffo, E.; Boldrin, E.; Dal Molin, A.; Bresolin, S.; Bonizzato, A.; Trentin, L.; Frasson, C.; Debatin, K.-M.; Meyer, L.H.; Kronnie, G.T.; et al. Circular RNA differential expression in blood cell populations and exploration of circRNA deregulation in pediatric acute lymphoblastic leukemia. Sci. Rep. 2019, 9, 14670. [Google Scholar] [CrossRef] [Green Version]
  79. Ke, Z.; Xie, F.; Zheng, C.; Chen, D. CircHIPK3 promotes proliferation and invasion in nasopharyngeal carcinoma by abrogating miR-4288-induced ELF3 inhibition. J. Cell. Physiol. 2019, 234, 1699–1706. [Google Scholar] [CrossRef] [PubMed]
  80. Liu, Y.; Xia, L.; Dong, L.; Wang, J.; Xiao, Q.; Yu, X.; Zhu, H. CircHIPK3 Promotes Gemcitabine (GEM) Resistance in Pancreatic Cancer Cells by Sponging miR-330-5p and Targets RASSF1. Cancer Manag. Res. 2020, 12, 921–929. [Google Scholar] [CrossRef] [Green Version]
  81. Shu, T.; Yang, L.; Sun, L.; Lu, J.; Zhan, X. CircHIPK3 Promotes Thyroid Cancer Tumorigenesis and Invasion through the Mirna-338-3p/RAB23 Axis. Med. Princ. Pract. 2020, 30, 311–319. [Google Scholar] [CrossRef] [PubMed]
  82. Kai, D.; Yannian, L.; Yitian, C.; Dinghao, G.; Xin, Z.; Wu, J. Circular RNA HIPK3 promotes gallbladder cancer cell growth by sponging microRNA-124. Biochem. Biophys. Res. Commun. 2018, 503, 863–869. [Google Scholar] [CrossRef] [PubMed]
  83. Zhu, X.; Sun, J. CircHIPK3 regulates melanoma cell behaviors by binding with miR-215–5p to upregulate YY1. Mol. Cell. Probes 2020, 53, 101644. [Google Scholar] [CrossRef] [PubMed]
  84. Stella, M.; Falzone, L.; Caponnetto, A.; Gattuso, G.; Barbagallo, C.; Battaglia, R.; Mirabella, F.; Broggi, G.; Altieri, R.; Certo, F.; et al. Serum Extracellular Vesicle-Derived circHIPK3 and circSMARCA5 Are Two Novel Diagnostic Biomarkers for Glioblastoma Multiforme. Pharmaceuticals 2021, 14, 618. [Google Scholar] [CrossRef] [PubMed]
  85. Samsky, M.D.; Morrow, D.A.; Proudfoot, A.G.; Hochman, J.S.; Thiele, H.; Rao, S.V. Cardiogenic Shock After Acute Myocardial Infarction: A Review. JAMA 2021, 326, 1840–1850. [Google Scholar] [CrossRef]
  86. Dong, K.; He, X.; Su, H.; Fulton, D.J.R.; Zhou, J. Genomic analysis of circular RNAs in heart. BMC Med. Genom. 2020, 13, 167. [Google Scholar] [CrossRef]
  87. Si, X.; Zheng, H.; Wei, G.; Li, M.; Li, W.; Wang, H.; Guo, H.; Sun, J.; Li, C.; Zhong, S.; et al. circRNA Hipk3 Induces Cardiac Regeneration after Myocardial Infarction in Mice by Binding to Notch1 and miR-133a. Mol. Ther. Nucleic Acids 2020, 21, 636–655. [Google Scholar] [CrossRef] [PubMed]
  88. Wang, Y.; Zhao, R.; Shen, C.; Liu, W.; Yuan, J.; Li, C.; Deng, W.; Wang, Z.; Zhang, W.; Ge, J.; et al. Exosomal CircHIPK3 Released from Hypoxia-Induced Cardiomyocytes Regulates Cardiac Angiogenesis after Myocardial Infarction. Oxidative Med. Cell. Longev. 2020, 2020, 8418407. [Google Scholar] [CrossRef] [PubMed]
  89. Wu, Y.; Wu, M.; Yang, J.; Li, Y.; Peng, W.; Wu, M.; Yu, C.; Fang, M. Silencing CircHIPK3 Sponges miR-93-5p to Inhibit the Activation of Rac1/PI3K/AKT Pathway and Improves Myocardial Infarction-Induced Cardiac Dysfunction. Front. Cardiovasc. Med. 2021, 8, 645378. [Google Scholar] [CrossRef] [PubMed]
  90. Liu, W.; Wang, Y.; Qiu, Z.; Zhao, R.; Liu, Z.; Chen, W.; Ge, J.; Shi, B. CircHIPK3 regulates cardiac fibroblast proliferation, migration and phenotypic switching through the miR-152-3p/TGF-beta2 axis under hypoxia. PeerJ 2020, 8, e9796. [Google Scholar] [CrossRef]
  91. Liu, J.; Cui, J.; Lin, Y. CircRNA circHIPK3: A novel, potential therapeutic target in the treatment of angiotensin II-induced cardiac fibrosis? Int. J. Cardiol. 2021, 322, 213. [Google Scholar] [CrossRef] [PubMed]
  92. Ni, H.; Li, W.; Zhuge, Y.; Xu, S.; Wang, Y.; Chen, Y.; Shen, G.; Wang, F. Inhibition of circHIPK3 prevents angiotensin II-induced cardiac fibrosis by sponging miR-29b-3p. Int. J. Cardiol. 2019, 292, 188–196. [Google Scholar] [CrossRef] [PubMed]
  93. Bai, M.; Pan, C.-L.; Jiang, G.-X.; Zhang, Y.-M.; Zhang, Z. CircHIPK3 aggravates myocardial ischemia-reperfusion injury by binding to miRNA-124-3p. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 10107–10114. [Google Scholar] [PubMed]
  94. Cheng, N.; Jin, C.; Jin, P.; Zhu, D.; Hou, Z. High glucose protects cardiomyocytes against ischaemia/reperfusion injury by suppressing myocardiocyte apoptosis via circHIPK3/miR-29b/AKT3 signalling. J. Cell. Mol. Med. 2021, 25, 6137–6147. [Google Scholar] [CrossRef]
  95. Qiu, Z.; Wang, Y.; Liu, W.; Li, C.; Zhao, R.; Long, X.; Rong, J.; Deng, W.; Shen, C.; Yuan, J.; et al. CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis. Cell Death Discov. 2021, 7, 64. [Google Scholar] [CrossRef]
  96. Wang, Y.; Zhao, R.; Liu, W.; Wang, Z.; Rong, J.; Long, X.; Liu, Z.; Ge, J.; Shi, B. Exosomal circHIPK3 Released from Hypoxia-Pretreated Cardiomyocytes Regulates Oxidative Damage in Cardiac Microvascular Endothelial Cells via the miR-29a/IGF-1 Pathway. Oxidative Med. Cell. Longev. 2019, 2019, 7954657. [Google Scholar] [CrossRef]
  97. Wei, M.-Y.; Lv, R.-R.; Teng, Z. Circular RNA circHIPK3 as a novel circRNA regulator of autophagy and endothelial cell dysfunction in atherosclerosis. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 12849–12858. [Google Scholar]
  98. Zhang, W.-B.; Qi, Y.-F.; Xiao, Z.-X.; Chen, H.; Liu, S.-H.; Li, Z.-Z.; Zeng, Z.-F.; Wu, H.-F. CircHIPK3 Regulates Vascular Smooth Muscle Cell Calcification Via the miR-106a-5p/MFN2 Axis. J. Cardiovasc. Transl. Res. 2022, 8, 269–277. [Google Scholar] [CrossRef]
  99. Kang, L.; Jia, H.; Huang, B.; Lu, S.; Chen, Z.; Shen, J.; Zou, Y.; Wang, C.; Sun, Y. Identification of Differently Expressed mRNAs in Atherosclerosis Reveals CDK6 Is Regulated by circHIPK3/miR-637 Axis and Promotes Cell Growth in Human Vascular Smooth Muscle Cells. Front. Genet. 2021, 12, 596169. [Google Scholar] [CrossRef]
  100. Fan, S.; Hu, K.; Zhang, D.; Liu, F. Interference of circRNA HIPK3 alleviates cardiac dysfunction in lipopolysaccharide-induced mice models and apoptosis in H9C2 cardiomyocytes. Ann. Transl. Med. 2020, 8, 1147. [Google Scholar] [CrossRef]
  101. Deng, Y.; Wang, J.; Xie, G.; Zeng, X.; Li, H. Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p-ADCY6 Axis. Int. J. Biol. Sci. 2019, 15, 2484–2496. [Google Scholar] [CrossRef] [PubMed]
  102. Xu, X.; Wang, J.; Wang, X. Silencing of circHIPK3 Inhibits Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction by Sponging miR-185-3p. Drug Des. Dev. Ther. 2020, 14, 5699–5710. [Google Scholar] [CrossRef] [PubMed]
  103. Tremblay, J.; Hamet, P. Environmental and genetic contributions to diabetes. Metabolism 2019, 100, 153952. [Google Scholar] [CrossRef]
  104. Rezaeinejad, F.; Mirzaei, A.; Khalvati, B.; Sabz, G.; Alipoor, B. Circulating expression levels of CircHIPK3 and CDR1as circular-RNAs in type 2 diabetes patients. Mol. Biol. Rep. 2022, 49, 131–138. [Google Scholar] [CrossRef] [PubMed]
  105. Liu, R.; Zhang, M.; Ge, Y. Circular RNA HIPK3 exacerbates diabetic nephropathy and promotes proliferation by sponging miR-185. Gene 2021, 765, 145065. [Google Scholar] [CrossRef] [PubMed]
  106. Wang, W.; Zhang, S.; Xu, L.; Feng, Y.; Wu, X.; Zhang, M.; Yu, Z.; Zhou, X. Involvement of circHIPK3 in the pathogenesis of diabetic cardiomyopathy in mice. Diabetologia 2021, 64, 681–692. [Google Scholar] [CrossRef] [PubMed]
  107. Cai, H.; Jiang, Z.; Yang, X.; Lin, J.; Cai, Q.; Li, X. Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1. Endocr. J. 2020, 67, 397–408. [Google Scholar] [CrossRef] [Green Version]
  108. Wang, L.; Luo, T.; Bao, Z.; Li, Y.; Bu, W. Intrathecal circHIPK3 shRNA alleviates neuropathic pain in diabetic rats. Biochem. Biophys. Res. Commun. 2018, 505, 644–650. [Google Scholar] [CrossRef]
  109. Shan, K.; Liu, C.; Liu, B.-H.; Chen, X.; Dong, R.; Liu, X.; Zhang, Y.-Y.; Liu, B.; Zhang, S.-J.; Wang, J.-J.; et al. Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus. Circulation 2017, 136, 1629–1642. [Google Scholar] [CrossRef]
  110. Wang, S.; Shi, M.; Li, J.; Zhang, Y.; Wang, W.; Xu, P.; Li, Y. Endothelial cell-derived exosomal circHIPK3 promotes the proliferation of vascular smooth muscle cells induced by high glucose via the miR-106a-5p/Foxo1/Vcam1 pathway. Aging 2021, 13, 25241–25255. [Google Scholar] [CrossRef]
  111. Cao, Y.; Yuan, G.; Zhang, Y.; Lu, R. High glucose-induced circHIPK3 downregulation mediates endothelial cell injury. Biochem. Biophys. Res. Commun. 2018, 507, 362–368. [Google Scholar] [CrossRef] [PubMed]
  112. Zhuang, L.; Wang, Z.; Hu, X.; Yang, Q.; Pei, X.; Jin, G. CircHIPK3 Alleviates High Glucose Toxicity to Human Renal Tubular Epithelial HK-2 Cells Through Regulation of miR-326/miR-487a-3p/SIRT1. Diabetes Metab. Syndr. Obes. 2021, 14, 729–740. [Google Scholar] [CrossRef] [PubMed]
  113. Jiang, J.; Gao, G.; Pan, Q.; Liu, J.; Tian, Y.; Zhang, X. Circular RNA circHIPK3 is downregulated in diabetic cardiomyopathy and overexpression of circHIPK3 suppresses PTEN to protect cardiomyocytes from high glucose-induced cell apoptosis. Bioengineered 2022, 13, 6272–6279. [Google Scholar] [CrossRef] [PubMed]
  114. Wu, Q.; Yuan, Z.H.; Ma, X.B.; Tang, X.H. Low expression of CircRNA HIPK3 promotes osteoarthritis chondrocyte apoptosis by serving as a sponge of miR-124 to regulate SOX8. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 7937–7945. [Google Scholar]
  115. Li, S.; Liu, J.; Liu, S.; Jiao, W.; Wang, X. Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis. J. Nanobiotechnol. 2021, 19, 194. [Google Scholar] [CrossRef]
  116. Lian, C.; Sun, J.; Guan, W.; Zhang, L.; Zhang, X.; Yang, L.; Hu, W. Circular RNA circHIPK3 Activates Macrophage NLRP3 Inflammasome and TLR4 Pathway in Gouty Arthritis via Sponging miR-561 and miR-192. Inflammation 2021, 44, 2065–2077. [Google Scholar] [CrossRef]
  117. Zhu, X.; Wang, X.; Wang, Y.; Zhao, Y. The regulatory network among CircHIPK3, LncGAS5, and miR-495 promotes Th2 differentiation in allergic rhinitis. Cell Death Dis. 2020, 11, 216. [Google Scholar] [CrossRef] [Green Version]
  118. Yin, X.; Zheng, W.; He, L.; Mu, S.; Shen, Y.; Wang, J. CircHIPK3 alleviates inflammatory response and neuronal apoptosis via regulating miR-382-5p/DUSP1 axis in spinal cord injury. Transpl. Immunol. 2022, 73, 101612. [Google Scholar] [CrossRef]
  119. Reddel, H.K.; Bacharier, L.B.; Bateman, E.D.; Brightling, C.E.; Brusselle, G.G.; Buhl, R.; Cruz, A.A.; Duijts, L.; Drazen, J.M.; FitzGerald, J.M.; et al. Global Initiative for Asthma Strategy 2021: Executive summary and rationale for key changes. Eur. Respir. J. 2022, 59, 2102730. [Google Scholar] [CrossRef]
  120. Lin, J.; Feng, X.; Zhang, J. Circular RNA circHIPK3 modulates the proliferation of airway smooth muscle cells by miR-326/STIM1 axis. Life Sci. 2020, 255, 117835. [Google Scholar] [CrossRef]
  121. Jiang, Y.; Guo, X.; Qin, J. Silencing of circHIPK3 hampers platelet-derived growth factor-induced proliferation and migration in airway smooth muscle cells through the miR-375/MMP-16 axis. Cytotechnology 2021, 73, 629–642. [Google Scholar] [CrossRef] [PubMed]
  122. Reid, I.R.; Billington, E.O. Drug therapy for osteoporosis in older adults. Lancet 2022, 399, 1080–1092. [Google Scholar] [CrossRef]
  123. Liang, J.; Shen, Y.-C.; Zhang, X.-Y.; Chen, C.; Zhao, H.; Hu, J. Circular RNA HIPK3 downregulation mediates hydrogen peroxide-induced cytotoxicity in human osteoblasts. Aging 2020, 12, 1159–1170. [Google Scholar] [CrossRef]
  124. Zhu, C.-Y.; Yao, C.; Zhu, L.-Q.; She, C.; Zhou, X.-Z. Dexamethasone-induced cytotoxicity in human osteoblasts is associated with circular RNA HIPK3 downregulation. Biochem. Biophys. Res. Commun. 2019, 516, 645–652. [Google Scholar] [CrossRef]
  125. Rao, G.N.; Khanna, R.; Payal, A. The global burden of cataract. Curr. Opin. Ophthalmol. 2011, 22, 4–9. [Google Scholar] [CrossRef] [PubMed]
  126. Cui, G.; Wang, L.; Huang, W. Circular RNA HIPK3 regulates human lens epithelial cell dysfunction by targeting the miR-221–3p/PI3K/AKT pathway in age-related cataract. Exp. Eye Res. 2020, 198, 108128. [Google Scholar] [CrossRef] [PubMed]
  127. Liu, X.; Liu, B.; Zhou, M.; Fan, F.; Yu, M.; Gao, C.; Lu, Y. Circular RNA HIPK3 regulates human lens epithelial cells proliferation and apoptosis by targeting the miR-193a/CRYAA axis. Biochem. Biophys. Res. Commun. 2018, 503, 2277–2285. [Google Scholar] [CrossRef] [PubMed]
Diagnostics 12 02469 g001 550
Figure 1. The biogenesis of circHIPK3.
Figure 1. The biogenesis of circHIPK3.
Diagnostics 12 02469 g001
Diagnostics 12 02469 g002 550
Figure 2. CircHIPK3 and the miRNAs that it sponges.
Figure 2. CircHIPK3 and the miRNAs that it sponges.
Diagnostics 12 02469 g002
Table
Table 1. The role of circHIPK3 in human cancers.
Table 1. The role of circHIPK3 in human cancers.
Cancer typesLocationExpressionClinical Samples (n)Cell Lines or ModelsAnimal ModelsSignaling PathwayRelevant Cell BiologyRelevant Clinical Features
lcCytoplasmUpregulatedn = 15A549 and BEAS-2B-miR-124/(SphK1, CDK4, STAT3)Proliferation, migration and invasion-
-A549, H1299, HCC-827, PC-9, H1975 and H838-miR-124-3p/STAT3Proliferation, migration and invasion-
n = 2516HBE, SPC-A1, A549, NCI-H1299, and NCI-H1650-miR-149/FOXM1Proliferation and apoptosis-
-H1299, A549, and BEAS-2B-miR-107/BDNFProliferation and migration-
Downregulatedn = 110A549--Gefitinib resistanceTumor size, TNM stage, lymph node metastasis
HCCCytoplasmUpregulatedn = 50Huh7, MHCC-LM3, HepG2, SMMC-7721, PLC, L02 and HEK293TNude micemiR-124/AQP3Proliferation and migrationHBV-DNA copy number, liver cirrhosis, tumor differentiation and TNM stage
n = 30HepG2, SMMC-7721, Bel-7402, Huh-7 and HL7702BALB/c male nude micemiR-124 or miR-506/PDK2Proliferation and invasion-
-HepG2, Hep3B, Huh-7, SKHep1 and THLE-3BALB/C nude micemiR-338-3p/ZEB2/EMTMigration and invasionSurvival
n = 19SMMC-7721, Huh7, HepG2 and Hep3B-miR-124-3p and miR-4524-5p/MRP4Migration and drug resistance-
ESCCCytoplasmUpregulatedn = 42kyse-150, kyse-410, KYSE-510, ECA-109, EC-18, TE-13 and NE1BALB/c female nude micemiR-599/c-MYCProliferation and invasion-
n = 32KYSE-150, KYSE-410, ECA-109 and KYSE180BALB/c nude micemiR-124/AKT3Proliferation and migration-
GCCytoplasmUpregulatedn = 63XGC-1, XGC-2, MGC-803 and BGC-823-miR-29b and miR-124Proliferation and invasion-
n = 30SGC-7901, MKN45, MGC-803, AGS, BGC-823, GES-1 and SGC-7901BALB/c male nude micemiR-107/BDNFProliferation and migration-
n = 26GES-1, HGC-27 and AGSBALB/c male nude micemiR-876-5p/PIK3R1Proliferation, migration and invasion-
n = 31MGC803 and BGC823-miR-653-5p and miR-338-3p/NRP1/ERK/AKTPromote metastasis-
n = 10BGC-823, CRL-5822, SGC-7901, AGS and GES-1-miR-637/AKT1Proliferation, migration and invasion-
n = 53BGC, MGC, SGC, MKN and GES-Wnt/β-cateninProliferation and migrationPrognosis
Downregulatedn = 30----Clinical stage, age
CRCCytoplasmUpregulatedn = 178FHC, HCT116, HT29, SW480, SW620,DLD1BALB/c male nude micemiR-7Proliferation, migration, invasion and apoptosisPathological T category, lymph node metastasis, distant metastasis, TNM stage and prognosis
n = 50HT29, LOVO, SW480, PKO and NCM460-miR-1207-5p/FMNL2Proliferation, migration and invasionPrognosis
n = 49HT29, HCT116, HEK293T, 5FU-resistant and OXA-resistant cellsBALB/c male nude micemiR-637/STAT3Drug resistance-
PCaCytoplasmUpregulatedn = 26RWPE-1, 22RV1, PC-3, DU145, and LNCaPBALB/c male nude micemiR-193a-3p/MCL1Proliferation and invasionPrognosis and tumor stage
n = 60RWPE-1, 22RV1, PC-3, DU145, and LNCaP-miR-338-3p/ADAM17Proliferation and invasion-
n = 45RWPE-1, 22RV1, PC-3, DU146, and LNCaP-miR-338-3p/Cdc2 and Cdc25BProliferation and G2/M transitionGleason score
n = 14PC-3, VCaP, DU145, LNCaP, 22RV1 and PWPE-1BALB/c male nude micemiR-448/MTDHProliferation, migration and invasion-
ExosomeUpregulatedn = 35 (blood)RWPE-1, 22RV1 and DU145BALB/c male nude micemiR-212/BMI-1Proliferation, migration, invasion and apoptosis-
RCCCytoplasmUpregulatedn = 48HK-2, Caki-1, ACHN, 786-O, 769-P and A498BALB/c female nude micemiR-485-3p/EMTProliferation, migration, invasion and apoptosis-
n = 50A498, 786-O, 769-P and HRPTEpiC-miR-5083p/CXCL13Proliferation, migration and invasion-
-RPTECs-miR -381-3p/MRP4Drug resistance-
Downregulatedn = 40Caki-1, 786O, ACHN, A498 and HK-2Nude micemiR-637Migration and invasion-
Bladder cancerCytoplasmDownregulatedn = 44T24, UMUC3, SV-HUC-1, HUVECBALB/c female nude micemiR-558/HPSEProliferation, migration, invasion, and angiogenesisLymph node metastasis
n = 68CCC-HB-2, SV-HUC-1, T24, J82 and UMUC3---Gemcitabine resistance, prognosis
n = 457RT4, HT1376, T24, FL3 and HCV29---Aggressiveness
Breast cancerCytoplasmUpregulatedn = 48MCF-10A, MCF7, SK-BR-3, BT549, BT20, MDA-MB-231-miR-326Proliferation, migration and invasion-
n = 48MCF-10A, MCF7, SK-BR-3, BT549, BT20, MDA-MB -231, MDA-MB-453BALB/c male nude micemiR-326Proliferation, migration and invasion-
n = 37MDA-MB-231, MCF-7, MDA-MB-231/PTX and MCF-7/PTXBALB/c nude micemiR-1286/HK2Proliferation and paclitaxel resistance-
n = 50MCF-10A, MCF-7, MDA-MB-231, MDA-MB-468 and MDA-MB-453Nude micemiR-193a/HMGB1/PI3K/AKTProliferation and invasion-
Exosome-MCF-7/Pr, MCF-7/Tr, SKBR3/Pr and SKBR3/TrBALB/c female nude mice-Trastuzumab chemoresistance-
-MCF-7, MDA-MB-231, MDA-MB-453, SK-BR-3, BT-474, HUVECBALB/c nude micemiR-124-3p/MTDHAngiogenesis-
OCCytoplasmUpregulatedn = 69HOEC, A2780, HO-8910, SKOV3 and CAOV3---Prognosis
n = 21A2780 and SKOV3--Proliferation, migration, invasion and apoptosis-
CCCytoplasmUpregulatedn = 70SiHa and HeLa-miR-485-3p/FGF2Proliferation, migration and invasion-
n = 45HeLa, CaSki, SiHa, C-33A, C-4I, SW756 and End1/E6E7-miR-338-3p/HIF-1α/EMTProliferation, migration, invasion and apoptosis-
OsteosarcomaCytoplasmUpregulatedn = 10U2OS and SW1353-miR-637/STAT3Migration and invasion-
n = 12hFOB 1.19, HOS, MG-63, U2OS and SJSA-miR-637/HDAC4Proliferation, migration and invasion-
Downregulatedn = 82SaoS2, HOS, KH-OS, MG63, 143B and U2-OS--Proliferation, migration and invasion-
GliomaCytoplasmUpregulatedn = 48NHAs, U87 and U251BALB/c female nude micemiR-654/IGF2BP3Proliferation, migration and invasionPrognosis
-HEB, U87, U251, LN229 and LN308-miR-124-3p/STAT3Proliferation, invasion, cell cycle and apoptosis-
UnknownSW1783, and U373-miR-124/CCND2Proliferation and invasion-
n = 80A172 and U251-miR-524-5p/KIF2AProliferation, migration, invasion and apoptosis, temozolomide resistance-
Exosonen = 56 (tumor and blood)NHA, A172, U251, A172/TR and U251/TRNude micemiR-421/ZIC5Proliferation, migration, invasion and apoptosis, temozolomide resistance-
OSCCCytoplasmUpregulatedn = 30HNOK, H357, SCC-15, SCC-4 and SCC-9BALB/c female nude micemiR-381-3p/YAP1Proliferation, migration, invasion and apoptosis-
n = 40NOK, OSCC-15, Tca8113, SCC-9, SCC-25, and HSC-2C57BL/6 nude micemiR-637/NUPR1/PI3K/AKTProliferation, invasion and apoptosisTumor size and histopathological grade
CMLCytoplasmUpregulatedn = 1001D3, K562, KCL22, AR230-r, LAMA84-s and Kasumi-4---Prognosis
ALLCytoplasmUpregulated-Mononuclear cells----
NPCCytoplasmUpregulatedn = 63NP69, SUNE1, CNE1, CNE2, SUNE2, and 6-10BBALB/c female nude micemiR-4288/ELF3Proliferation and invasion-
Pancreatic cancerCytoplasmUpregulatedn = 28PANC-1 and SW 1990BALB/c nude micemiR-330-5p/RASSF1Proliferation, migration, invasion, apoptosis and gemcitabine resistance-
Thyroid cancerCytoplasmUpregulatedn = 10K1, CAL-62, TPC1, Nthy-ori 3-1-miR- 338-3p/RAB23Proliferation, migration and invasion-
GBCCytoplasmUpregulatedn = 13Mz-ChA-1, QBC939 and GBC-SD-miR-124/ROCK1/CDK6Proliferation and apoptosis-
MelanomaCytoplasmUpregulatedn = 23HEMa-LP, CHL-1 and A375-miR-215-5p/YY1Proliferation and apoptosis-
GlioblastomaExtracellular vesicleUpregulated-.-----
Abbreviations: LC, lung cancer; SphK1, sphingosine kinase 1; CDK4, cyclin-dependent kinase 4; STAT3, signal transducer and activator of transcription 3; FOXM1, forkhead box M1; BDNF, brain-derived neurotrophic factor; HCC, hepatocellular carcinoma; AQP3, aquaporin 3; PDK2, pyruvate dehydrogenase kinase 2; MRP4, multidrug resistance protein 4; ZEB2, zinc finger E-box binding homeobox 2; EMT, epithelial-mesenchymal transition; ESCC, esophageal squamous cell carcinoma; AKT3, serine/threonine kinase 3; GC, gastric cancer; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1; NRP1, neuropilin 1; ERK, extracellular signal-regulated kinase; AKT, protein kinase B; AKT1, serine/threonine kinase 1; CRC, colorectal cancer; FMNL2, formin-like 2; PCa, prostate cancer; MCL1, myeloid cell leukemia 1; ADAM17, a disintegrin and metalloproteinases 17; MTDH, metadherin; BMI-1, B-cell specific MMLV insertion site-1; RCC, renal cell carcinoma; CXCL13, chemokine ligand 13; HPSE, heparanase; HMGB1, high mobility group box-1; PI3K, phosphoinositide-3-kinase; HK2, hexokinase 2; OC, ovarian cancer; CC, cervical cancer; FGF2, fibroblast growth factor 2; HIF-1α, hypoxia-inducible factor-1alpha; HDAC4, histone deacetylase 4; IGF2BP3, insulin-like growth factor 2 mRNA-binding protein 3; CCND2, cyclin D2; ZIC5, zinc finger of the cerebellum 5; KIF2A, kinesin family member 2A; OSCC, oral squamous cell carcinoma; YAP1, Yes-associated protein1; NUPR1, nuclear protein 1; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; NPC, nasopharyngeal cancer; ELF3, E74 like ETS transcription factor 3; RASSF1, RAS-Association domain family 1; RAB23, Ras-like in rat brain 23; GBC, gallbladder cancer; ROCK1, rho-associated protein kinase 1; CDK6, cyclin-dependent kinase 6; YY1, Yin Yang 1.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Feng, Y.; Yang, Z.; Lv, B.; Xu, X. The Diagnostic and Therapeutic Role of Circular RNA HIPK3 in Human Diseases. Diagnostics 2022, 12, 2469. https://doi.org/10.3390/diagnostics12102469

AMA Style

Feng Y, Yang Z, Lv B, Xu X. The Diagnostic and Therapeutic Role of Circular RNA HIPK3 in Human Diseases. Diagnostics. 2022; 12(10):2469. https://doi.org/10.3390/diagnostics12102469

Chicago/Turabian Style

Feng, Yanfei, Zitong Yang, Bodong Lv, and Xin Xu. 2022. "The Diagnostic and Therapeutic Role of Circular RNA HIPK3 in Human Diseases" Diagnostics 12, no. 10: 2469. https://doi.org/10.3390/diagnostics12102469

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop