Circular RNA is a popular molecule in tumors of the digestive system (Review)
- Authors:
- Published online on: April 27, 2020 https://doi.org/10.3892/ijo.2020.5054
- Pages: 21-42
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
1. Introduction
Circular RNA (circRNA) is a common class of non-coding RNAs produced by back splicing, which is an unconventional splicing event and are characterized as having no 5′ end cap structures or 3′ end poly-adenylation tails (1). Although Sanger et al (2) discovered this special type of RNA molecule in 1976, scientists generally believed that it was a product of incorrect splicing and were generally neglected since. That was not until 2013, when Hansen et al (3) and Memczak et al (4) reported that circRNA served an endogenous role as a microRNA (miRNA) sponge, that gradually changed the perception of researchers. In recent years, with continuous advancements in sequencing technology, an increasing number of circRNAs have been discovered and subsequently studied. Accumulating evidence have suggested that circRNA serves a significant role in the progression of a number of diseases, including Alzheimer's disease, cardiovascular disease, diabetes and cancer (3-6). Since circRNA is highly conserved and is stably expressed in various tissues and bodily fluids, it can be applied to predict disease and evaluate the effect of diagnosis and treatment (7). However, the emerging role of circRNA as a biomarker in cancer is becoming particularly prominent.
Digestive system malignancies account for a large proportion of all cancer cases. According to the 2018 Global Cancer Statistics Report released by the World Health Organization, colorectal, gastric, hepatocellular and esophageal cancers were ranked amongst the top 10 in terms of morbidity (8), whilst colorectal, gastric, hepatocellular, esophageal and pancreatic cancers were ranked amongst the top 10 in terms of mortality (8). In addition, colorectal and stomach cancer are ranked amongst the top five in terms of both morbidity and mortality (8). These data suggested that digestive system malignancies have become a significant threat to global health. In recent decades, diagnosis and treatment of tumors of the digestive system have been markedly improved, where several novel strategies have been developed. However, since patients are frequently diagnosed at an advanced stage, the survival rate of patients with digestive system malignancies remain unsatisfactory.
In the present review, the biogenesis, function and role of circRNA in the development of tumors of the digestive system were summarized, where the possibility and emerging role of circRNA as a tumor marker in the digestive system was explored, providing a referencing point for the study of digestive system malignancies.
2. Biogenesis and function of circRNA
Biogenesis of circRNA
CircRNA is a non-coding RNA that is produced by two possible models of loop generation previously proposed by Jeck et al (9): i) Intron-pairing-driven circularization; and ii) lariat-driven circularization, both of which are widely accepted. Intron-pairing-driven circularization occurs as a result of complementary base pairing between different introns in the sequence, bringing adjacent exons to close proximity, following which the spliceosome cut away the adjacent exons and paired introns to form the circRNA. Lariat-driven circularization relies on the covalent interaction between the splice acceptor and donor, resulting in a circRNA containing the exon lariat (9). Intron circRNA is another subtype of circRNA discovered in recent years (10). The 11-nucleotide C-rich element and 7-nucleotide G-rich element in the parent gene of the intron circRNA combine to form a circular structure which are then spliced by the spliceosome (10). The spliceosome mechanism serves a significant role in the biogenesis of circRNA, which depends on trans-acting factors and cis-regulatory elements (11). Zhang et al (12) used four thiopurines to label newly generated RNA to reveal that low levels of circRNA may be a by-product of incomplete pre-RNA splicing, whilst the transcription of RNA polymerase II (pol II) occurred simultaneously with the formation of circRNA, suggesting that rapid extension of the strand may promote the reverse splicing of complementary paired sequences. In addition, the activity of pol II is strictly controlled by cis-regulatory elements (12). A number of circRNAs can be detected after pre-mRNA transcription is complete, suggesting that the biogenic process of circRNA may be post-transcriptional (13). In addition to pre-RNA and pol II, the biogenesis of circRNA is also regulated by a variety of proteins, enzymes, intron sequences and active elements. A previous study showed that RNA-binding proteins can also serve as regulators of circRNA production, which is a particularly prevalent mechanism observed during epithelial-mesenchymal transition (EMT) in tumors (14). The RNA helicase DExH-box helicase 9 (DHX9) specifically recognizes the reverse repeat Alu element, which is involved in the regulation of RNA post-transcriptional splicing (15). Alu elements are a class of functional sequences that are widely found in primates and are closely associated with the biogenesis of circRNAs (15). The expression levels of DHX9 affects the formation of splicing products, the deletion of which has been found to increase circRNA biogenesis of (15). In addition, exon circularization is dynamic process that is regulated by neighboring introns, where individual and flanking introns compete to regulate the formation of circRNA through base pairing (16). Modifications to the mRNA have been previously demonstrated to regulate transcription, alternative splicing, formation of advanced structures, translation and stability. Tang et al (17) found that N6-methyladenosine (m6A) modification can promote the generation of circRNA carrying open reading frames in mouse male germ cells. In addition, the level of other circRNAs in tissues can also adversely affect the biogenesis of circRNA (18).
Function of circRNA
CircRNA can be classified into exon circRNA, exon-intron circRNA and intron circRNA, according to their origins (19,20). Exon circRNA is generally more commonly observed in eukaryotes (19). Compared with corresponding linear RNA of the same sequence, circRNA is more stable and less susceptible to degradation by RNase R (21), which is one of the main factors for circRNA being considered as a potential biomarker.
CircRNA has a multitude of reported functions (Fig. 1), the most studied of which is its property as an endogenous competitive RNA to sponge miRNA (22). miR-7 is a widely studied miRNA that has been reported to participate in cell proliferation, differentiation, migration, invasion and a number of signaling pathways in various types of malignancies, including lung, breast and thyroid cancer (23-25). Hollensen et al (26) previously demonstrated that cerebellar degeneration-related autoantigen 1, antisense can (ciRS7 or CDR1AS) act as an negative upstream regulator of miR-7, downregulating miR-7 expression in cells. In recent years, an increasing number of studies have shown miRNA sponging to be the most common function of circRNA. In addition to sponging miRNA, complex interactions between circRNA and proteins have been observed in regulating biological processes. CircRNA can also act as a protein sponge to directly regulate the expression of functional proteins (27). Du et al (28) found that circular RNA-forkhead box O3 blocked cell cycle progression by forming a complex with p21 and cyclin dependent kinase (Cdk)2. By contrast, certain circular RNAs have been demonstrated to act synergistically with specific proteins in response to extracellular stimuli (29). Li et al (29) found that the synergy between circRNA and the immune factor interleukin enhancer binding factor 3 promoted cellular responses to viral infections. A small number of circRNAs have also been documented to encode genes that can be translated into proteins directly involved in the regulation of physiological functions (30). Circ-ZNF609 binds ribosomes via an internal ribosome entry site and translates into ZNF609 to regulate the proliferation of myoblasts (31). Yang et al (30) reported in 2017 that m6A drives the initiation of circRNA translation in human cells. CircRNA has also been shown to regulate the splicing of pre-RNA and the function of the parental gene (10,16). This is mainly due to the role of some circRNAs located in the nucleus. For example, the circRNA ciankrd52 has been reported to interact with pol II to promote parental ankyrin repeat domain 52 pre-mRNA transcription (10). In summary, circRNA has a variety of biological functions, though this field of research remains incomplete (10).
3. CircRNA in digestive system malignancies
As an important subtype of non-coding RNA, circRNA has received considerable attention in cancer research in recent decades, where an increasing number of studies have shown that circRNA may serve significant roles in a multiple types of digestive system malignancies. By sponging miRNA, circRNA can regulate the expression of target proteins, in turn affecting the pathophysiology of tumors of the digestive system (Fig. 2). This section describes the differential expression profiles and reported functions of circRNA in various types of digestive system malignancies.
Esophageal and gastric cancer
Esophageal cancer is a tumor of the upper digestive tract, which ranks 7th and 6th in terms morbidity and mortality among all cancers, respectively (10). By contrast, gastric cancer ranks 5th and 3rd in terms of morbidity and mortality among all cancers, respectively (8). Although a number of advancements have been made in the diagnosis and treatment of esophageal and gastric cancer in recent years, the etiology of these two malignancies remain to be fully elucidated and the survival rates of patients with advanced disease remain poor. The lack of effective early diagnostic indicators is also an important cause for the high mortality rates observed in patients with these two types of malignancies. Accumulating evidence have shown that circRNA serves a pivotal role in the proliferation, invasion, migration, cell cycle progression and drug resistance of esophageal (Table I) and gastric cancers (Table II).
Since 2016, the number of studies on the relationship between circRNAs and esophageal cancer has increased gradually. The elevated expression levels of several circRNAs in esophageal cancer has been demonstrated to promote the proliferation of esophageal cancer cells, including circ-discs large homolog 1, circRNA_100876 and hsa_circ_0067934 (32-34). In addition to proliferation, aberrant circRNA expression has also been reported to influence the ability of cancer cells to invade and migrate, which is a crucial cause of tumor metastasis and subsequent mortality. Zhong et al (35) found that circ-plasmacytoma variant translocation (circ-PVT1) upregulated the expression of paired box proteins and peroxisome proliferator-activated receptors by sponging miR-4663, resulting in the promotion of esophageal cancer cell proliferation and migration. The elevated expression levels of circ-tetratricopeptide repeat domain 17, circ-fibronectin type III domain containing 3B (circFNDC3B) and hsa_circ_0000337 have also been revealed to be involved in the proliferation and migration of esophageal cancer cells (36-38). Hsa_circ_0006168, circ-protein kinase Cι (circ-PRKCI), c-zinc finger protein 292 (cZNF292), circRAD23B, circ-ubiquitin associated protein 2 (circUBAP2) and hsa_circ_0004370 were all found to be upregulated in esophageal cancer cells and tissues, where they have the reported function of promoting proliferation, invasion and migration (39-44). Mechanistically, hsa_circ_0006168, circ-PRKCI, cZNF292, circRAD23B regulate the PI3K/AKT/mTOR signaling pathway by sponging miR-100, miR-3680-3p, miR-206 and miR-5095, respectively; whilst circUBAP2 and hsa_circ_0004370 regulate Rab10 and LIM And SH3 protein 1 by sponging miRNA-422a and miR-1294, respectively (39-44). miR-7 is a widely studied miRNA, the expression of which has been previously found to be reduced as a result of competition from ciRS7 in esophageal cancer, leading to the activation of NF-κB signaling, causing changes to the immune micro-environment to potentiate tumorigenesis (45). In addition to proliferation, invasion and migration, evidence also exists demonstrating the role of circRNA in tumor sensitivity to radiotherapy. He et al (46) previously found that the down-regulation of circ-vaccinia-related kinase 1 (circVRK1) in patients with esophageal cancer was associated with a lower survival rates, whilst the overexpression of circVRK1 could effectively inhibit EMT and resistance to radiotherapy in esophageal cancer cells.
Similar to esophageal cancer, research on the association between circRNA and gastric cancer has been gradually increasing since 2017. In 2017, studies discovered that circRNA_100269, circRNA_La ribonucleoprotein 4, hsa_circ_0000705, hsa_circ_0001895, hsa_circ_00001649, hsa_circ_0000745 and hsa_circ_0000190 are all significantly downregulated in gastric cancer, which were found to be closely associated with the increased cell proliferation, differentiation, subcellular localization, stage, Borrmann type and invasion (47-53). By contrast, circ-PVT1 was demonstrated to serve as a proliferative factor regulating downstream gene expression by sponging miR-125 in gastric cancer (54). miRNA sponging remains to be the predominant mechanism through which circRNA promotes the proliferation, invasion and migration of gastric cancer cells. By sponging miR-509-3-5p, circ-myeloid/lymphoid or mixed-lineage leukemia has been found to be regulated by the expression of GINS4, which binds to and activates Rac1/cell division cycle to promote cell growth and metastasis in vivo and in vitro, whilst inhibiting apoptosis (55). Circ-nuclear receptor interacting protein 1, circ-cactin, circ-neurofibromatosis type 1 along with 37 other circRNAs have been previously revealed to regulate the expression of downstream target genes in gastric cancer through miRNA sponging to promote the proliferation and invasion of gastric cancer (Table II) (56-95). Disorder in fat metabolism is the main cause of cachexia in patients with advanced gastric cancer and systemic inflammation (96). CiRS-133 is a plasma exosomal circRNA that has been found to be significantly upregulated in gastric cancer (96). Zhang et al (96) found that it can activate PR/SET domain 16 by inhibiting miR-133, causing the browning of white adipose tissues in patients with gastric cancer. Other circRNAs can also affect the invasion and metastasis of gastric cancer by regulating EMT. The increased expression of circFNDC3B and the reduced expression of circSMAD7 and circ-hippocampus abundant transcript 1 (circHIAT1) in gastric cancer has been found to promote EMT in gastric cancer and induce distant metastasis, which is the primary cause of poor prognosis in patients with advanced gastric cancer (97-99). Hsa_circ_0081143 is another circRNA that is highly expressed in gastric cancer, which is positively associated with lymph node metastasis and TNM staging in advanced gastric cancer (100), the silencing of which can inhibit the development of gastric cancer and enhance the sensitivity of gastric cancer cells to chemotherapeutic agents such as cisplatin (100). Similarly, circAKT3 and circ-fibronectin 1 were found to enhance cisplatin resistance by sponging miR-198 and miR-182-5p, respectively (101,102).
Pancreatic cancer
Pancreatic cancer is a common tumor of the digestive system. Although the rates of morbidity associated with pancreatic cancer is not as high as other types of digestive system malignancies, including gastric, esophageal, colorectal and hepatocellular cancers, its mortality rate ranks among the highest (8). Pancreatic cancer is mainly divided into two subtypes: Pancreatic ductal adenocarcinoma and pancreatic squamous cell carcinoma, both of which have a poor prognosis, with a 5-year survival rate of <10% (103). Identifying specific biomarkers and therapeutic targets is important for improving the survival rates of patients with pancreatic cancer.
Interestingly, the majority of circRNAs associated with pancreatic cancer that have been discovered are found to be upregulated (Table III). CircRNAs, including hsa_circRNA_0007334, circ-Ras homolog family member T1, hsa_circ_0006215, circ-zinc finger MYM-type containing 2, circ-disintegrin and metalloproteinase domain-containing protein (ADAM) 9 and ciRS-7, compete with miRNAs to promote pancreatic cancer proliferation and inhibit apoptosis (104-109). Other circRNAs can regulate endothelial monolayer permeability, thereby promoting the invasion and migration of pancreatic cancer cells. Circ-low density lipoprotein receptor class a domain containing 3 promotes lymphatic and venous metastasis by sponging miR-137-3p, whilst circ-isoleucyl-tRNA synthetase enhances endothelial monolayer permeability by sponging miR-122 (110,111). Abnormalities in the immune microenvironment are common changes observed in advanced pancreatic cancer. Circ_0000977 has been previously found to increase the expression of hypoxia-inducible factor 1 and ADAM10 by competitively binding to miR-153, where circ_0000977 silencing can significantly enhance the cytotoxic effects of natural killer cells on pancreatic cancer (112). Drug resistance is another important underlying cause of poor prognosis in patients with advanced pancreatic cancer. Liu et al (113) previously found that knocking down circ-homeodomain interacting protein kinase 3 expression can effectively improve the sensitivity of pancreatic cancer to gemcitabine. In general, there have been a number of studies on the relationship between pancreatic cancer and circRNA, where the role of circRNA in the development of pancreatic cancer require further exploration.
Hepatocellular carcinoma
As of 2018, liver cancer ranks 6th in terms of prevalence and 4th in terms of mortality rates among other cancers (8). Liver cancer can be divided into three main subtypes: Hepatocellular carcinoma, bile duct carcinoma and mixed carcinoma by cell type, of which hepatocellular carcinoma is the most frequently observed. Viral hepatitis B (HBV) is one of the main causes of liver cancer in China whereas alcoholic fatty liver disease is the main cause in the Western world (114). Hepatocellular carcinoma as a result of both HBV infection and excessive alcohol consumption are associated with high rates of morbidity and mortality (8). Due to the lack of symptoms in the early developmental stage of hepatocellular carcinoma, many are not diagnosed until advanced stages of the disease (115). Studying the molecular mechanism of circRNA in hepatocellular carcinoma is of great importance for the early diagnosis and treatment of this disease.
In 2016, Yu et al (116) found that circ-cerebellar degeneration related protein 1; antisense served as a cancer promotor by binding to miR-7 and upregulating the expression of cyclin E1 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit d, promoting the proliferation and metastasis of hepatocellular carcinoma. Studies into the role of circRNA in hepatocellular carcinoma has since increased annually. A total of four studies were published the following year, which reported that circRNA serves as an endogenous competitor by regulating the expression of downstream target genes by sponging miRNA to promote hepatocellular carcinoma proliferation, invasion, migration and differentiation, whilst inhibiting apoptosis. This suggests that circRNA can be applied as a biomarker for hepatocellular carcinoma (Table IV) (117-120). The number of studies on circRNA in relation to hepatocellular carcinoma increased to 16 in 2018, where it was revealed that in addition to sponging miRNA, circRNA can also participate in the progression of hepatocel-lular carcinoma by directly binding to proteins to regulate their function (Table IV) (121-136). For example, circ-cullin 2 was previously demonstrated to promote epithelial-mesenchymal transition by combining vimentin under the regulation of Twist1 in hepatocellular carcinoma (130).
The association between circRNA and cancer, especially that of hepatocellular carcinoma, has become a popular topic of research over the last 2 years. In early 2020, a total of 56 related research articles reporting the relationship between circRNA and hepatocellular carcinoma have been published, which is higher than the number recorded in previous years (Table IV) (137-192). The expression of several circRNAs has been reported to be dysregulated in hepatocellular carcinoma, which compete with miRNAs to regulate the expression of downstream target proteins and affect the proliferation, invasion and migration of hepatocellular carcinoma. Some of these circRNAs include hsa_circ_0101432, circ-PVT1, circ-tripartite motif containing 33-12, circRNA-104718, circ-SET domain containing 3, actin histidine methyltransferase, has_circ_0078710, hsa_circ_0064428, circHIAT1, circ-adducin3, hsa_circ_0001649, circ-ADAM metallopeptidase with thrombospondin type 1 motif 14, circ_0008450, hsa_circRNA_103809, circ-homer scaffold protein 1, hsa_circ_0003645, circ-SMG1.72, hsa_circ_0091581, hsa_ circ_0000092, hsa_circ_0056836, circ-TCF4.85, circ-protein arginine methyltransferase 5 (circPRMT5), circ_0001955, circ-pecanex 1, circRNA-5692, circ-ATP binding cassette subfamily B member 10 and circ-ArfGAP with SH3 domain, ankyrin repeat and PH Domain 1 (137,138,140,145,147-150, 155-157,163,166,176-180,183-185,187,189-192). Previous studies have demonstrated that circRNA in exosomes can regulate the development of hepatocellular carcinoma by deubiquitylation. Circ-leptin receptor, circ-matrix metallopeptidase 2 and hsa_circ_0051443 are common exosomal circRNAs found in hepatocellular carcinoma (142,181,186). Hypoxia is a principal characteristic of the tumor microenvironment that is considered to be an important factor affecting sensitivity to radiotherapy and chemotherapy (146). Yang et al (146) previously found that knocking down cZNF292 expression can inhibit angiogenesis, cell proliferation and resistance to radiotherapy in hepatocellular carcinoma, which may be due to the hypoxic environment induced by cZNF292. Similar to cZNF292, the dysregulation of circRNA_101505, circRNA_104797 and circ_0003418 expression in hepatocellular carcinoma has been demonstrated to increase the resistance of hepatocytes to sorafenib and cisplatin, which is considered to be one of the main underlying causes of poor prognosis in patients with advanced hepatocellular carcinoma (162,168,174). CircRNA can also directly bind to protein components of important signaling pathways, thereby affecting the physiological behavior of hepatocellular carcinoma. The expression of hsa_circ_0079929 and circ-insulin-like growth factor 1 receptor in hepatocellular carcinoma was demonstrated to be significantly reduced, which induced cell cycle arrest and inhibited apoptosis through the PI3K/AKT/mTOR signal transduction pathway (139,170). Circ-BTB domain and CNC homolog 1 was found to be highly expressed in hepatocellular carcinoma, which binds to the embryonic lethal, abnormal vision, drosophila, homolog-like 1 protein and p27 to regulate cell cycle progression and promotes the growth of tumor cells (182). Ma et al (161) previously found that circARSP91 enhance innate immune monitoring by enhancing NK cell cytotoxicity and its downregulation in hepatocellular carcinoma promotes immune escape of hepatocellular cancer cells.
In conclusion, circRNA serves a significant role in proliferation, invasion, migration, differentiation, apoptosis, cell cycle and sensitivity to chemotherapy in hepatocellular carcinoma. Future research should focus on identifying specific and sensitive circRNAs that can serve as biomarkers for the early diagnosis and effective treatment of hepatocellular carcinoma, to improve the survival rate of patients with hepatocellular carcinoma.
Gallbladder cancer
Compared with hepatocellular carcinoma, although the rates of morbidity associated with gallbladder cancer is not as high, the rates of mortality are high where its prognosis poor, due to the highly invasive properties which is frequently diagnosed during the advanced stages of the disease (193). Studies have found that circRNA promotes the proliferation of gallbladder cancer cells through miRNA sponging and direct binding to proteins. As a miRNA sponge, circ-forkhead box protein P1 regulates the expression of pyruvate kinase L/R by sponging miR-370, enhancing the Warburg effect and promoting the proliferation and invasion of gallbladder cancer cells (194). In addition, circ-homeodomain interacting protein kinase 3 has been previously found to increase the expression of Rho-associated coiled-coil containing protein kinase 1-CDK6 by sponging miR-124, promoting the proliferation of gallbladder cancer cells (195). Circ-Erb-B2 binds to the circErb-B2 receptor tyrosine kinase 2 located in the nucleus, which regulates proliferation-associated 2G4-dependent ribosomal DNA transcription and promotes the proliferation of gallbladder cancer (196). In conclusion, research on the mechanism of circRNA involvement in the occurrence and development of gallbladder cancer remains limited (Table V) and several important issues have yet to be explained. Therefore, there remains room for exploration in this particular field.
Colorectal cancer
Colorectal cancer ranks 3rd and 2nd worldwide in terms of morbidity and mortality, respectively, among other types of cancers. (8). Advancements in colonoscopy have facilitated the detection and treatment of precancerous colorectal polyps. However, the mortality and risk associated with colorectal cancer have changed little since 1997 (197). At present, there is an urgent need in identifying novel tumor biomarkers and targeted treatment strategies to improve the early diagnosis and survival rate of patients with colorectal cancer.
Studies into the relationship between colorectal cancer and circRNA preceded those of other digestive system malignancies. In 2015, a study on 31 clinical samples of colorectal cancer found that the elevated expression of hsa_circ_001988 in colorectal cancer is closely associated with the differentiation and infiltration of tumor cells (198). In 2016, circRNA_001569 and hsa_circ_0000069 were found to be highly expressed in patients with colorectal cancer (199,200). CircRNA_001569 was demonstrated to regulate the expression of Bcl-2-associated athanogene 4, transcription factor E2F5 and formin like 2 by adsorbing miR-145, though the mechanism mediated by hsa_circ_0000069 remain unknown (199,200). In 2017, it was found that the expression of circRNA0003906, circ-BTG3-associated nuclear protein and hsa_circ_0020397 were dysregulated in colorectal cancer (201-203). A total of 10 studies reporting that circRNA regulated the development of colorectal cancer were published in 2018 (Table VI) (204-213), which rose to 17 in 2019 and 9 related articles have already been published in the first 2 months of 2020 (Table VI) (214-239). Over the last 5 years, the number of studies into the role of circRNA in colorectal cancer has been increasing annually. Most aberrantly expressed circRNAs in colorectal cancer exert their function by adsorbing miRNAs, regulating proteins associated with proliferation, invasion and metastasis, thereby promoting the progression of colorectal cancer. Particular circRNAs of interest include hsa_circ_0136666, circCBL.11, hsa_circRNA_102958, circ-vesicle-associated membrane protein-associated protein A, circ-formin 2, circ_0021977, circ_0026344, circ-integrin subunit-α7, has_circ_0055625, circ-calmodulin regulated spectrin associated protein 1, hsa_circ_0007142, circ-HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1, circ-chaperonin containing TCP1 subunit 3, circ_0000218, hsa_circ_0001178, circPRMT5 and hsa_circ_0004277 (215- 220,223,226,227,229-234,236,238). CircRNAs have been reported to serve either a synergistic or antagonistic role by directly binding to downstream target proteins to regulate various aspects of colorectal cancer pathophysiology. Circ-catenin b1 (circ-CTNNB1) mainly exists in the nucleus and directly binds to DEAD-box helicase 3/yin and yang 1, resulting in b-catenin activation and promoting the growth and metastasis of colorectal cancer (225). CircRNA_104916, circ-zinc finger protein 609 and circ-protein tyrosine kinase 2 have been previously demonstrated to function in a similar manner to circ-CTNNB1 (221,228,237). Exosome circRNA has been a topic of particular research interest in recent years, as it is believed that circRNA may regulate tumor development. Using nanoparticle tracking analysis and transmission electron microscopy, Pan et al (222) verified the exosomes in the peripheral blood of patients with colorectal cancer. Hsa_circ_0004771, ciRS-122 and circ-ATP binding cassette subfamily C Member 1 were found to be significantly increased in these exosomes, suggesting their possible application as a suitable biomarker for this disease (222,235,239).
Gastrointestinal stromal tumor
A gastrointestinal stromal tumor is a non-epithelial type of tumor that can occur in the esophagus, stomach, small intestine, colorectum and abdominal cavity that can cause a variety of symptoms, including pain, bleeding and abdominal discomfort (240). Surgical resection is currently the most common treatment method (240). In a recent study, Jia et al (241) used a selective binding complementary competitive endogenous RNA array to analyze gastrointestinal stromal tumors, which found circ_0084097, circ_0069765 and circ_0079471 to be aberrantly expressed in gastrointestinal stromal tumors. Although further study suggested these circRNAs to serve a regulatory role by sponging mir-144-3p, mir-142-5-p and mir-485-3p (241), there is no experimental data on the mechanism of circRNA involved in the development of gastrointestinal stromal tumors. It remains unclear if circRNA can be applied as a biomarker and therapeutic target for the diagnosis of gastrointestinal stromal tumors at present.
4. Non-coding RNAs in digestive system malignancies
Non-coding RNA is comprised of a large family of different subtypes of RNA molecules. In addition to circRNA, it also includes miRNA, long non-coding RNA (lncRNA), piwi-interacting RNA, transfer RNA, ribosomal RNA and small interfering RNA. Over the past decade, numerous studies have demonstrated that non-coding RNAs can exert regulatory effects. They serve an irreplaceable role in transcription, post-transcriptional modification, protein remodeling and cell signal transduction (242). Supporting this, non-coding RNA dysfunction has been documented to be associated with the occurrence and progression of various chronic diseases and tumors (242).
miRNA is a family of single-stranded, non-coding RNA that are typically 21-25 nucleotides in length and negatively regulates >60% of coding genes (243). Most miRNAs contain a 2-7 nucleotide seed sequence at the 3′untranslated region (3′-UTR) end, which can conservatively bind to a variety of target protein-coding genes to inhibit target mRNA translation (243). The function of miRNA itself is under negative regulation by circRNA- or lncRNA-mediated sponging (243). In a previous study, miR-7 was found to inhibit osteosar-coma cell proliferation and migration, but circRNA-CDR1as promotes osteosarcoma growth by sponging miR-7 (244) Similar cancer-promoting effects as a result of reduced miR-7 expression have also been reported in gastric cancer, colorectal cancer, pancreatic cancer and hepatocellular carcinoma (109,206,245,246). However, it should be noted that not all miRNAs have a seed sequence at the 3′UTR end. In addition to directly inhibiting mRNA translation, a number of miRNAs can also participate in pre-transcriptional regulation by binding to the argonaute-2 protein in the nucleus (247). However, this phenomenon is yet to be observed in tumors of digestive system.
LncRNA is a type of non-coding RNA that are >200 nucleotides in length, which has been previously shown to serve a significant role in maintaining the tumor microenvironment and the progression of various digestive system malignancies (248). Similar to circRNA, many lncRNAs also have the ability to sponge miRNAs. Yuan et al (248) found that the lncRNA SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily C member 2 upregulates transmembrane serine protease 2 by binding to miR-551b-3p, promoting the proliferation and invasion of gastric cancer. LncRNA can also directly interact with double-stranded RNA to regulate the activity of some proteins (249). A previous study has found that LINC00665 can activate and enhance the expression of protein kinase R by protecting it from ubiq-uitin-dependent degradation, in turn upregulating the NF-κB signaling pathway and the widespread expression of inflammatory factors, resulting in changes to the microenvironment and the occurrence of hepatocellular carcinoma (249).
In short, non-coding RNA forms a complex network of interactions in the body. where dysfunctions in any one of the nodes will significantly impact the entire non-coding RNA network, resulting in the development of diseases. The occurrence and procession of digestive system malignancies are closely associated with the aberrant expression of these non-coding RNAs. CircRNA is an important part of the non-coding RNA family, where its function in tumors has garnered attention in recent years. The present study reviewed the research status of circRNA in seven types of tumors in the digestive system, where the potential mechanism underlying circRNA function in their respective malignancies were discussed in detail and the possibility of using circRNA as a diagnostic and prognostic marker for tumors in the digestive system was demonstrated. However, this article is associated with limitations, since it did not discuss in detail the role of circRNAs in cellular and signal transduction pathways. CircRNA has a complex intracellular mechanism of action, which is regulated by a variety of transcriptional regulatory factors and can also affect downstream biological functions by direct interaction with miRNAs and proteins. In addition, circRNA can exert biological functions in the nucleus, cytoplasm or through exosomes secreted into bodily fluids. The associated in-depth mechanism in digestive system malignancies remain to be fully elucidated and require further investigation in future studies.
5. Conclusions and perspectives
The present review briefly explored the biogenesis and function of circRNA and reviewed in detail the current status of circRNA research in various types of digestive system malignancies. CircRNA is a class of endogenous non-coding RNA that is evolutionarily conserved, the expression of which was found to be dysregulated in a variety of digestive system tumors. In digestive system malignancies, the majority of circRNAs serve an endogenous competitive role through miRNA sponging, whilst a selective number of circRNAs can directly bind to proteins either as sponges or synergistic factors to regulate tumor growth, invasion and migration, in turn influencing patient prognosis. Compared with traditional linear RNA and other families of RNA molecules, including long-chain non-coding RNA and miRNA, circRNA is widely expressed in various tissues, cells and bodily fluids, where its expression is stable, increasing their potential as biomarkers and targets for therapy. With continuous advancements in experimental technology and continuing research, it is hoped that novel functions and modes of action mediated by circRNA will be discovered and clarified in the future. With the joint efforts of researchers and clinicians, the pathogenesis of various malignant tumors of the digestive system will be elucidated, so that patients will have an increased chance of survival.
Funding
The present study was supported by the National Natural Science Foundation of China (grant nos. 71964021 and 81570783), National Key R&D Program of China (grant nos. 2016YFC1302201 and 2016YFC0107006), Key Research and Development Program of Gansu Province (grant no. 18YF1FA110), the Key Program of the Natural Science Foundation of Gansu Province (grant no. 18JR3RA366), the Foundation of The First Hospital of Lanzhou University (grant no. ldyyyn2018-54), the Open Fund of State Key Laboratory of Cancer Biology (grant no. CBSKL201718).
Availability of data and materials
All data analyzed during this review are included in this published article.
Authors' Contributions
HW, YW, and XZ consulted and analyzed the literature, produced the figures and wrote the manuscript. YZ and QG were responsible for reviewing and correcting the manuscript. RJ and YZ proposed and built the theoretical framework of the article. All authors read and approved the final version of this manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Acknowledgments
Not applicable.
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