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Circular RNAs: The crucial regulatory molecules in colorectal cancer
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Review
Circular RNAs: The crucial regulatory molecules in colorectal cancer Kaixuan Zenga,b, Shukui Wanga,b,* a b
School of Medicine, Southeast University, Nanjing, 210009, China General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
A R T I C LE I N FO
A B S T R A C T
Keywords: NcRNAs circRNAs Colorectal cancer Biomarkers
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Recent studies have shown that circular RNAs (circRNAs) play critical roles in the pathogenesis and progression of CRC. CircRNAs are a special class of endogenous non-coding RNAs (ncRNAs) that harbor covalently closed ring structure with high conservation and stability, which are expressed in a tissue- and developmental-stage-specific manner. A growing body of evidence suggests that circRNAs are abnormally expressed in CRC tissues, cell lines and plasma, and are closely linked with CRC clinical malignant features. CircRNAs participate in various biological processes of CRC cells, including cell proliferation, apoptosis, senescence, migration and invasion and so on, through acting as “microRNA (miRNA) sponges”, binding to protein and even translating protein. In the present review, we systematically introduce the CRC-related circRNAs and their functional mechanisms, as well as the potential applications for CRC diagnosis and prognosis.
1. Introduction Colorectal cancer (CRC) is one of the most common malignancies in the world, ranking third in incidence and second in mortality among all cancer [1]. According to the epidemiological investigation, it is estimated that there will be more than 1.8 million new CRC cases and 881000 deaths in 2018, accounting for about one tenth of cancer cases and deaths [2]. Even worse, the global burden of CRC is expected to increase by 60 % to more than 2.2 million new cases and 1.1 million deaths by 2030 [3]. For the vast majority of people, age is a major factor in increasing the risk of CRC, especially after age 50 years; however, emerging evidence shows that more and more young adults are being diagnosed with CRC [4], especially in China [5], hinting that the increase in the malignancy of CRC. In the past several decades, despite some novel therapeutic schedules including laparoscopic surgery, radiotherapy, neoadjuvant and palliative chemotherapies have emerged, the cure rate and long-term survival rate of CRC are still very low [6], mainly due to the lack of sensitive and stable diagnostic or prognostic biomarkers and inadequate understanding of its pathogenesis. With the completion of the human genome project, only about 2% of the genes in the human genome can translate proteins, while the remaining 98 % belong to non-coding RNAs (ncRNAs) [7]. For a long time, the large number of ncRNAs has been regarded as the "noise" of genome transcription without definite biological function. However,
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this is not the case, more and more recent evidence suggests that ncRNAs are involved in a wide range of important biological activities [8]. As a special type of ncRNAs, circular RNAs (circRNAs) are characterized by covalently closed loop structure with neither 3′-5′end polarity nor polynucleotide tails, they are highly stable and evolutionarily conservative [9]. CircRNAs are derived from the back-splicing of premRNA and are divided into different subtypes according to different sources: exon circRNAs (ecircRNAs), intron circRNAs (ciRNAs), exon and intron circRNAs (EIciRNAs), intergenic circRNAs and fusion circRNAs (f-circRNAs) (due to chromosomal translocations) [10]. And 80 % of circRNAs are ecircRNAs, which are mainly located in the cytoplasm [11], while ciRNAs and ciRNAs are frequently observed in the nucleus [12]. With the development of experimental techniques such as circRNA microarry screening and high-throughput sequencing, the mystery of circRNA has gradually been revealed, and its function and application value have gradually emerged. Accumulated evidence shows that circRNAs are abundant in eukaryotes and expressed in a tissue- and developmental-stage-specific pattern [13], and the abundances of some circRNAs are even more than 10 times higher than those of their respective homologous linear mRNAs [14]. Up to now, a large number of dysregulated circRNAs have been identified in human cancers, including CRC [15]. CircRNAs were shown to participate in the proliferation, differentiation, apoptosis, senescence, migration and invasion of tumor cells by regulating different signaling pathways [16,17].
Correspondence author at: School of Medicine, Southeast University, Nanjing, 210009, China. E-mail address: [email protected] (S. Wang).
https://doi.org/10.1016/j.prp.2020.152861 Received 22 December 2019; Received in revised form 20 January 2020; Accepted 10 February 2020 0344-0338/ © 2020 Elsevier GmbH. All rights reserved.
Please cite this article as: Kaixuan Zeng and Shukui Wang, Pathology - Research and Practice, https://doi.org/10.1016/j.prp.2020.152861
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significantly decreased in CRC tissues and cell lines. Further investigation showed that circ-ITGA7 increased ITGA7 transcription level through inhibiting RREB1 via the oncogenic Ras signaling pathway. Depletion of circ-ITGA7 or ITGA7 resulted in the enhanced proliferation and metastasis of CRC cells both in vitro and in vivo [51]. Subsequently, another study also confirmed the tumor-inhibiting effect of circ-ITGA7 in CRC [52]. Interestingly, Dou Y et al. performed circRNA sequencing and compared the levels of circRNA candidates between the mutant and wild-type KRAS CRC cell lines [53]. Totally, 748 downregulated circRNAs were identified in mutant KRAS cells as compared with wildtype KRAS cells, while only 18 circRNAs were shown to be upregulated, suggesting that downregulation of circRNA in KRAS mutant CRC cells is a universal event. Importantly, they also found that circRNAs could be secreted into extracellular-vesicles, especially exosomes [53]. Besides, there are also numerous downregulated circRNAs identified in CRC, which play an important role in inhibiting CRC tumorigenesis and progression. They are summarized in Table 2, as shown below.
Herein, we focused on the roles of circRNAs in CRC, and systematically summarized the molecular mechanisms by which circRNAs functioned in CRC and their potential utilities as diagnostic and prognostic biomarkers. 2. The dysregulated circRNAs in CRC 2.1. The upregulated circRNAs in CRC Hsiao KY et al. performed circRNA high-throughput sequencing in 12 CRC and adjacent normal tissues, and found numerous abnormally expressed circRNAs [18]. Further, they found that circ-CCDC66, a circRNA derived from CCDC66 exon 8∼10, was significantly elevated in CRC tissues and cell lines and facilitated CRC cell proliferation, migration, invasion, and anchorage-independent growth both in vitro and in vivo. Circ-CCDC66 was able to increase the levels of a panel of oncogenes, such as DNMT3B, EZH2, MYC and YAP1, thereby promoting CRC tumorigenesis and metastasis [18]. Furthermore, a recent study confirmed the pro-tumor role of circ-CCDC66 in CRC, and found that circ-CCDC66 could weaken the radio-sensitivity of CRC cells [19]. To search for CRC metastasis-associated circRNAs, Chen LY et al. established a mouse model of liver metastasis and conducted circRNA sequencing [20]. They identified one circRNA, circ-NSD2, as a driver of CRC metastasis. CRC patients with high circ-NSD2 were more likely to have lymph node and distant metastasis than those with low circ-NSD2 expression, and circ-NSD2 evidently enhanced CRC cell migratory and invasive abilities both in vitro and in vivo by modulating the miR-199b5p/DDR1/JAG1 signaling axis [20]. Besides, Xu H et al. performed circRNA sequencing in the tissue samples from three CRC patients with liver metastasis and three matched CRC patients, and identified that circRNA_0001178 and circRNA_0000826 were significantly upregulated in metastatic CRC tissues and had the potential for diagnosis of CRC liver metastasis [21]. Zhu M et al. found that circ-BANP was dysregulated in CRC by performing human circRNA microarray in 3 paired CRC cancerous and adjacent normal tissues [22]. And subsequent qRT-PCR analysis confirmed that circ-BANP was frequently overexpressed in CRC tissues and cell lines. siRNA-mediated silencing of circ-BANP markedly inhibited CRC cell proliferation [22]. Likewise, hsa_circ_000984 was proposed to be notably increased in CRC and knockdown of hsa_circ_000984 retarded CRC cell proliferation, migration, invasion in vitro and tumor formation in vivo [23]. In addition, a series of upregulated circRNAs in CRC were identified by different research groups, which promoted CRC initiation, development and progression through regulation of different genes and signaling pathways. We summarized these circRNAs in Table 1, as shown below.
3. The functional patterns of circRNAs in CRC Emerging evidence suggests that circRNAs play the essential functional roles in CRC by acting as a sponge for microRNA (miRNA), physically interacting with proteins and even translating proteins (Fig. 1). 3.1. Acting as “miRNA sponges” miRNA is a kind of endogenous ncRNA found with a length of about 20∼25bp [69]. It is an important gene posttranscriptional regulator that can directly match with the 3′- untranslated region (3′-UTR) of mRNA to promote mRNA degradation or inhibit translation process [70]. Studies have shown that some ncRNAs (such as lncRNAs) have miRNA response elements (MREs) that can act as competing endogenous RNAs (ceRNAs) and compete with mRNA to bind miRNAs, thereby reducing the inhibitory effects of miRNAs on their target genes [71]. In 2013, two different research groups first found that circRNA can sponge miRNAs, in which CDR1as had more than 70 conserved miR-7 binding sites, which could largely adsorb miR-7 and inhibit its activity, thus upregulating the expression of a series of miR-7 target genes [72,73]. A large number of subsequent studies have confirmed that circRNAs can function as ceRNAs to sponge miRNAs and regulate gene expression in human cancers, including CRC [74]. In our previous study, we found that circ-HIPK3 was significantly upregulated in CRC and potentiated CRC growth and metastasis both in vitro and in vivo [29]. Circ-HIPK3 was able to abundantly sponge miR-7 and elevate oncogenic FAK, IGF1R, EGFR and YY1 expression [29]. In addition, many circRNAs, such as circ-CCDC66 [18], hsa_circ_0009361 [49], etc, have been identified to be key regulators in CRC through functioning as “miRNA sponges”, as shown in Tables 1 and 2.
2.2. The downregulated circRNAs in CRC Geng Y et al. found that hsa_circ_0009361 was significantly downregulated in CRC through using circRNA microarry and qRT-PCR analysis in 10 pairs of CRC and adjacent normal tissues [49]. Reactivation of hsa_circ_0009361 could notably inhibit the proliferation and epithelial-mesenchymal transition (EMT) of CRC cells and delay tumor growth and metastasis in vivo. In-depth investigation revealed that hsa_circ_0009361 was capable to increase APC2 expression and dampen the Wnt/β-catenin signaling via inhibiting miR-582 [49]. Another research group performed circRNA sequencing in 4 paired CRC tissues and totally found 448 differentially expressed circRNAs, including 394 upregulated and 54 downregulated circRNAs [50]. Further, they focused on circ-DDX17 and identified it as a tumor suppressor in CRC. Silencing of circ-DDX17 significantly promoted CRC cell proliferation, migration, invasion, and inhibited apoptosis [50]. Circ-ITGA7 was a recently discovered circRNA associated with CRC progression [51]. Circ-ITGA7 and its linear host gene ITGA7 were both
3.2. Interacting with protein Emerging evidence shows that circRNAs can also function by directly interacting with protein [75]. For example, Du WW et al. reported that circ-Foxo3 could directly bind CDK2 and p21 to form a ternary complex that blocked the transition from G1 phase to S phase, thus inhibiting the progression of cell cycle [76]. Fang L et al. found that circ-CCNB1 directly interacted with CCNB1 and CDK1, breaking the connection between CCNB1 and CDK1 and hindering cell mitosis [77]. CircRNA FECR1 was proposed to directly recruit TET1 to the FLI1 promoter, resulting in DNA demethylation; meanwhile, FECR1 could also bind to methyltransferase DNMT1 and reduce its expression level [78]. Likewise, in CRC, circ-ACC1 was capable of forming a ternary complex with the regulatory β and γ subunits to stabilize and increase AMPK activation, thereby promoting CRC cell fatty acid β-oxidation, 2
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Table 1 The characteristics of upregulated circRNAs in CRC. CircRNA
Biological function
Related genes/signaling pathways
Biomarker
References
hsa_circ_001569 hsa_circ_0000069 circ-BANP ciRS-7
Promotes CRC cell proliferation and invasion Promotes CRC cell proliferation, migration, and invasion Promotes CRC cell proliferation Promotes CRC cell proliferation, migration, invasion and inhibits apoptosis Promotes CRC growth and metastasis
miR-145/E2F5/BAG4/ FMNL2 N/A N/A miR-7/EGFR1/RAF1/MAPK
N/A N/A Prognosis Prognosis
[24] [25] [22] [26]
miR-33b/miR-93/DNMT3B/EZH2/ MYC/YAP1 miR-138/TERT/PD-L1 miR-106b/CDK6 N/A miR-7/FAK/IGF1R/EGFR/YY1 miR-600/EZH2 miR-516b//FZD4/Wnt/β-catenin miR-21-5p/Tiam1 miR-150/Gli1 miR-199b-5p/DDR1/JAG1 miR-101
[18]
miR-145 circPPP1R12A-73aa/Hippo/YAP c-Jun/AMPK
Diagnosis& prognosis N/A N/A N/A Prognosis N/A Prognosis N/A N/A Prognosis Diagnosis& prognosis Prognosis Prognosis N/A
circLgr4-peptide/Lgr4/Wnt/β-catenin
N/A
[38]
miR-103a-2-5p miR-585/CDC25B N/A miR-203a-3p.1/CREB1 miR-2467-3p/MMP14 IGF2BP2/HMGA2 miR-382/587/616/ZEB1 miR-1182/hTERT miR-328-5p/E2F1
N/A Prognosis Prognosis Prognosis N/A Prognosis Prognosis N/A Diagnosis& prognosis N/A
[39] [40] [41] [42] [43] [44] [45] [46] [47]
circ-CCDC66 has_circ_0020397 hsa_circ_000984 hsa_circ_0007534 circ-HIPK3 hsa_circ_0071589 circRNA_100290 circ-ACAP2 circ-ZNF609 circ-NSD2 circ-VAPA
hsa_circ_0007142 hsa_circ_102958 hsa_circ_0122319/0079480/0087391 hsa_circ_0079993 hsa_circ_0053277 circ-NSUN2 hsa_circ_0001178 circ-FMN2 circ-CAMSAP1
Promotes CRC cell viability and invasion Promotes CRC growth and metastasis Promotes proliferation and inhibits apoptosis Promotes CRC growth and metastasis Promotes CRC carcinogenesis Promotes CRC progression Promotes CRC cell proliferation, migration and invasion Promotes CRC cell migration Promotes CRC metastasis Promotes CRC cell proliferation, migration, invasion, and inhibit apoptosis Promotes CRC metastasis Promotes CRC pathogenesis and metastasis Promotes CRC cell fatty acid β-oxidation, glycolysis and growth Promotes CRC stem cell self-renewal, tumorigenesis and invasion Promotes CRC cell proliferation, migration and invasion Promotes CRC tumorigenesis Promotes CRC metastasis Promotes CRC cell proliferation and growth Promotes CRC development Promotes CRC liver metastasis Promotes CRC invasion and metastasis Promotes CRC proliferation and tumorigenesis Promotes CRC growth
hsa_circ_0005963
Promotes CRC cell glycolysis and chemoresistance
circ-PVT1 circ-PPP1R12A circ-ACC1 circ-Lgr4
miR-122/PKM2
[27] [23] [28] [29] [30] [31] [32] [33] [20] [34] [35] [36] [37]
[48]
Table 2 The characteristics of downregulated circRNAs in CRC. CircRNA
Biological function
Related genes/signaling pathways
Biomarker
References
circ-ITCH hsa_circ_001988 hsa_circ_0003906 hsa_circ_0000567 hsa_circ_0001649 hsa_circ_0014717 hsa_circ_0026344 circ-ITGA7 hsa_circ_0000711 hsa_circ_103809 circ-MTO1 circ-DDX17 hsa_circ_0002138 hsa_circ_104916 hsa_circ_0009361 circ-ZNF609 circ-CBL.11 circ-CDYL
Inhibits N/A N/A Inhibits N/A Inhibits Inhibits Inhibits N/A Inhibits Inhibits Inhibits Inhibits Inhibits Inhibits Induces Inhibits Inhibits
ITCH/Wnt/β-catenin N/A N/A N/A N/A p16 miR-21/miR-31 ITGA7/RREB1/Ras or miR-3187-3p/ ASXL1 N/A miR-532-3p/FOXO4 Wnt/β-catenin N/A N/A N/A APC2/Wnt/β-catenin p53 miR-6778-5p/YWHAE miR-150-5p/c-Myc/cyclin D1
N/A Diagnosis Diagnosis Diagnosis Diagnosis Prognosis Prognosis N/A Diagnosis&prognosis N/A Prognosis N/A Diagnosis Prognosis N/A Diagnosis N/A N/A
[54] [55] [56] [57] [58] [59] [60] [51,52] [61] [62] [63] [50] [64] [65] [49] [66] [67] [68]
CRC cell proliferation
CRC cell proliferation and migration CRC cell proliferation, colony formation and growth CRC cell growth and invasion and induces apoptosis CRC growth and metastasis CRC cell proliferation and migration CRC cell proliferation and invasion CRC cell proliferation, migration, invasion, and induces apoptosis CRC cell proliferation CRC cell proliferation, migration, invasion, and induces apoptosis CRC progression apoptosis CRC cell proliferation CRC cell growth and migration
proliferation-related circRNA, circ-ZNF609, which was abundantly enriched in polysome fractions and was translated into a protein in a splicing-dependent and cap-independent manner [80]. Subsequently, Yang Y et al. found that circ-FBXW7 encoded a novel 21-kDa protein termed as FBXW7-185aa, which reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization [81]. Of note, an interesting study showed that consensus N6-methyladenosine (m6A) motifs were enriched in circRNAs and a single m6A site is sufficient to drive translation initiation, and this process required initiation factor eIF4G2 and m6A reader YTHDF3 [82], confirming that the circRNA-mediated
glycolysis and in vivo growth [37].
3.3. Translating protein Due to the lack of 5′-cap structure and 3′-polyadenylation tail, as well as the lack of typical internal ribosome entry site (IRES), circRNA is initially considered unable to translate protein. However, recent studies have shown that circRNA can produce protein in a cap-independent manner [79]. Fox example, by performing the high-content functional genomic screen, Legnini I et al. found a myoblast 3
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Fig. 1. The mechanisms of circRNA functions in CRC: a, some circRNAs (such as circ-HIPK3) can act as miRNA sponges to inhibit miRNA activity. b, some circRNAs (such as circ-ACC1) can directly bind to proteins and affect their functions and translocations. c, some circRNAs (such as circ-LRG4) have protein-coding capacity and can encode proteins.
[90]. Moreover, the three-circRNA panel could evidently improve the ability to diagnose CEA-negative and CA19-9-negative CRC, hinting that these three plasma circRNAs could serve as a novel and independent diagnostic biomarkers for CRC. In our recent study, we analyzed two Gene Expression Omnibus (GEO) databases containing circulating exosomal circRNAs in peripheral blood of CRC patients [91]. Further, we focused on exosomal hsa_circ_0004771 and found that it was significantly elevated in serum of CRC patients as compared to healthy controls and patients with benign intestinal diseases (BIDs) [91]. The AUC value of exosomal hsa_circ_0004771 was 0.59, 0.86 and 0.88 to differentiate BIDs, stage I/II CRC patients and CRC patients from healthy controls, respectively, suggesting that it can serve as a novel potential diagnostic biomarker for CRC. Of note, a recent pair-wise meta-analysis containing 1430 patients with CRC showed that the summary AUC of circRNA for the discriminative efficacy between patients with and without CRC was estimated to be 0.79, corresponding to a weighted sensitivity of 0.77, specificity of 0.67 and diagnostic odds ratio (DOR) of 7.52 [92]. And the performance of upregulated circRNAs for CRC detection was significantly superior to that of downregulated circRNAs (AUC:0.86 vs 0.75; DOR:10.63 vs 6.55) [92], suggesting that abnormally expressed circRNAs may be auxiliary biomarkers facilitating CRC diagnosis.
translation can be proceeded without 5′-cap structure. In CRC, circ-Lgr4 was found to be highly expressed and could be translated into a protein with the sequence of LQTASDESYKDPTNIQLSK. This protein was identified to interact with Lgr4 and subsequently activate the Wnt/β-catenin signaling, leading to enhancing CRC stem cell self-renewal, tumorigenesis and invasion [38]. Besides, Zheng X et al. showed that circ-PPP1R12A carried an open reading frame (ORF) that could encode a functional protein termed as circPPP1R12A-73aa [36]. CircPPP1R12A-73aa, but not circPPP1R12A, promoted CRC cell proliferation and metastasis both in vitro and in vivo through activating hippo-YAP signaling pathway [36]. A very recent study has found that a large number of ncRNAs have the function of translating protein, including circRNAs, such as circCFLAR, circ-SLC8A1, circ-MYBPC3 and circ-RYR2 [83]. At present, the research on the translation function of circRNA is still in its infancy. Sun P et al. recently developed the CircCode tool that can commendably identify the coding ability of circRNA with a low false discovery rate and high sensitivity [84]. It is believed that many studies focused on the translation function of circRNA will emerge in the future. 4. CircRNAs as biomarkers in CRC Studies have shown that circRNAs can be used as ideal disease biomarkers for the following reasons: I: CircRNAs lack of 5′-cap structure and 3′-polyadenosine tail, which makes circRNAs highly resistant to exonuclease [85]. II: CircRNAs are evolutionally highly conserved and stable with a half-life of more than 48 h, whereas linear RNAs have an average half-life of 10 h [86]. III: CircRNAs are expressed in a cell- or tissues- or disease-context-dependent manner [87]. IV: CircRNAs are stable in a variety of tissues and body fluids, even in paraffin-embedded tissues [88].
4.2. CircRNAs as prognostic biomarkers in CRC Weng W et al. detected the expression of ciRS-7 in the training and validation cohorts containing primary CRC and matched normal mucosae tissues, and found that it was significantly upregulated in CRC and closely associated with malignant clinical behaviors [26]. CRC patients with high ciRS-7 expression had shorter overall survival than patients with low ciRS-7 expression, and the multivariate survival analysis revealed that ciRS-7 emerged as an independent risk factor for overall survival of CRC patients [26], suggesting that ciRS-7 is a promising prognostic biomarker of CRC. Recently, we found that circ-HIPK3 was frequently overexpressed in CRC tissues and cell lines [29]. High circ-HIPK3 expression was positively correlated with T status of tumor, lymph node metastasis, distant metastasis and advanced clinical stage. The survival time of patients with high circ-HIPK3 was significantly shorter than that of patients with low circ-HIPK3. Further Cox multivariate survival analysis indicated that high circHIPK3 expression was an independent risk prognostic factor for overall survival of CRC patients [29]. Thus, circ-HIPK3 may have considerable potential as a prognostic biomarker in CRC. Accurate risk stratification for patients with stage II/III colon cancer is critical in determining postoperative treatment. In a very recent retrospective study, Ju HQ et al. performed circRNA sequencing in postoperative 20 paired frozen tissues, and profiled differentially
4.1. CircRNAs as diagnostic biomarkers in CRC Recently, Ye DX et al. performed circRNA microarray in plasma samples from 4 CRC patients and 4 healthy controls, and found that hsa_circ_0082182, hsa_circ_0000370 and hsa_circ_0035445 had diagnostic values for CRC, the area under the curve (AUC) values of these three circRNAs were 0.8152, 0.7371 and 0.7028, respectively [89]. Importantly, the AUC value of the mixture of three circRNAs was 0.8347, highlighting their promising diagnostic utility as a panel of non-invasive biomarkers for early CRC [89]. In addition, Lin J et al. reported that the plasma levels of three circRNAs (circ-CCDC66, circ-ABCC1 and circ-STIL) were significantly downregulated in CRC patients in comparison with healthy controls [90]. And the AUC value of these three-circRNA panel was 0.780, which was higher than that of traditional protein biomarkers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) 4
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expressed circRNAs between patients with and without recurrence [41]. Next, they generated a four-circRNA-based cirScore (hsa_circ_0122319, hsa_circ_0087391, hsa_circ_0079480 and hsa_circ_0008039) to classify patients into high-risk and low-risk groups, raising the possibility that circRNAs may be supplementary to the traditional clinicopathological risk factors as a prognostic scheme [41].
[7]
[8] [9]
5. Conclusions Nowadays, the field of circRNAs has attracted great attention. With the development of new generation of high-throughput sequencing technology, more and more circRNAs have been found and expressed abnormally in human CRC tissues, cells and plasma. They play a role in inhibiting or promoting CRC by regulating different molecules and signal pathways. Some circRNAs are closely related to CRC clinical grade, pathological stage, recurrence, metastasis, drug resistance and outcome, suggesting that circRNAs are pivotal players in the pathogenesis, diagnosis and treatment of CRC. Although existing studies have gradually uncovered the mystery of circRNA, we have gained a preliminary understanding of its source, function and regulatory mechanism, there are still many important issues not clarified, for instance, what are the key molecules for circRNA nucleo-cytoplasmic shuttling (except for the length of the circRNA [93]) as well as for circRNA degradation? In addition to m6A modification, whether there are other factors controlling the translation of protein by circRNA in a 5′-cap independent manner, and whether this process is proceeded in a tissue- or developmental-stage-specific pattern? Furthermore, to date, the vast majority of studies focused on circRNA as biomarkers are single-center and retrospective, and the techniques used to identify and validate circRNAs are primarily experimental, with methods yet to be standardized. Therefore, there is much work to be done to translate circRNAs into clinical application and benefit patients.
[10] [11] [12]
[13]
[14]
[15] [16]
[17] [18]
[19]
[20]
Funding [21]
This work was supported by grant from the Postgraduate Research & Practice Innovation Program of Jiangsu Province to KXZ (KYCX18_0169), National Nature Science Foundation of China (No.81972806, No.81802093), Jiangsu Provincial Key Research and Development Plan (BE2019614), Key Project of Science and Technology Development of Nanjing Medicine (ZDX16001) to SKW; Innovation team of Jiangsu provincial health-strengthening engineering by science and education (CXTDB2017008); Jiangsu Youth Medical Talents Training Project to BSH (QNRC2016066) and YQP (QNRC2016074); Key Project of Science and Technology Development of Nanjing Medicine (ZKX18030). Jiangsu 333 High-level Talents Cultivating Project (no. BRA201702) and Jiangsu Cancer Personalized Medicine Collaborative Innovation Center.
[22]
[23]
[24]
[25]
[26]
Declaration of Competing Interest
[27]
Authors have no conflicts of interest to report. [28]
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Review
Circular RNAs: The crucial regulatory molecules in colorectal cancer Kaixuan Zenga,b, Shukui Wanga,b,* a b
School of Medicine, Southeast University, Nanjing, 210009, China General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
A R T I C LE I N FO
A B S T R A C T
Keywords: NcRNAs circRNAs Colorectal cancer Biomarkers
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Recent studies have shown that circular RNAs (circRNAs) play critical roles in the pathogenesis and progression of CRC. CircRNAs are a special class of endogenous non-coding RNAs (ncRNAs) that harbor covalently closed ring structure with high conservation and stability, which are expressed in a tissue- and developmental-stage-specific manner. A growing body of evidence suggests that circRNAs are abnormally expressed in CRC tissues, cell lines and plasma, and are closely linked with CRC clinical malignant features. CircRNAs participate in various biological processes of CRC cells, including cell proliferation, apoptosis, senescence, migration and invasion and so on, through acting as “microRNA (miRNA) sponges”, binding to protein and even translating protein. In the present review, we systematically introduce the CRC-related circRNAs and their functional mechanisms, as well as the potential applications for CRC diagnosis and prognosis.
1. Introduction Colorectal cancer (CRC) is one of the most common malignancies in the world, ranking third in incidence and second in mortality among all cancer [1]. According to the epidemiological investigation, it is estimated that there will be more than 1.8 million new CRC cases and 881000 deaths in 2018, accounting for about one tenth of cancer cases and deaths [2]. Even worse, the global burden of CRC is expected to increase by 60 % to more than 2.2 million new cases and 1.1 million deaths by 2030 [3]. For the vast majority of people, age is a major factor in increasing the risk of CRC, especially after age 50 years; however, emerging evidence shows that more and more young adults are being diagnosed with CRC [4], especially in China [5], hinting that the increase in the malignancy of CRC. In the past several decades, despite some novel therapeutic schedules including laparoscopic surgery, radiotherapy, neoadjuvant and palliative chemotherapies have emerged, the cure rate and long-term survival rate of CRC are still very low [6], mainly due to the lack of sensitive and stable diagnostic or prognostic biomarkers and inadequate understanding of its pathogenesis. With the completion of the human genome project, only about 2% of the genes in the human genome can translate proteins, while the remaining 98 % belong to non-coding RNAs (ncRNAs) [7]. For a long time, the large number of ncRNAs has been regarded as the "noise" of genome transcription without definite biological function. However,
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this is not the case, more and more recent evidence suggests that ncRNAs are involved in a wide range of important biological activities [8]. As a special type of ncRNAs, circular RNAs (circRNAs) are characterized by covalently closed loop structure with neither 3′-5′end polarity nor polynucleotide tails, they are highly stable and evolutionarily conservative [9]. CircRNAs are derived from the back-splicing of premRNA and are divided into different subtypes according to different sources: exon circRNAs (ecircRNAs), intron circRNAs (ciRNAs), exon and intron circRNAs (EIciRNAs), intergenic circRNAs and fusion circRNAs (f-circRNAs) (due to chromosomal translocations) [10]. And 80 % of circRNAs are ecircRNAs, which are mainly located in the cytoplasm [11], while ciRNAs and ciRNAs are frequently observed in the nucleus [12]. With the development of experimental techniques such as circRNA microarry screening and high-throughput sequencing, the mystery of circRNA has gradually been revealed, and its function and application value have gradually emerged. Accumulated evidence shows that circRNAs are abundant in eukaryotes and expressed in a tissue- and developmental-stage-specific pattern [13], and the abundances of some circRNAs are even more than 10 times higher than those of their respective homologous linear mRNAs [14]. Up to now, a large number of dysregulated circRNAs have been identified in human cancers, including CRC [15]. CircRNAs were shown to participate in the proliferation, differentiation, apoptosis, senescence, migration and invasion of tumor cells by regulating different signaling pathways [16,17].
Correspondence author at: School of Medicine, Southeast University, Nanjing, 210009, China. E-mail address: [email protected] (S. Wang).
https://doi.org/10.1016/j.prp.2020.152861 Received 22 December 2019; Received in revised form 20 January 2020; Accepted 10 February 2020 0344-0338/ © 2020 Elsevier GmbH. All rights reserved.
Please cite this article as: Kaixuan Zeng and Shukui Wang, Pathology - Research and Practice, https://doi.org/10.1016/j.prp.2020.152861
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significantly decreased in CRC tissues and cell lines. Further investigation showed that circ-ITGA7 increased ITGA7 transcription level through inhibiting RREB1 via the oncogenic Ras signaling pathway. Depletion of circ-ITGA7 or ITGA7 resulted in the enhanced proliferation and metastasis of CRC cells both in vitro and in vivo [51]. Subsequently, another study also confirmed the tumor-inhibiting effect of circ-ITGA7 in CRC [52]. Interestingly, Dou Y et al. performed circRNA sequencing and compared the levels of circRNA candidates between the mutant and wild-type KRAS CRC cell lines [53]. Totally, 748 downregulated circRNAs were identified in mutant KRAS cells as compared with wildtype KRAS cells, while only 18 circRNAs were shown to be upregulated, suggesting that downregulation of circRNA in KRAS mutant CRC cells is a universal event. Importantly, they also found that circRNAs could be secreted into extracellular-vesicles, especially exosomes [53]. Besides, there are also numerous downregulated circRNAs identified in CRC, which play an important role in inhibiting CRC tumorigenesis and progression. They are summarized in Table 2, as shown below.
Herein, we focused on the roles of circRNAs in CRC, and systematically summarized the molecular mechanisms by which circRNAs functioned in CRC and their potential utilities as diagnostic and prognostic biomarkers. 2. The dysregulated circRNAs in CRC 2.1. The upregulated circRNAs in CRC Hsiao KY et al. performed circRNA high-throughput sequencing in 12 CRC and adjacent normal tissues, and found numerous abnormally expressed circRNAs [18]. Further, they found that circ-CCDC66, a circRNA derived from CCDC66 exon 8∼10, was significantly elevated in CRC tissues and cell lines and facilitated CRC cell proliferation, migration, invasion, and anchorage-independent growth both in vitro and in vivo. Circ-CCDC66 was able to increase the levels of a panel of oncogenes, such as DNMT3B, EZH2, MYC and YAP1, thereby promoting CRC tumorigenesis and metastasis [18]. Furthermore, a recent study confirmed the pro-tumor role of circ-CCDC66 in CRC, and found that circ-CCDC66 could weaken the radio-sensitivity of CRC cells [19]. To search for CRC metastasis-associated circRNAs, Chen LY et al. established a mouse model of liver metastasis and conducted circRNA sequencing [20]. They identified one circRNA, circ-NSD2, as a driver of CRC metastasis. CRC patients with high circ-NSD2 were more likely to have lymph node and distant metastasis than those with low circ-NSD2 expression, and circ-NSD2 evidently enhanced CRC cell migratory and invasive abilities both in vitro and in vivo by modulating the miR-199b5p/DDR1/JAG1 signaling axis [20]. Besides, Xu H et al. performed circRNA sequencing in the tissue samples from three CRC patients with liver metastasis and three matched CRC patients, and identified that circRNA_0001178 and circRNA_0000826 were significantly upregulated in metastatic CRC tissues and had the potential for diagnosis of CRC liver metastasis [21]. Zhu M et al. found that circ-BANP was dysregulated in CRC by performing human circRNA microarray in 3 paired CRC cancerous and adjacent normal tissues [22]. And subsequent qRT-PCR analysis confirmed that circ-BANP was frequently overexpressed in CRC tissues and cell lines. siRNA-mediated silencing of circ-BANP markedly inhibited CRC cell proliferation [22]. Likewise, hsa_circ_000984 was proposed to be notably increased in CRC and knockdown of hsa_circ_000984 retarded CRC cell proliferation, migration, invasion in vitro and tumor formation in vivo [23]. In addition, a series of upregulated circRNAs in CRC were identified by different research groups, which promoted CRC initiation, development and progression through regulation of different genes and signaling pathways. We summarized these circRNAs in Table 1, as shown below.
3. The functional patterns of circRNAs in CRC Emerging evidence suggests that circRNAs play the essential functional roles in CRC by acting as a sponge for microRNA (miRNA), physically interacting with proteins and even translating proteins (Fig. 1). 3.1. Acting as “miRNA sponges” miRNA is a kind of endogenous ncRNA found with a length of about 20∼25bp [69]. It is an important gene posttranscriptional regulator that can directly match with the 3′- untranslated region (3′-UTR) of mRNA to promote mRNA degradation or inhibit translation process [70]. Studies have shown that some ncRNAs (such as lncRNAs) have miRNA response elements (MREs) that can act as competing endogenous RNAs (ceRNAs) and compete with mRNA to bind miRNAs, thereby reducing the inhibitory effects of miRNAs on their target genes [71]. In 2013, two different research groups first found that circRNA can sponge miRNAs, in which CDR1as had more than 70 conserved miR-7 binding sites, which could largely adsorb miR-7 and inhibit its activity, thus upregulating the expression of a series of miR-7 target genes [72,73]. A large number of subsequent studies have confirmed that circRNAs can function as ceRNAs to sponge miRNAs and regulate gene expression in human cancers, including CRC [74]. In our previous study, we found that circ-HIPK3 was significantly upregulated in CRC and potentiated CRC growth and metastasis both in vitro and in vivo [29]. Circ-HIPK3 was able to abundantly sponge miR-7 and elevate oncogenic FAK, IGF1R, EGFR and YY1 expression [29]. In addition, many circRNAs, such as circ-CCDC66 [18], hsa_circ_0009361 [49], etc, have been identified to be key regulators in CRC through functioning as “miRNA sponges”, as shown in Tables 1 and 2.
2.2. The downregulated circRNAs in CRC Geng Y et al. found that hsa_circ_0009361 was significantly downregulated in CRC through using circRNA microarry and qRT-PCR analysis in 10 pairs of CRC and adjacent normal tissues [49]. Reactivation of hsa_circ_0009361 could notably inhibit the proliferation and epithelial-mesenchymal transition (EMT) of CRC cells and delay tumor growth and metastasis in vivo. In-depth investigation revealed that hsa_circ_0009361 was capable to increase APC2 expression and dampen the Wnt/β-catenin signaling via inhibiting miR-582 [49]. Another research group performed circRNA sequencing in 4 paired CRC tissues and totally found 448 differentially expressed circRNAs, including 394 upregulated and 54 downregulated circRNAs [50]. Further, they focused on circ-DDX17 and identified it as a tumor suppressor in CRC. Silencing of circ-DDX17 significantly promoted CRC cell proliferation, migration, invasion, and inhibited apoptosis [50]. Circ-ITGA7 was a recently discovered circRNA associated with CRC progression [51]. Circ-ITGA7 and its linear host gene ITGA7 were both
3.2. Interacting with protein Emerging evidence shows that circRNAs can also function by directly interacting with protein [75]. For example, Du WW et al. reported that circ-Foxo3 could directly bind CDK2 and p21 to form a ternary complex that blocked the transition from G1 phase to S phase, thus inhibiting the progression of cell cycle [76]. Fang L et al. found that circ-CCNB1 directly interacted with CCNB1 and CDK1, breaking the connection between CCNB1 and CDK1 and hindering cell mitosis [77]. CircRNA FECR1 was proposed to directly recruit TET1 to the FLI1 promoter, resulting in DNA demethylation; meanwhile, FECR1 could also bind to methyltransferase DNMT1 and reduce its expression level [78]. Likewise, in CRC, circ-ACC1 was capable of forming a ternary complex with the regulatory β and γ subunits to stabilize and increase AMPK activation, thereby promoting CRC cell fatty acid β-oxidation, 2
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Table 1 The characteristics of upregulated circRNAs in CRC. CircRNA
Biological function
Related genes/signaling pathways
Biomarker
References
hsa_circ_001569 hsa_circ_0000069 circ-BANP ciRS-7
Promotes CRC cell proliferation and invasion Promotes CRC cell proliferation, migration, and invasion Promotes CRC cell proliferation Promotes CRC cell proliferation, migration, invasion and inhibits apoptosis Promotes CRC growth and metastasis
miR-145/E2F5/BAG4/ FMNL2 N/A N/A miR-7/EGFR1/RAF1/MAPK
N/A N/A Prognosis Prognosis
[24] [25] [22] [26]
miR-33b/miR-93/DNMT3B/EZH2/ MYC/YAP1 miR-138/TERT/PD-L1 miR-106b/CDK6 N/A miR-7/FAK/IGF1R/EGFR/YY1 miR-600/EZH2 miR-516b//FZD4/Wnt/β-catenin miR-21-5p/Tiam1 miR-150/Gli1 miR-199b-5p/DDR1/JAG1 miR-101
[18]
miR-145 circPPP1R12A-73aa/Hippo/YAP c-Jun/AMPK
Diagnosis& prognosis N/A N/A N/A Prognosis N/A Prognosis N/A N/A Prognosis Diagnosis& prognosis Prognosis Prognosis N/A
circLgr4-peptide/Lgr4/Wnt/β-catenin
N/A
[38]
miR-103a-2-5p miR-585/CDC25B N/A miR-203a-3p.1/CREB1 miR-2467-3p/MMP14 IGF2BP2/HMGA2 miR-382/587/616/ZEB1 miR-1182/hTERT miR-328-5p/E2F1
N/A Prognosis Prognosis Prognosis N/A Prognosis Prognosis N/A Diagnosis& prognosis N/A
[39] [40] [41] [42] [43] [44] [45] [46] [47]
circ-CCDC66 has_circ_0020397 hsa_circ_000984 hsa_circ_0007534 circ-HIPK3 hsa_circ_0071589 circRNA_100290 circ-ACAP2 circ-ZNF609 circ-NSD2 circ-VAPA
hsa_circ_0007142 hsa_circ_102958 hsa_circ_0122319/0079480/0087391 hsa_circ_0079993 hsa_circ_0053277 circ-NSUN2 hsa_circ_0001178 circ-FMN2 circ-CAMSAP1
Promotes CRC cell viability and invasion Promotes CRC growth and metastasis Promotes proliferation and inhibits apoptosis Promotes CRC growth and metastasis Promotes CRC carcinogenesis Promotes CRC progression Promotes CRC cell proliferation, migration and invasion Promotes CRC cell migration Promotes CRC metastasis Promotes CRC cell proliferation, migration, invasion, and inhibit apoptosis Promotes CRC metastasis Promotes CRC pathogenesis and metastasis Promotes CRC cell fatty acid β-oxidation, glycolysis and growth Promotes CRC stem cell self-renewal, tumorigenesis and invasion Promotes CRC cell proliferation, migration and invasion Promotes CRC tumorigenesis Promotes CRC metastasis Promotes CRC cell proliferation and growth Promotes CRC development Promotes CRC liver metastasis Promotes CRC invasion and metastasis Promotes CRC proliferation and tumorigenesis Promotes CRC growth
hsa_circ_0005963
Promotes CRC cell glycolysis and chemoresistance
circ-PVT1 circ-PPP1R12A circ-ACC1 circ-Lgr4
miR-122/PKM2
[27] [23] [28] [29] [30] [31] [32] [33] [20] [34] [35] [36] [37]
[48]
Table 2 The characteristics of downregulated circRNAs in CRC. CircRNA
Biological function
Related genes/signaling pathways
Biomarker
References
circ-ITCH hsa_circ_001988 hsa_circ_0003906 hsa_circ_0000567 hsa_circ_0001649 hsa_circ_0014717 hsa_circ_0026344 circ-ITGA7 hsa_circ_0000711 hsa_circ_103809 circ-MTO1 circ-DDX17 hsa_circ_0002138 hsa_circ_104916 hsa_circ_0009361 circ-ZNF609 circ-CBL.11 circ-CDYL
Inhibits N/A N/A Inhibits N/A Inhibits Inhibits Inhibits N/A Inhibits Inhibits Inhibits Inhibits Inhibits Inhibits Induces Inhibits Inhibits
ITCH/Wnt/β-catenin N/A N/A N/A N/A p16 miR-21/miR-31 ITGA7/RREB1/Ras or miR-3187-3p/ ASXL1 N/A miR-532-3p/FOXO4 Wnt/β-catenin N/A N/A N/A APC2/Wnt/β-catenin p53 miR-6778-5p/YWHAE miR-150-5p/c-Myc/cyclin D1
N/A Diagnosis Diagnosis Diagnosis Diagnosis Prognosis Prognosis N/A Diagnosis&prognosis N/A Prognosis N/A Diagnosis Prognosis N/A Diagnosis N/A N/A
[54] [55] [56] [57] [58] [59] [60] [51,52] [61] [62] [63] [50] [64] [65] [49] [66] [67] [68]
CRC cell proliferation
CRC cell proliferation and migration CRC cell proliferation, colony formation and growth CRC cell growth and invasion and induces apoptosis CRC growth and metastasis CRC cell proliferation and migration CRC cell proliferation and invasion CRC cell proliferation, migration, invasion, and induces apoptosis CRC cell proliferation CRC cell proliferation, migration, invasion, and induces apoptosis CRC progression apoptosis CRC cell proliferation CRC cell growth and migration
proliferation-related circRNA, circ-ZNF609, which was abundantly enriched in polysome fractions and was translated into a protein in a splicing-dependent and cap-independent manner [80]. Subsequently, Yang Y et al. found that circ-FBXW7 encoded a novel 21-kDa protein termed as FBXW7-185aa, which reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization [81]. Of note, an interesting study showed that consensus N6-methyladenosine (m6A) motifs were enriched in circRNAs and a single m6A site is sufficient to drive translation initiation, and this process required initiation factor eIF4G2 and m6A reader YTHDF3 [82], confirming that the circRNA-mediated
glycolysis and in vivo growth [37].
3.3. Translating protein Due to the lack of 5′-cap structure and 3′-polyadenylation tail, as well as the lack of typical internal ribosome entry site (IRES), circRNA is initially considered unable to translate protein. However, recent studies have shown that circRNA can produce protein in a cap-independent manner [79]. Fox example, by performing the high-content functional genomic screen, Legnini I et al. found a myoblast 3
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Fig. 1. The mechanisms of circRNA functions in CRC: a, some circRNAs (such as circ-HIPK3) can act as miRNA sponges to inhibit miRNA activity. b, some circRNAs (such as circ-ACC1) can directly bind to proteins and affect their functions and translocations. c, some circRNAs (such as circ-LRG4) have protein-coding capacity and can encode proteins.
[90]. Moreover, the three-circRNA panel could evidently improve the ability to diagnose CEA-negative and CA19-9-negative CRC, hinting that these three plasma circRNAs could serve as a novel and independent diagnostic biomarkers for CRC. In our recent study, we analyzed two Gene Expression Omnibus (GEO) databases containing circulating exosomal circRNAs in peripheral blood of CRC patients [91]. Further, we focused on exosomal hsa_circ_0004771 and found that it was significantly elevated in serum of CRC patients as compared to healthy controls and patients with benign intestinal diseases (BIDs) [91]. The AUC value of exosomal hsa_circ_0004771 was 0.59, 0.86 and 0.88 to differentiate BIDs, stage I/II CRC patients and CRC patients from healthy controls, respectively, suggesting that it can serve as a novel potential diagnostic biomarker for CRC. Of note, a recent pair-wise meta-analysis containing 1430 patients with CRC showed that the summary AUC of circRNA for the discriminative efficacy between patients with and without CRC was estimated to be 0.79, corresponding to a weighted sensitivity of 0.77, specificity of 0.67 and diagnostic odds ratio (DOR) of 7.52 [92]. And the performance of upregulated circRNAs for CRC detection was significantly superior to that of downregulated circRNAs (AUC:0.86 vs 0.75; DOR:10.63 vs 6.55) [92], suggesting that abnormally expressed circRNAs may be auxiliary biomarkers facilitating CRC diagnosis.
translation can be proceeded without 5′-cap structure. In CRC, circ-Lgr4 was found to be highly expressed and could be translated into a protein with the sequence of LQTASDESYKDPTNIQLSK. This protein was identified to interact with Lgr4 and subsequently activate the Wnt/β-catenin signaling, leading to enhancing CRC stem cell self-renewal, tumorigenesis and invasion [38]. Besides, Zheng X et al. showed that circ-PPP1R12A carried an open reading frame (ORF) that could encode a functional protein termed as circPPP1R12A-73aa [36]. CircPPP1R12A-73aa, but not circPPP1R12A, promoted CRC cell proliferation and metastasis both in vitro and in vivo through activating hippo-YAP signaling pathway [36]. A very recent study has found that a large number of ncRNAs have the function of translating protein, including circRNAs, such as circCFLAR, circ-SLC8A1, circ-MYBPC3 and circ-RYR2 [83]. At present, the research on the translation function of circRNA is still in its infancy. Sun P et al. recently developed the CircCode tool that can commendably identify the coding ability of circRNA with a low false discovery rate and high sensitivity [84]. It is believed that many studies focused on the translation function of circRNA will emerge in the future. 4. CircRNAs as biomarkers in CRC Studies have shown that circRNAs can be used as ideal disease biomarkers for the following reasons: I: CircRNAs lack of 5′-cap structure and 3′-polyadenosine tail, which makes circRNAs highly resistant to exonuclease [85]. II: CircRNAs are evolutionally highly conserved and stable with a half-life of more than 48 h, whereas linear RNAs have an average half-life of 10 h [86]. III: CircRNAs are expressed in a cell- or tissues- or disease-context-dependent manner [87]. IV: CircRNAs are stable in a variety of tissues and body fluids, even in paraffin-embedded tissues [88].
4.2. CircRNAs as prognostic biomarkers in CRC Weng W et al. detected the expression of ciRS-7 in the training and validation cohorts containing primary CRC and matched normal mucosae tissues, and found that it was significantly upregulated in CRC and closely associated with malignant clinical behaviors [26]. CRC patients with high ciRS-7 expression had shorter overall survival than patients with low ciRS-7 expression, and the multivariate survival analysis revealed that ciRS-7 emerged as an independent risk factor for overall survival of CRC patients [26], suggesting that ciRS-7 is a promising prognostic biomarker of CRC. Recently, we found that circ-HIPK3 was frequently overexpressed in CRC tissues and cell lines [29]. High circ-HIPK3 expression was positively correlated with T status of tumor, lymph node metastasis, distant metastasis and advanced clinical stage. The survival time of patients with high circ-HIPK3 was significantly shorter than that of patients with low circ-HIPK3. Further Cox multivariate survival analysis indicated that high circHIPK3 expression was an independent risk prognostic factor for overall survival of CRC patients [29]. Thus, circ-HIPK3 may have considerable potential as a prognostic biomarker in CRC. Accurate risk stratification for patients with stage II/III colon cancer is critical in determining postoperative treatment. In a very recent retrospective study, Ju HQ et al. performed circRNA sequencing in postoperative 20 paired frozen tissues, and profiled differentially
4.1. CircRNAs as diagnostic biomarkers in CRC Recently, Ye DX et al. performed circRNA microarray in plasma samples from 4 CRC patients and 4 healthy controls, and found that hsa_circ_0082182, hsa_circ_0000370 and hsa_circ_0035445 had diagnostic values for CRC, the area under the curve (AUC) values of these three circRNAs were 0.8152, 0.7371 and 0.7028, respectively [89]. Importantly, the AUC value of the mixture of three circRNAs was 0.8347, highlighting their promising diagnostic utility as a panel of non-invasive biomarkers for early CRC [89]. In addition, Lin J et al. reported that the plasma levels of three circRNAs (circ-CCDC66, circ-ABCC1 and circ-STIL) were significantly downregulated in CRC patients in comparison with healthy controls [90]. And the AUC value of these three-circRNA panel was 0.780, which was higher than that of traditional protein biomarkers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) 4
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expressed circRNAs between patients with and without recurrence [41]. Next, they generated a four-circRNA-based cirScore (hsa_circ_0122319, hsa_circ_0087391, hsa_circ_0079480 and hsa_circ_0008039) to classify patients into high-risk and low-risk groups, raising the possibility that circRNAs may be supplementary to the traditional clinicopathological risk factors as a prognostic scheme [41].
[7]
[8] [9]
5. Conclusions Nowadays, the field of circRNAs has attracted great attention. With the development of new generation of high-throughput sequencing technology, more and more circRNAs have been found and expressed abnormally in human CRC tissues, cells and plasma. They play a role in inhibiting or promoting CRC by regulating different molecules and signal pathways. Some circRNAs are closely related to CRC clinical grade, pathological stage, recurrence, metastasis, drug resistance and outcome, suggesting that circRNAs are pivotal players in the pathogenesis, diagnosis and treatment of CRC. Although existing studies have gradually uncovered the mystery of circRNA, we have gained a preliminary understanding of its source, function and regulatory mechanism, there are still many important issues not clarified, for instance, what are the key molecules for circRNA nucleo-cytoplasmic shuttling (except for the length of the circRNA [93]) as well as for circRNA degradation? In addition to m6A modification, whether there are other factors controlling the translation of protein by circRNA in a 5′-cap independent manner, and whether this process is proceeded in a tissue- or developmental-stage-specific pattern? Furthermore, to date, the vast majority of studies focused on circRNA as biomarkers are single-center and retrospective, and the techniques used to identify and validate circRNAs are primarily experimental, with methods yet to be standardized. Therefore, there is much work to be done to translate circRNAs into clinical application and benefit patients.
[10] [11] [12]
[13]
[14]
[15] [16]
[17] [18]
[19]
[20]
Funding [21]
This work was supported by grant from the Postgraduate Research & Practice Innovation Program of Jiangsu Province to KXZ (KYCX18_0169), National Nature Science Foundation of China (No.81972806, No.81802093), Jiangsu Provincial Key Research and Development Plan (BE2019614), Key Project of Science and Technology Development of Nanjing Medicine (ZDX16001) to SKW; Innovation team of Jiangsu provincial health-strengthening engineering by science and education (CXTDB2017008); Jiangsu Youth Medical Talents Training Project to BSH (QNRC2016066) and YQP (QNRC2016074); Key Project of Science and Technology Development of Nanjing Medicine (ZKX18030). Jiangsu 333 High-level Talents Cultivating Project (no. BRA201702) and Jiangsu Cancer Personalized Medicine Collaborative Innovation Center.
[22]
[23]
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[25]
[26]
Declaration of Competing Interest
[27]
Authors have no conflicts of interest to report. [28]
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