The circular RNA HIPK3 (circHIPK3) and its regulation in cancer progression: Review

Journal Pre-proof The circular RNA HIPK3 (circHIPK3) and its regulation in cancer progression: Review

Yimin Xie, Xuefeng Yuan, Weimin Zhou, Anthony Adebayiga Kosiba, Haifeng Shi, Jie Gu, Zhenqian Qin PII:

S0024-3205(19)31180-4

DOI:

https://doi.org/10.1016/j.lfs.2019.117252

Reference:

LFS 117252

To appear in:

Life Sciences

Received date:

15 October 2019

Revised date:

24 December 2019

Accepted date:

28 December 2019

Please cite this article as: Y. Xie, X. Yuan, W. Zhou, et al., The circular RNA HIPK3 (circHIPK3) and its regulation in cancer progression: Review, Life Sciences(2019), https://doi.org/10.1016/j.lfs.2019.117252

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2019 Published by Elsevier.

Journal Pre-proof

The circular RNA HIPK3 (circHIPK3) and its regulation in cancer progression: Review

Yimin Xie a, Xuefeng Yuan a, Weimin Zhou a, Anthony Adebayiga Kosiba b, Haifeng Shi b, Jie Gu b, Zhenqian Qin a*

a

Affiliated Hospital of Jiangsu University-Yixing People's Hospital, Yixing, Jiangsu,

Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China

Corresponding author at:

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214200, China

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Department of urology, Affiliated Hospital of Jiangsu University-Yixing Hospital,

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(Zhenqian Qin)

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Zhenguan Road 75, Yixing, Jiangsu, China. E-mail address: [email protected]

Journal Pre-proof Abstract Circular RNAs (circRNAs) are a class of covalently closed continuous loops of single-stranded RNA molecules, and broadly expressed in the cytoplasm of eukaryotic cells. CircRNAs have attracted considerable research attention in recent years, an attention primarily attributed to their critical roles in the development and progression of diseases, especially in cancers. The circRNA homeodomain-interacting protein

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kinase 3 (circHIPK3) is a recently identified circRNA, acknowledged to be relevant to

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human pathology and cancer progression. Here, we summarize the origin and

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functions of the circHIPK3 and its target molecules in cancer, and thus, providing a

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broader knowledge to our current understanding of circRNAs. This review will

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therefore be essential to enriching our knowledge on the roles of circRNAs in cancers

cancer.

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by outlining their potential values and application in the diagnosis and treatment of

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Keywords: CircRNA, CircHIPK3, Cancer, MicroRNA, Tumor progression

Journal Pre-proof 1. Introduction Circular RNAs (circRNAs) form a continuous covalently closed loop structures with neither a 5ʹ cap or a 3ʹ tail polarity nor polyadenylated tails which are characteristic features of linear RNAs [1, 2]. Historically, circRNAs were discovered about 49 years ago in RNA viruses [2]. Following this discovery, circRNAs were sporadically reported and misinterpreted as by-products of splicing errors [3]. Now,

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with the emergence of deep sequencing RNA technology and bioinformatics, recent

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works have revealed that large numbers of circRNAs are endogenously abundant,

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conserved and stable in mammalian cells [3-8]. They are widely expressed in

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eukaryotic cells, with thousands of them existing in human tissues as has been

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detected by high-throughput sequencing [9]. Usually, circRNAs primarily reside in the cytoplasm, whereas a small number of circRNAs are located in the nucleus [6].

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There about a third of circRNAs are conserved among different species [10] and

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exhibit tissue-specific and dynamic developmental stage-expression patterns [7]. In addition, circRNAs are much more stable in cells and play regulatory roles at the levels of transcription or post-transcription [6]. CircRNAs are expected to perform other functions independent of their host genes, which may be related to their prolonged half-life compared with linear RNA transcripts [11].

CircRNAs perform diverse functions in gene regulation, including: (1) Acting as microRNA (miRNA) sponges. CircRNAs share miRNA response elements with other RNAs such as mRNAs, pseudogenes and long noncoding RNAs (lncRNAs), which

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can compete for miRNA binding sites [6, 12]. The presence or absence of competitive-endogenous RNAs influences the activities of miRNAs regarding their regulation of gene expression. (2) Regulating alternative splicing or transcription. CircRNAs compete with pre-mRNA splicing to reduce linear mRNA and exclude specificity from pre-mRNA to change the composition of processed mRNA [13, 14].

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Moreover, stable circRNAs located in the nucleus bind to RNAs to promote transcription. (3) Interacting with RNA-binding proteins (RBPs). CircRNAs bind

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RBPs and ribonucleoprotein complexes to prevent these factors from playing a

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“storage” function [13, 15]. (4) Translation. CircRNAs were initially defined as a

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distinct class of non-coding RNAs that could not translate. However, recent studies

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have shown that some circRNAs can also encode proteins when driven by an internal

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ribosome entry point (IRES) [16-19]. (5) Regulating epigenetic alterations. CircRNAs have also been found to regulate epigenetic alterations, such as circFECR1, which

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induces extensive CpG DNA demethylation in the promoter of friend leukemia virus integration 1 (FLI1) and thus epigenetically activates FLI1 [20]. (6) Transporting substances and information. CircRNAs are found to be abundant and stable in exosomes and are also involved in the process of exosome function, which mediates the transport of substances and information [21, 22]. Due to the critical role of circRNAs in cellular function, several databases have been established, including circBase, CircInteractome, CircNet, Circ2Traits, CircR2Disease, TCSD, and CSCD, which are helpful in the assessment of diverse features of circRNAs [9, 23-28].

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In recent years, circRNAs have been attracting considerable research attention attributed to their critical roles in the development and progression of human diseases, especially in cancer [29-35]. An understanding of circRNAs in the hallmarks, stemness, resistance of cancer, as well as potential biomarkers in cancer will enrich our knowledge of cancer and provide new opportunities for cancer therapy [36-38].

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By RNA deep sequencing, the circRNA homeodomain-interacting protein kinase 3 (circHIPK3) has identified to be abundantly expressed in human cells [39]. Previous

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studies have indicated that circHIPK3 sponges multiple miRNAs including miR-124

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and miR-558 [39, 40]. By sponging miR-124, circHIPK3 inhibits its activity and

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induces a strong proliferative effect in cancer cells [39]. However, circHIPK3 sponges

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miR-558 to suppress bladder cancer growth [40]. This indicates that circHIPK3 plays

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dual roles in cancer progression by sponging different miRNAs and targeted protein or signaling. Due to it significance to the study of cancer, it is necessary to clarify the

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multiple effects and underlying mechanisms of circHIPK3 in the development of a variety of cancers. In the subsequent sections, we present an overview of the characteristics, functions and functional mechanisms of the circHIPK3 in cancer, and thus providing a foundational basis for the further study and to provide a new direction toward the early diagnosis and targeted therapy of cancer.

2. CircRNA HIPK3 (circHIPK3) HIPK3 is a part of the larger HIPK family, which is made up of four nuclear serine-threonine kinases (HIPK1, HIPK2, HIPK3, and HIPK4) [41]. HIPKs are

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nuclear kinases, which function as co-repressors of homeodomain transcription factors [42]. HIPK1, HIPK2, HIPK3, and HIPK4 harbor the serine/threonine kinase catalytic domains at their N-termini and the residues within their kinase catalytic domains are conserved among all four kinases [43]. All members of the family, with the exception of smaller size HIPK4, share about a 90% homology (Fig. 1) [43].

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HIPK3 has emerged as the most important member of the family in pancreatic physiology [41]. The circular RNA HIPK3 (circHIPK3) originates from exon 2 of the

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HIPK3 gene (1,099 bp), and its sequence in circBase is shown in figure 2 (Fig. 2) [39,

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40], which is a large exon, flanked by long introns on both sides containing many

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complementary Alu repeats [40]. The exon 2 of the HIPK3 gene is preferentially

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circularized because it is sterically easier for 3ʹ to 5ʹ splicing at canonical splice sites

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[44, 45]. It has been demonstrated that circHIPK3 is preferentially localized in the cytoplasm, stably and abundantly expressed in different human tissues [39].

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CircHIPK3 mediates retinal microvascular dysfunction in diabetes mellitus [46], and its downregulation is found to mediate high glucose-induced endothelial cell injury [47]. In addition, it has been verified to be involved in tumorigenesis and was also named bladder cancer-related circular RNA-2 (BCRC-2, GenBank: KU921433.1) [40].

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Figure 1. Alignment of human HIPK1, 2, 3 and 4 amino acid sequences.

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Figure 2. Schematic diagram illustrates the biogenesis of circHIPK3. The circularization of HIPK3 exon 2 forms circHIPK3 (black arrow). Red arrow represents “head-to-tail” splicing sites of circHIPK3.

3. CircHIPK3 functions as miRNA sponges

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It has been demonstrated that circHIPK3 acts as a miRNA sponge absorbing

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several miRNAs (Fig. 3). Among these miRNAs, miR-124 exerts tumor suppressive

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functions in several cancer types, including breast, prostate, liver and lung carcinoma

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[48-50]. By sponging miR-124, circHIPK3 inhibits its activity and induces a strong

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proliferative effect in cancer cells [39]. CircHIPK3 is also able to sponge miR-506 and miR-7 in cervical cancer and colorectal cancer (CRC) respectively [51, 52].

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Furthermore, circHIPK3 also regulates miR-654 and miR-124-3p in glioma progression [53, 54]. MiR-4288 is a target of circHIPK3 in lung cancer and nasopharyngeal carcinoma [55, 56]. In bladder cancer, there exist two accessible binding sites for circHIPK3 sponging of miR-588 by which regulates cancer progression [40]. On the other hand, circHIPK3 plays a negative regulatory role on miR-124/miR-29b expression and is associated with the progression of gastric cancer (GC) including the T stage and Ming's classification in GC [57]. The miRNAs regulated by circHIPK3 in various cancers are shown in Table 1.

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Figure 3. Schematic diagram of circHIPK3 functions as miRNA sponges. CircHIPK3 is released from the nucleus and can function as sponges for the indicated miRNAs, which regulate the respective target genes to promote or inhibit tumor progression. Standard-shaped arrow: stimulation; T-shaped arrow: inhibition.

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Table 1. Expressions and functions of circHIPK3 in different cancers Cancer types

Target miRNAs and genes

Associated cell process

Associated clinical features

Reference

Up

Colorectal cancer (CRC)

miR-7/EGFR, FAK, IGF1R, YY1

Metastasis, clinical stage and survival time

[63]

Up

Epithelial ovarian cancer (EOC)

-

Inhibit cell proliferation, migration, invasion, and induce apoptosis -

Lymph node invasion, FIGO stage, worse disease-free survival (DFS) and overall survival (OS)

[60]

Up

Gallbladder cancer (GC)

miR-124/ROCK1, CDK6 miR-29b

Promote cell survival and proliferation, inhibit cell apoptosis

T stage and Ming's classification

[61]

Up

Glioma

miR-654/IGF2BP3 miR-124-3p/STAT3

Promote cell proliferation, and cell invasion

-

[53, 54]

Up

Hepatocellular carcinoma (HCC)

miR-124-AQP3

Promote cell proliferation, induce cell migration

-

[20]

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Expression

Journal Pre-proof miR-124/SphK1, CDK4, STAT3

Promote cell proliferation, reduce apoptosis, autophagy Promote invasion

-

[56, 67]

Up

Nasopharynge al carcinoma

miR-4288/ELF3

-

[55]

Up

Prostate cancer

miR-193a-3p/MCL 1 miRNA-338-3p/AD AM17

Promote invasion

-

[59, 66]

Down

Bladder cancer (Bca)

miR-558/HPSE, VEGF

Inhibit migration, invasion, and angiogenesis

Tumor grade, invasion, lymph node metastasis

[40]

Down

Gastric cancer (GC)

miR-124,miR-29b

-

Age and M classification

[57]

Down

Ovarian cancer

-

Promote proliferation, inhibit apoptosis, promote migration and invasion

Lymph node invasion and overall survival of patients

[68]

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Lung cancer

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Up

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4. Expression of circHIPK3 in cancers

Earlier studies have shown that circHIPK3 is expressed differently in many

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cancerous tissues and cell lines. Cancerous cell lines are prone to express a more

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diverse pattern of circRNAs compared with non-cancerous cell lines [58]. Recent studies broadly identify circHIPK3 expression from many adjacent non-tumor and tumor specimens including bladder cancer [40], CRC [52], glioma [53], prostate cancer [59] and cervical cancer [51]. CircHIPK3 is markedly overexpressed in CRC tissues and cell lines, and positively associated with advanced clinical stage and poor survival of CRC patients [52]. The expression of circHIPK3 is upregulated in epithelial ovarian cancer (EOC) tissues compared with normal ovarian epithelium tissues [60]. CircHIPK3 was shown to be upregulated in human gallbladder cancer (GC) tissues and cells [61], whereas its expression was found to be significantly downregulated in GC tumoral tissues compared with their paired adjacent

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nonneoplastic counterparts, with its expression levels were related with age and M classification [62]. CircHIPK3 expression is upregulated in human lung cancer cells compared to its low level in the lung epithelial cells [56]. These studies indicate that circHIPK3 expression is dynamically regulated in different cancer progression, and exerts its regulatory functions via multiple ways.

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5. Dual roles of circHIPK3 in cancers

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5.1. Cancer growth

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CircHIPK3 has been proposed to be involved in tumorigenesis by reversing

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tumor suppressive miRNAs and their target oncogenes. As a tumor suppressor, miR-7

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targets an important trigger of the signaling transduction of the growth factors, epidermal growth factor receptor (EGFR) that regulates cell growth and various

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biological processes [63, 64]. Overexpression of circHIPK3 effectively reverses

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miR-7-induced attenuation of CRC cell progression by upregulating the expression of several key miR-7 target genes, including EGFR, IGF1R, FAK and YY1 [63]. On the other hand, circHIPK3 knockdown significantly inhibits CRC cell proliferation but induces cell apoptosis [52]. Cyclin dependent kinase 6 (CDK6) is regulated by miRNA-124 in medulloblastoma by which it modulates medulloblastoma cell growth [65]. In gallbladder cancer cells, silencing of circHIPK3 decreases the proliferative and survival capacities, inducing apoptosis through sponging the tumor-suppressive miR-124, and increasing the expressions of miR-124 targeting [61]. Overexpression of circHIPK3 also sponges miR-124, inhibiting its activity and elevating its target proliferation-promoting

genes

IL6R

and

DLX2

to

increase

cell

growth.

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Downregulation of circHIPK3, but not HIPK3 mRNA, significantly suppresses cell growth in different cell types (i.e. Huh7, HCT-116 and HeLa) [39]. CircHIPK3 promotes cell proliferation by regulating miRNAs-mediated signaling in cancer cells, including

miR-654/IGF2BP3

and

miR-124-3p/STAT3

in

glioma

cells,

or

miR-193a-3p/MCL1 and miRNA-338-3p/ADAM17 in prostate cancer cells [51, 53,

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54, 66, 67]. In hepatocellular carcinoma, circHIPK3 promotes cell proliferation, as well as in vivo tumor growth via the miR-124-AQP3 axis [20, 55]. In addition,

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circHIPK3 promotes proliferation in nasopharyngeal carcinoma by abrogating

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miR-4288-induced ELF3 inhibition [55]. Moreover, circHIPK3 acts as miR-124

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sponge and regulates the expression of miR-124 mRNA targets (i.e. SphK1, CDK4

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and STAT3) in lung cancer cells to promote cell proliferation but reduce apoptosis

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[56], and autophagy is involved in this signaling in STK11 mutant lung cancer [67]. However, circHIPK3 also shows the tumor-suppressive function in cancer growth.

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Overexpression of circHIPK3 significantly suppresses bladder cancer growth in vivo [40], whereas silencing of circHIPK3 promotes proliferation but inhibits apoptosis of ovarian cancer cells (A2780 and SKOV3) and normal ovarian epithelial cells (IOSE80) [68].

5.2. Metastasis CircHIPK3 and its target miRNAs and genes are involved in regulating tumor metastasis. Functional investigation indicates that circHIPK3 promotes glioma cell invasion and tumor propagation in vivo [51, 53]. CircHIPK3 promotes invasion of prostate cancer by sponging miR-193a-3p and targeting MCL1 expression, or through

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regulating miRNA-338-3p and targeting ADAM17 expression [59, 66]. In hepatocellular carcinoma, circHIPK3 acts as a miR-124 sponge and regulates the expression of the miR-124-targeted gene AQP3 to induce cell migration [20]. In nasopharyngeal

carcinoma,

circHIPK3

promotes

invasion

by

abrogating

miR-4288-induced ELF3 inhibition [55]. Overexpression of circ-HIPK3 promotes the

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invasive capacities of glioma cells by sponging miR-124-3p to upregulate STAT3 expression [54]. The function of circHIPK3 in ovarian cancer metastasis appears to be

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debatable. Silencing of circHIPK3 promotes migration and invasion of ovarian cancer

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cells (A2780 and SKOV3) and normal ovarian epithelial cells (IOSE80) [68].

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However, in EOC, overexpression of circHIPK3 is correlated with lymph node

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invasion and overall survival of patients [60]. In addition, in bladder cancer,

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circHIPK3 negatively correlates with invasion as well as lymph node metastasis, respectively. Overexpression of circHIPK3 effectively inhibits migration and invasion

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of bladder cancer cells in vitro and suppresses bladder cancer metastasis in vivo [40].

5.3. Angiogenesis

Angiogenesis is an important process for tumor progression as it supplies the tumor with oxygen and nutrients and disposes the wastes by forming new blood vessels around the solid tumors. Vascular endothelial growth factor (VEGF) is one of the most potent cytokines, which plays a key regulatory role in angiogenesis [69]. CircHIPK3 is significantly down-regulated in bladder cancer tissues and cell lines, but an in vitro study in bladder cancer cells shows that overexpression of circHIPK3 effectively suppresses angiogenesis through the sponging of miR-558 and subsequent

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inhibition of heparanase and VEGF [40]. This indicates the tumor suppressive role of circHIPK3 in bladder cancer. However, circHIPK3 also plays a role in diabetic retinopathy leading to increased endothelial proliferation and vascular dysfunction by blocking miR-30a function and increasing vascular endothelial growth factor-C, FZD4, and WNT2 expression [46]. In addition, the angiogenesis inhibitory effect of

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downregulating circHIPK3 is speculated to lead to inadequate spiral artery remodeling, involving the pathogenesis of preeclampsia related to poor placentation

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angiogenesis [70]. High glucose induces the downregulation of circHIPK3, which

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causes miRNA-124 accumulation in human umbilical vein endothelial cells

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(HUVECs) and primary aortic endothelial cells (HAECs). miRNA-124 inhibition and

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circHIPK3 overexpression inhibits high glucose-induced cell death and apoptosis,

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which suggests circHIPK3-targeting miRNA-124 exacerbates angiogenesis [47]. However, the exact roles of circHIPK3 and its underlying mechanism of angiogenesis

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in cancer need further clarification.

6. Conclusions

Investigation into circRNAs have gained prominence among researchers in recent years due to their usefulness as therapeutic targets, their unique properties such as stability, conservation, universality (broadly expressed in the eukaryotic cells) and specificity, and their potential value as promising prognostic and diagnostic biomarkers in cancer treatment [3]. Existing data supports that circRNA are stably expressed and present in relatively high amounts in human body fluids like plasma,

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serum, and saliva [71, 72]. Deregulation of the circRNA circHIPK3 can affect cancer cell proliferation, apoptosis, migration or invasion and angiogenesis, which might directly impact their roles in cancer development. Currently, accumulating evidence suggests that there are no preclinical reports on the application of individual circRNA as a target or therapeutic vector for cancer treatment. Therefore, researchers can

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explore this interesting area in future studies on circRNAs, such as the circHIPK3. As a therapeutic vector, its unique cellular stability and capacity to sponge miRNAs and

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proteins makes it a promising vehicle for the delivery of therapeutic drugs, while

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harnessing its multiple binding sites for oncogenic miRNAs or proteins may restore

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controlled cell proliferation or induce apoptosis of cancer cells. Most current studies

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are trying to understand and unravel how circRNAs interact with miRNAs in cancer.

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In spite of that, further studies are needed to extensively explore the interaction network of circRNAs in cancer including miRNAs, lncRNAs, and protein degrading

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pathways, such as autophagy, as well as in immune cells. Although some circRNAs have been discovered and investigated, the function of thousands of circRNAs remains unclear. With the efforts of scientists and the application of new methods, more circRNAs could be discovered, and an advanced understanding of circRNAs will provide beneficial insights into cancer pathogenesis. We hope that circRNAs can be applied in clinical practice of cancer therapy in the near future.

Acknowledgments This work was supported by the National Natural Science Foundation of China (31600952 and 31271272), the Foundation of Health and Family Planning

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Commission of Wuxi (Q201807 and MS201812), and the Start-Up Research Funding of Jiangsu University for Distinguished Scholars (5501330001). Conflict of interest: The authors declare no conflict of interest.

Reference

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[1] L.L. Chen, L. Yang. Regulation of circRNA biogenesis, RNA Biol. 12 (4) (2015) 381-388. [2] S. Qu, et al. Circular RNA: A new star of noncoding RNAs, Cancer Lett. 365 (2) (2015) 141-148. [3] W.R. Jeck, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats, RNA. 19 (2) (2013) 141-157. [4] J.U. Guo, et al. Expanded identification and characterization of mammalian circular RNAs, Genome Biol. 15 (7) (2014) 409. [5] Z. Li, et al. Exon-intron circular RNAs regulate transcription in the nucleus, Nat Struct Mol Biol. 22 (3) (2015) 256-264. [6] S. Memczak, et al. Circular RNAs are a large class of animal RNAs with regulatory potency, Nature. 495 (7441) (2013) 333-338. [7] J. Salzman, et al. Cell-type specific features of circular RNA expression, PLoS Genet. 9 (9) (2013) e1003777. [8] Y. Zhang, et al. Circular intronic long noncoding RNAs, Mol Cell. 51 (6) (2013) 792-806. [9] S. Xia, et al. Comprehensive characterization of tissue-specific circular RNAs in the human and mouse genomes, Brief Bioinform. 18 (6) (2017) 984-992. [10] X. Chen, et al. Noncoding RNAs: New Players in Cancers, Adv Exp Med Biol. 927 (2016) 1-47. [11] X. Li, et al. The Biogenesis, Functions, and Challenges of Circular RNAs, Mol Cell. 71 (3) (2018) 428-442. [12] X. Gu, et al. Identification and integrated analysis of differentially expressed lncRNAs and circRNAs reveal the potential ceRNA networks during PDLSC osteogenic differentiation, BMC Genet. 18 (1) (2017) 100. [13] R. Ashwal-Fluss, et al. circRNA biogenesis competes with pre-mRNA splicing, Mol Cell. 56 (1) (2014) 55-66. [14] L.L. Chen. The biogenesis and emerging roles of circular RNAs, Nat Rev Mol Cell Biol. 17 (4) (2016) 205-211. [15] S.J. Conn, et al. The RNA binding protein quaking regulates formation of circRNAs, Cell. 160 (6) (2015) 1125-1134. [16] I. Legnini, et al. Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis, Mol Cell. 66 (1) (2017) 22-37.e29. [17] M. Zhang, et al. A novel protein encoded by the circular form of the SHPRH

Journal Pre-proof

Jo ur

na

lP

re

-p

ro

of

gene suppresses glioma tumorigenesis, Oncogene. 37 (13) (2018) 1805-1814. [18] N.R. Pamudurti, et al. Translation of CircRNAs, Mol Cell. 66 (1) (2017) 9-21.e27. [19] B.X. Chu, et al. Interplay between autophagy and apoptosis in lead(II)-induced cytotoxicity of primary rat proximal tubular cells, J Inorg Biochem. 182 (2018) 184-193. [20] N. Chen, et al. A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1, Genome Biol. 19 (1) (2018) 218. [21] Y. Li, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis, Cell Res. 25 (8) (2015) 981-984. [22] Z. Li, et al. Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer, Cancer Lett. 432 (2018) 237-250. [23] D.B. Dudekula, et al. CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs, RNA Biol. 13 (1) (2016) 34-42. [24] S. Ghosal, et al. Circ2Traits: a comprehensive database for circular RNA potentially associated with disease and traits, Frontiers in genetics. 4 (2013) 283. [25] P. Glazar, et al. circBase: a database for circular RNAs, RNA. 20 (11) (2014) 1666-1670. [26] Y.C. Liu, et al. CircNet: a database of circular RNAs derived from transcriptome sequencing data, Nucleic Acids Res. 44 (D1) (2016) D209-215. [27] S. Xia, et al. CSCD: a database for cancer-specific circular RNAs, Nucleic Acids Res. 46 (D1) (2018) D925-d929. [28] C. Fan, et al. CircR2Disease: a manually curated database for experimentally supported circular RNAs associated with various diseases, Database (Oxford). 2018 (2018). [29] Y. Bai, et al. Circular RNA DLGAP4 Ameliorates Ischemic Stroke Outcomes by Targeting miR-143 to Regulate Endothelial-Mesenchymal Transition Associated with Blood-Brain Barrier Integrity, J Neurosci. 38 (1) (2018) 32-50. [30] L. Chen, et al. Retraction Note: circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family, Oncogene. 38 (28) (2019) 5750. [31] Y. Geng, et al. Function and clinical significance of circRNAs in solid tumors, J Hematol Oncol. 11 (1) (2018) 98. [32] J. Guarnerio, et al. Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations, Cell. 166 (4) (2016) 1055-1056. [33] Y. Guo, et al. Circular RNAs and their roles in head and neck cancers, Mol Cancer. 18 (1) (2019) 44. [34] L.M. Holdt, et al. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans, Nature communications. 7 (2016) 12429. [35] Z. Zhou, et al. circRNA Mediates Silica-Induced Macrophage Activation Via HECTD1/ZC3H12A-Dependent Ubiquitination, Theranostics. 8 (2) (2018) 575-592. [36] D.H. Bach, et al. Circular RNAs in Cancer, Molecular therapy Nucleic acids. 16 (2019) 118-129.

Journal Pre-proof

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ro

of

[37] S. Qu, et al. The emerging functions and roles of circular RNAs in cancer, Cancer Lett. 414 (2018) 301-309. [38] M. Su, et al. Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers, Mol Cancer. 18 (1) (2019) 90. [39] Q. Zheng, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs, Nature communications. 7 (2016) 11215. [40] Y. Li, et al. CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells, EMBO reports. 18 (9) (2017) 1646-1659. [41] A. Conte, G.M. Pierantoni. Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs, MicroRNA (Shariqah, United Arab Emirates). 7 (3) (2018) 178-186. [42] Y.H. Kim, et al. Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors, J Biol Chem. 273 (40) (1998) 25875-25879. [43] Q. He, et al. Characterization of Human Homeodomain-interacting Protein Kinase 4 (HIPK4) as a Unique Member of the HIPK Family, Mol Cell Pharmacol. 2 (2) (2010) 61-68. [44] W.R. Jeck, N.E. Sharpless. Detecting and characterizing circular RNAs, Nat Biotechnol. 32 (5) (2014) 453-461. [45] S. Starke, et al. Exon circularization requires canonical splice signals, Cell Rep. 10 (1) (2015) 103-111. [46] K. Shan, et al. Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus, Circulation. 136 (17) (2017) 1629-1642. [47] Y. Cao, et al. High glucose-induced circHIPK3 downregulation mediates endothelial cell injury, Biochem Biophys Res Commun. 507 (1-4) (2018) 362-368. [48] S. Du, et al. MicroRNA-124 inhibits cell proliferation and migration by regulating SNAI2 in breast cancer, Oncol Rep. 36 (6) (2016) 3259-3266. [49] L. Xu, et al. Methylation-regulated miR-124-1 suppresses tumorigenesis in hepatocellular carcinoma by targeting CASC3, Oncotarget. 7 (18) (2016) 26027-26041. [50] M. Wang, et al. MiR-124 Inhibits Growth and Enhances Radiation-Induced Apoptosis in Non-Small Cell Lung Cancer by Inhibiting STAT3, Cell Physiol Biochem. 44 (5) (2017) 2017-2028. [51] H.B. Ma, et al. Extensive profiling of circular RNAs and the potential regulatory role of circRNA-000284 in cell proliferation and invasion of cervical cancer via sponging miR-506, American journal of translational research. 10 (2) (2018) 592-604. [52] K. Zeng, et al. CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7, Cell Death Dis. 9 (4) (2018) 417. [53] P. Jin, et al. CircRNA circHIPK3 serves as a prognostic marker to promote glioma progression by regulating miR-654/IGF2BP3 signaling, Biochem Biophys Res Commun. 503 (3) (2018) 1570-1574. [54] D. Hu, Y. Zhang. Circular RNA HIPK3 promotes glioma progression by

Journal Pre-proof

Jo ur

na

lP

re

-p

ro

of

binding to miR-124-3p, Gene. 690 (2019) 81-89. [55] Z. Ke, et al. CircHIPK3 promotes proliferation and invasion in nasopharyngeal carcinoma by abrogating miR-4288-induced ELF3 inhibition, J Cell Physiol. 234 (2) (2019) 1699-1706. [56] H. Yu, et al. Circular RNA HIPK3 exerts oncogenic properties through suppression of miR-124 in lung cancer, Biochem Biophys Res Commun. 506 (3) (2018) 455-462. [57] J. Cheng, et al. Regulatory network of circRNA-miRNA-mRNA contributes to the histological classification and disease progression in gastric cancer, J Transl Med. 16 (1) (2018) 216. [58] Y. Gao, et al. CIRI: an efficient and unbiased algorithm for de novo circular RNA identification, Genome Biol. 16 (2015) 4. [59] D. Chen, et al. Circular RNA circHIPK3 promotes cell proliferation and invasion of prostate cancer by sponging miR-193a-3p and regulating MCL1 expression, Cancer Manag Res. 11 (2019) 1415-1423. [60] N. Liu, et al. CircHIPK3 is upregulated and predicts a poor prognosis in epithelial ovarian cancer, Eur Rev Med Pharmacol Sci. 22 (12) (2018) 3713-3718. [61] D. Kai, et al. Circular RNA HIPK3 promotes gallbladder cancer cell growth by sponging microRNA-124, Biochem Biophys Res Commun. 503 (2) (2018) 863-869. [62] S. Ghasemi, et al. Down-regulation of circular RNA ITCH and circHIPK3 in gastric cancer tissues, Turkish journal of medical sciences. 49 (2) (2019) 687-695. [63] X. Sun, et al. miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways, Oncotarget. 7 (33) (2016) 53558-53570. [64] Z. Yang, et al. Circular RNAs: Regulators of Cancer-Related Signaling Pathways and Potential Diagnostic Biomarkers for Human Cancers, Theranostics. 7 (12) (2017) 3106-3117. [65] J. Pierson, et al. Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma, J Neurooncol. 90 (1) (2008) 1-7. [66] C. Cai, et al. CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p, Onco Targets Ther. 12 (2019) 3363-3372. [67] X. Chen, et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in STK11 mutant lung cancer, Autophagy. (2019) 1-13. [68] F. Teng, et al. Comprehensive circular RNA expression profiles and the tumor-suppressive function of circHIPK3 in ovarian cancer, Int J Biochem Cell Biol. 112 (2019) 8-17. [69] R. Roskoski, Jr. Vascular endothelial growth factor (VEGF) signaling in tumor progression, Crit Rev Oncol Hematol. 62 (3) (2007) 179-213. [70] Y. Zhang, et al. CircHIPK3 is decreased in preeclampsia and affects migration, invasion, proliferation, and tube formation of human trophoblast cells, Placenta. 85 (2019) 1-8. [71] L. Arantes, et al. Serum, plasma and saliva biomarkers for head and neck

Journal Pre-proof

Jo ur

na

lP

re

-p

ro

of

cancer, Expert Rev Mol Diagn. 18 (1) (2018) 85-112. [72] X. Lin, et al. Noncoding RNAs in human saliva as potential disease biomarkers, Frontiers in genetics. 6 (2015) 175.

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Highlights  CircHIPK3 originates from exon 2 from the HIPK3 gene.  CircHIPK3 acts as miRNA sponges.  CircHIPK3 differently expressed in cancer tissues and cell lines.  CircHIPK3 plays dual roles in cancer growth, metastasis and angiogenesis.  CircHIPK3 might be potential target of cancer therapy.