Recent advances of circular RNAs in gastrointestinal cancer

Abstract

Non-coding RNAs, which do not encode proteins, significantly influence signal regulation. Circular RNAs (circRNAs), produced through a post-splicing mechanism, constitute a recently identified subset of non-coding RNAs distinguished by their multifunctional covalently closed loop structures. With an in-depth exploration of circRNAs' biological characteristics, their potential roles in gastrointestinal cancer have garnered significant attention. CircRNAs can significantly influence tumor initiation and progression. This review consolidates recent research progress on circRNAs in digestive system cancers such as esophageal, gastric, hepatic, pancreatic, and colorectal cancer. We explore the potential of circRNAs as biomarkers and therapeutic targets, alongside their roles in immune modulation and chemoresistance. This review seeks to offer a thorough understanding of circRNAs' implications in digestive system tumors by outlining the current research landscape and identifying existing challenges, thereby encouraging further exploration in this emerging field.

Key Words: CircRNAs; Gastrointestinal cancer; Immune modulation; Signal pathway; Biomarker

Core Tip: Circular RNAs (circRNAs) represents a distinct class of non-coding RNAs characterized by a closed circular conformation, wherein the terminal ends are covalently bonded, resulting in a unique structure devoid of 5' cap and 3' poly(A) tail. This structural feature imparts enhanced stability to circRNAs compared to linear RNAs. CircRNAs are implicated in a myriad of physiological processes, including cellular proliferation, differentiation, apoptosis, and immune responses. This review delineates the recent advancements in circRNAs research concerning digestive system tumors, emphasizing their pronounced influence not only on the regulation of gene expression but also on the mechanisms of chemoresistance, immune modulation and treatment.

INTRODUCTION

Tumors of the digestive system rank among the main causes of cancer-related mortality globally, primarily encompassing esophageal, gastric, liver, pancreatic, and colorectal cancers. These tumors develop through various molecular mechanisms, among which circular RNAs (circRNAs) are a novel regulatory factor that has gradually attracted widespread attention from researchers. CircRNAs are a newly identified type of non-coding RNAs characterized by a circular shape formed via back-splicing[1]. This structure gives it greater stability and specific expression in cells compared to linear RNAs. CircRNAs play a vital role in the genesis and development of numerous tumors, particularly digestive system cancers[2,3]. The distinctive characteristics of circRNAs indicate their vast potential as both biomarkers and therapeutic targets. Research has revealed that circRNAs can modulate downstream gene by functioning as sponges for microRNAs (miRNAs), influencing biological processes[3,4]. Some studies have indicated that abnormal circRNA expression in gastric and colorectal cancers is closely linked to tumor development, providing a theoretical basis for its potential as a biomarker[5,6].

Furthermore, circRNAs are also closely related to drug resistance in digestive system tumors. Researchers believe that circRNAs affect tumor cells' sensitivity and resistance to chemotherapy by regulating drug targets and related signaling pathways[7]. Liu et al[8] prove that in pancreatic cancer, circRNA hsa_circ_0014784 promotes tumor cell proliferation and metastasis by regulating the miR-214-3p/YAP1 signaling pathway. Although research on circRNAs in digestive system tumors has made some progress, further exploration of their specific biological functions and mechanisms is still needed. Future research should prioritize elucidating the role of circRNAs in the tumor microenvironment, their mutual effect with other non-coding RNAs, and clinical applications[9,10]. A rounded exploration of the roles and underlying mechanisms of circRNAs may yield novel strategies and insights for therapeutic interventions and prognostic evaluation of tumors within the digestive system. In summary, circRNAs, recognized as a promising therapeutic target, hold significant potential in the research about digestive system tumors and warrant increased focus in forthcoming investigations.

OVERVIEW OF CIRCRNA

CircRNAs represent a distinctive category of non-coding RNAs, identifiable by their closed circular configuration formed via back-splicing. Compared to linear RNAs, circRNAs have significant advantages in terms of stability, expression specificity, and evolutionary conservation. The structure of circRNAs makes them resistant to degradation by nucleases, thereby positioning them as a viable marker and therapeutic target.

The biosynthesis of circRNAs is mainly generated through the back-splicing process, involving specific splicing factors and regulatory elements. Its formation mechanisms include exon circularization and intron circularization. The classification of circRNAs according to their origin can be divided into three distinct categories: Exon circRNAs (ecircRNAs), intron circRNAs (ciRNAs), and exon-intron circRNAs (EIciRNAs)[11]. Of these, ciRNAs and EIciRNAs are predominantly nuclear in their function, and further research is required to elucidate their mechanisms. In contrast, ecircRNAs primarily exert regulatory effects in the cytoplasm and can be secreted as exosomes into bodily fluids, thus making them the current focus of research. The degradation of circRNAs in cells is relatively slow and mainly relies on specific RNA-binding proteins (RBPs) and endogenous nucleases. Studies have shown that the stability and expression of circRNAs are influenced by various factors, including the regulation of transcription factors and the selection of splicing factors[4]. Typically, circRNAs modulate the downstream genes by functioning as a sponge for miRNA, whereas long non-coding RNAs may influence gene transcription via interaction with transcription factors[12,13]. The functional mechanisms of circRNAs are diverse, mainly including acting as miRNA sponges, regulating the activity of RNA-binding proteins, participating in transcriptional regulation, and encoding short peptides. Through the binding of miRNAs, circRNAs can mitigate the inhibitory influence of miRNA on target genes.

CircRNAs operate as regulators of cellular activity, principally through four discussed mechanisms (Figure 1). Firstly, they function as miRNA sponges. An increasing body of evidence substantiates that circRNAs possess miRNA binding sites, enabling them to obstruct the binding of miRNA to target mRNAs[10,14]. Secondly, circRNAs interact with RBPs. Certain circRNAs can serve as decoys, influencing gene expression by binding to or dissociating proteins, while others can act as protein scaffolds to facilitate protein-protein interactions[5,15]. Thirdly, circRNAs are implicated in the regulation of gene transcription. A majority of studies indicate that circRNAs may participate in the transcriptional regulation of their parental genes, primarily through their accumulation in the transcriptional regions of these genes, thus enhancing the activity of polymerase II (Pol II) to modulate transcription[16]. Fourthly, accumulating data suggest that circRNAs can be translated into peptides or proteins[17].

Figure 1 Functions of circular RNAs. A: MiRNA sponging; B: Protein interactions; C: Gene transcription regulation; D: Translation template (Created with http://biogdp.com[51]). circRNA: Circular RNAs; miRNA: MicroRNAs; Ago2: Argonaute 2; RBP: RNA binding proteins; U1 snRNP: U1 small nuclear ribonucleoproteins; Pol II: RNA polymerase II.

ABNORMAL EXPRESSION AND FUNCTION OF CIRCRNA IN DIGESTIVE SYSTEM TUMORS

Increasing research manifests that circRNAs exhibit aberrant expression profiles in gastrointestinal cancer (Table 1).

Table 1 Circular RNAs in gastrointestinal cancer.

Type of cancer	circRNAs	Expression	miRNAs, RBPs, peptides, pathways	Function	Ref.
Esophageal cancer	circTMEM45A	Up	U2AF2, NLRP3/caspase 1/IL-1β	Promotes malignant progression and inflammatory progression	[52]
Esophageal cancer	circPRKCA	Up	YBX1/CSF2	Promotes migration, invasion, and angiogenesis	[53]
Esophageal cancer	circNF1	Up	ANXA1, JAK/STAT3	Increases proliferation, metastasis, and tumor evasion	[54]
Esophageal cancer	circMMP11	Up	miR-671-5p	Increases proliferation, migration, and invasion	[55]
Esophageal cancer	hsa_circ_0087104	Down	miR-542-3p/PIK3R1	Inhibits metastasis	[56]
Esophageal cancer	hsa_circ_0001165	Up	EIF4A3, miR-381-3p/TNS3	Promotes proliferation, invasion, and migration	[57]
Esophageal cancer	circJPH1	Up	NF-κB/HERC5, XRCC6	Promotes proliferation, invasion, and migration	[58]
Esophageal cancer	hsa_circ_0001615	Down	miR-142-5p/β-catenin	Inhibits proliferation, migration, and invasion, promotes apoptosis	[59]
Esophageal cancer	circPDE5A	Down	PI3K/AKT	Inhibits proliferation and metastasis	[60]
Esophageal cancer	circSSPO	Up	miR-6820-5p/KLK8/PKD1	Promotes tumorigenesis and metastasis	[61]
Esophageal cancer	circUBE4B	Up	MAPK/ERK	Promotes proliferation	[62]
Esophageal cancer	circ-TNRC6B	Down	miR-452-5p/DAG1	Inhibits proliferation and invasion	[63]
Gastric cancer	circSCAF8	Up	miR-1293/TIMP1	Promotes proliferation, invasion, and migration	[64]
Gastric cancer	circPFKP	Down	miR-346/CAMD3	Inhibits proliferation, invasion, and migration	[65]
Gastric cancer	hsa_circ_0079226	Up	miR-155-5p/FOXK1/AKT	Promotes proliferation, invasion, and migration	[66]
Gastric cancer	hsa_circ_0008126	Down	EIF4A3, APC/β-Catenin	Inhibits progression and metastasis	[67]
Gastric cancer	circATP8A1	Up	miR-1-3p/STAT6	Promotes proliferation and invasion	[68]
Gastric cancer	circBIRC6	Up	miR-488/GRIN2D	Promotes malignant progression	[69]
Gastric cancer	circPAK2	Up	IGF2BPs/VEGFA	Promotes lymph node metastasis	[70]
Gastric cancer	hsa_circ_0136666	Up	miR-375/PRKDC, PD-L1	Promotes progression and tumor immune escape	[71]
Gastric cancer	circSTAU2	Down	miR-589/CAPZA1	Inhibits proliferation, invasion, and migration	[72]
Gastric cancer	circGAPVD1	Down	miR-4424/STK4, GAPVD1-137aa	Inhibits tumor progression, encodes GAPVD1-137aa	[73]
Gastric cancer	circZNF131	Down	ZNF131-354aa	Encodes ZNF131-354aa, inhibits tumor progression	[24]
Gastric cancer	hsa_circ_0002301	Down	HECTD1-463aa	Encodes HECTD1-463aa, inhibits ferroptosis	[74]
Gastric cancer	circ0003692	Down	FNDC3B-267aa	Encodes FNDC3B-267aa, inhibits metastasis	[75]
Gastric cancer	circPGD	Up	miR-16-5p/ABL2, PGD-219aa	Promotes tumor progression, encodes PGD-219aa	[25]
Liver cancer	circFADS1	Up	EIF4A3, Wnt/β-Catenin	Promotes proliferation and inhibits apoptosis	[76]
Liver cancer	circDCUN1D4	Down	miR-590-5p/ TIMP3	Suppresses proliferation, migration, and invasion	[77]
Liver cancer	circTTC13	Up	miR-513a-5p/SLC7A11	Promotes sorafenib resistance	[78]
Liver cancer	circPIAS1	Up	miR-455-3p/NUPR1/FTH1	Promotes tumor progression	[79]
Liver cancer	circPTPN12	Down	ESRP1, PDLIM2/ NF-κB	Suppresses proliferation, poor prognosis	[80]
Liver cancer	hsa_circ_0044539	Up	miR-29a-3p/VEGFA	Promotes lymph node metastasis	[81]
Liver cancer	circPHKB	Up	miR-1234-3p/CYP2W1	Promotes sorafenib resistance	[82]
Liver cancer	circUSP10	Up	miR-211-5p/TCF12/EMT	Promotes tumor progression	[83]
Liver cancer	circMRCKα	Up	circMRCKα-227aa	Encodes circMRCKα-227aa, promotes glycolysis and progression	[84]
Liver cancer	circSTX6	Up	HNRNPD/ATF3, circSTX6-144aa	Encodes circSTX6-144aa, promotes tumor progression	[85]
Liver cancer	circMAP3K4	Up	circMAP3K4-455aa	Encodes circMAP3K4-455aa, inhibits apoptosis	[28]
Pancreatic cancer	circPHF14	Up	EIF4E, Wnt/β-catenin	Promotes growth and metastasis	[86]
Pancreatic cancer	circCEACAM5	Up	METTL3, DKC1	Promotes proliferation, invasion, and migration, inhibits apoptosis	[87]
Pancreatic cancer	hsa_circ_0004781	Up	miR-9-5p/KLF5, miR-338-3p/ADAM17	Promotes proliferation and migration	[88]
Pancreatic cancer	circCGNL1	Down	NUDT4/HDAC4/RUNX2/GAMT	Inhibits proliferation, promoting apoptosis	[89]
Pancreatic cancer	circRPS29	Up	miR-770-5p/TRIM29, MEK/ERK	Promotes gemcitabine resistance	[90]
Pancreatic cancer	circDUSP22	Down	miR-1178-3p/BNIP3	Restrains cancer development	[91]
Pancreatic cancer	circSTK39	Up	miR-140-3p/TRAM2	Promotes proliferation and migration	[92]
Colorectal cancer	hsa_circ_0009022	Down	miR-576-5p, FMRP	Inhibits proliferation and migration	[93]
Colorectal cancer	circMVP	Up	METTL3/CTNNB1/β-catenin	Increases proliferation, invasion, and tumorigenesis	[94]
Colorectal cancer	circEIF3I	Up	miR-328-3p/NCAPH	Promotes metastasis	[95]
Colorectal cancer	circMYBL2	Down	p185 protein	Suppresses cancer progression, encodes p185 protein	[96]
Colorectal cancer	hsa_circ_0000467	Up	eIF4A3/c-Myc	Promotes growth and metastasis	[97]
Colorectal cancer	hsa_circ_0017065	Up	miR-3174/RBFOX2	Promotes proliferation and metastasis	[98]
Colorectal cancer	circSTIL	Up	miR-431/SLC7A11	Inhibits ferroptosis	[99]
Colorectal cancer	circCAPRIN1	Up	STAT2/ACC1	Promotes proliferation, migration, and EMT	[100]
Colorectal cancer	circINSIG1	Up	circINSIG1-121aa	Encodes circINSIG1-121aa, promotes proliferation and metastasis	[101]
Colorectal cancer	circATG4B	Up	circATG4B-222aa	Encodes circATG4B-222aa, promotes autophagy and oxaliplatin resistance	[32]

circRNA: Circular RNAs; miRNA: MicroRNAs; aa: Amino acid; EMT: Epithelial-mesenchymal transition.

CircRNAs in esophageal cancer

Esophageal cancer is a highly malignant and invasive digestive tract tumor with high incidence and mortality rates worldwide. Increasing research has demonstrated that circRNAs play a pivotal role in the pathology of this condition. Research by Lin et al[18] has indicated that circRNA TCFL5 is markedly elevated in esophageal cancer, facilitating tumor cell growth and migration through the regulation of M2 macrophage polarization. Furthermore, circRNA-0008717 has been shown to interact with miR-203, influencing the expression of Slug and thereby impacting the multiplication and migratory capabilities of esophageal cancer cells[19].

CircRNAs in gastric cancer

Recent years have witnessed a surge in research focusing on circRNAs in gastric cancer, revealing that numerous circRNAs are intricately related to the onset and progression of this disease. For instance, circRNA hsa_circ_0008035 enhances the growth and invasive properties of gastric cancer cells by sponging miR-375[20]. Moreover, circRNA circSMC3 exhibits upregulation in gastric cancer tissues, with its heightened expression correlating with unfavorable prognostic outcomes for patients[21]. Studies have also found that circRNA DLG1 is upregulated in anti-programmed cell death protein-1 treatment, possibly related to the immune evasion mechanism of gastric cancer[22]. Furthermore, proteins encoded by circRNAs also play an important role in tumorigenesis and progression, particularly in the regulation of key processes such as cell proliferation, migration, and apoptosis[23]. The research by Wu et al[24] indicates that circZNF131 encodes the peptide ZNF131-aa, which has been shown to suppress the progression of gastric cancer. In contrast, the research by Liu et al[25] found that the peptide PGD-219aa encoded by circPGD promotes tumor progression. These insights offer novel avenues for early diagnostic strategies and targeted therapeutic interventions in gastric cancer.

CircRNAs in liver cancer

The role of circRNAs in liver cancer has gradually gained attention. Research indicates that circRNA_10156 is upregulated in hepatitis B virus-associated liver cancer, influencing the proliferation and migratory behavior of liver cancer cells through the modulation of miR-149-3p expression[26]. Additionally, circRNA KIF5B exerts its regulatory effects on miR-192 via a sponge mechanism, thereby impacting the growth and metastatic potential of liver cancer cells[27]. Duan et al’s research indicates that circMAP3K4 can encode the small peptide circMAP3K4-455aa[28], which may promote tumor progression by inhibiting apoptosis in liver cancer cells. These studies reveal the biological functions of circRNAs in liver cancer.

CircRNAs in pancreatic cancer

Pancreatic cancer is characterized by a notably poor prognosis, and the role of circRNA in its pathogenesis has increasingly come into focus. Investigations have revealed that circRNA circHIPK3 is highly expressed in pancreatic cancer cells, promoting tumor cell proliferation and migration by regulating miR-637 and FASN[29]. Additionally, circRNA-0087502 enhances the resistance of pancreatic cancer cells to chemotherapy drugs by regulating the miR-1179/TGFBR2 pathway[27].

CircRNAs in colorectal cancer

Colorectal cancer is one of the most common malignant tumors in the digestive system, and the role of circRNAs in its development is increasingly emphasized. Research findings indicate that hsa_circ_0000190 inhibits the proliferation and migration of colorectal cancer cells by modulating the expression levels of miR-1252 and PAK3[30]. Additionally, circDENND4C promotes glycolysis and supports the proliferation of colorectal cancer cells through the regulation of GLUT1[31]. Pan et al[32] consider that circATG4B mediates autophagy and oxaliplatin resistance in colorectal cancer through the encoded protein circATG4B-222aa, thereby influencing tumor progression. These studies provide a novel idea and direction for its targeted therapy of colorectal cancer.

THE IMPACT OF CIRCRNA ON CHEMOTHERAPY RESISTANCE IN DIGESTIVE SYSTEM TUMORS

In the treatment of digestive system tumors, chemotherapy remains one of the main treatment methods. However, the occurrence of chemotherapy resistance often leads to treatment failure, becoming a major obstacle to patient survival. Recent investigations have increasingly highlighted the pivotal role of circRNAs in mediating resistance to chemotherapy in tumors. CircRNAs modulate the sensitivity and resistance of tumor cells to chemotherapeutic agents through multiple mechanisms. Primarily, circRNAs sponge with miRNAs, inhibiting the latter’s regulation of target genes through miRNA binding. An illustrative example is circRNA_0014784, which enhances the growth and metastasis of pancreatic cancer by combining with miR-214-3p and modulating the expression of YAP1[8]. This regulation of miRNAs not only impacts tumor growth but may also significantly contribute to the development of resistance to chemotherapy. Moreover, circRNAs can affect the efficacy of chemotherapy by influencing drug metabolism and transport mechanisms. For instance, circRNAs may influence the concentration of drugs within tumor cells, thereby altering the cells' sensitivity to chemotherapy drugs. Evidence suggests that circRNAs can bolster the resistance of tumor cells to chemotherapeutic agents by regulating the expression of drug efflux pumps[33]. Additionally, circRNAs may further promote the development of chemotherapy resistance by affecting mechanisms such as cell apoptosis and DNA damage repair.

Research focusing on circRNAs in gastrointestinal tumors reveals their potential as both a biomarker and a therapeutic target. For instance, circRNA_0001649 has been linked to chemotherapy resistance in colorectal cancer, with its elevated expression correlating with a poor prognosis in affected patients[34]. Furthermore, circRNAs may influence tumor chemotherapy resistance through the regulation of immune responses within the tumor microenvironment. By modulating immune cell function, circRNAs could play a critical role in tumor immune evasion and resistance[4]. In clinical applications, the stability and specificity of circRNAs make them a potential biomarker for monitoring the occurrence of chemotherapy resistance. For instance, the expression quantity of hsa_circ_0041150 in cancer patients is markedly associated with chemotherapy resistance, serving as a biomarker for supervising chemotherapy response[35]. This characteristic makes circRNAs important for personalized treatment. CircRNAs play a complex and important role in chemotherapy resistance in digestive system tumors. By regulating miRNA activity, influencing drug metabolism and transport, and modulating the tumor microenvironment, circRNAs provide new insights into understanding tumor resistance mechanisms. This will provide new insights and strategies for improving treatment outcomes and prognosis for patients suffering from digestive system tumors.

THE IMPACT OF CIRCRNA ON IMMUNE REGULATION IN DIGESTIVE SYSTEM TUMORS

CircRNAs have a stable structure and specific tissue expression, capable of influencing tumor development through various mechanisms. Emerging evidence indicates that circRNAs play a vital regulatory role in the immune microenvironment of digestive system tumors, affecting the functions of immune cells and tumor immune evasion.

CircRNAs has the capacity to diminish the extent to which specific miRNAs suppress their target genes through direct binding, subsequently facilitating the growth and metastasis of tumor cells[2]. In digestive system tumors, various circRNAs have emerged as significant contributors to immune evasion by tumors, as they can modulate tumor cell interactions with the immune system via the regulation of immune checkpoint gene expression. A notable example is circCPA4, which has been identified as a promoter of programmed death ligand 1 (PD-L1) expression, thereby aiding the immune evasion capabilities of tumor cells[36]. Furthermore, circRNAs also influence the tumor microenvironment by modulating immune cell functions. CircRNAs can influence the anti-cancer immune response by adjusting the exhaustion state of T cells[37]. In digestive system tumors, circRNAs correlate with the degree of immune infiltration, suggesting that they may serve as important regulatory factors in the tumor immune microenvironment. Moreover, the application prospects of circRNAs in tumor immunotherapy have also garnered attention. Due to the stability and specificity of circRNAs, they may become new immunotherapy targets. For instance, the development of circRNA vaccines provides new ideas for tumor immunotherapy. Researchers are exploring how to utilize circRNAs as vaccine components to activate specific immune responses, thereby enhancing the efficacy of immunotherapy[4].

However, the specific mechanisms of circRNAs in immune regulation in digestive system tumors still require further research. We should focus on the localization, transport, and degradation mechanisms of circRNAs in the tumor microenvironment, as well as the specific pathways of their interactions with immune cells. Accomplishing this will provide fresh perspectives and strategies for the diagnosis and therapeutic management of digestive system tumors. In summary, circRNAs are an important area of research for understanding immune regulation in digestive system tumors, and future studies are expected to reveal their potential applications in tumor immunotherapy.

CIRCRNA AS A BIOMARKER IN DIGESTIVE SYSTEM TUMORS

CircRNAs not only play a significant role in tumor occurrence and development but are also considered a potential biomarker for early diagnosis and prognostic assessment. The expression levels of circRNAs are also significantly correlated with clinical pathological features of tumors. For instance, elevated levels of hsa_circ_0001649 and hsa_circ_0001178 in gastric cancer and colorectal cancer have been correlated with unfavorable prognoses[1]. The abnormal expression not only reflects the biological characteristics of tumors but may also become an important indicator for assessing patient prognosis in clinical settings. The secretion of circRNAs into body fluids occurs in the form of exosomes, a characteristic that suggests the potential of exosomal circRNAs as an effective biomarker for tumor diagnosis and prognosis. For instance, in the context of esophageal cancer, studies have demonstrated that exosomal circ_0000337 fosters resistance to cisplatin by modulating the miR-377-3p and JAK2 signaling pathways[38]. Due to its stability in plasma and tissues, circRNAs can serve as a biomarker for non-invasive detection. More research indicates that the expression levels of specific circRNAs in plasma can effectively distinguish healthy individuals from patients with digestive system tumors, providing new ideas for early diagnosis[4]. Additionally, combining the expression profiles of multiple circRNAs can further enhance diagnostic accuracy; using multiple circRNAs for gastric cancer diagnosis can demonstrate high sensitivity and specificity[39].

In terms of prognostic assessment, the expression quantity of circRNAs are closely related to patient survival rates. Research indicates that specific oncogenic circRNAs, such as hsa_circ_0002917, correlate with unfavorable survival rates in individuals diagnosed with gastrointestinal malignancies, whereas elevated levels of tumor-suppressive circRNAs may be associated with improved prognoses[2,3]. This differential expression pattern provides clinicians with new prognostic assessment tools, aiding in the formulation of individualized treatment plans. In summary, circRNAs as a biomarker for digestive system tumors have broad application prospects. They can be used not only for early diagnosis and prognostic assessment of tumors but may also become new therapeutic targets.

IMPACT OF CIRCRNA ON THE TREATMENT OF DIGESTIVE SYSTEM TUMORS

Targeting circRNAs in tumor treatment strategies

Multiple studies have shown that circRNAs can regulate tumor phenotype through various mechanisms. For instance, circRNAs can sponge with miRNA, inhibiting miRNA's suppressive effects on target genes[2]. Treatment strategies targeting circRNAs mainly include using small molecule drugs, antibodies, or RNA interference techniques to inhibit the expression of specific circRNAs, thereby restoring the function of tumor suppressor genes or enhancing circRNA expression to suppress tumor progression[3]. Research has found that circRNA_0000074 acts as a tumor suppressor in gastric cancer, targeting and inhibiting the proliferation and invasion abilities of tumor cells[4]. Thus, circRNA-targeted treatment strategies present novel perspectives for managing gastrointestinal tumors.

CircRNAs as drug delivery carriers

Due to their stability and biocompatibility, circRNAs can serve as ideal carriers for drug delivery. Relevant studies have found that circRNAs can effectively encapsulate drug molecules and enter target cells through cell membranes, thereby improving the bioavailability and targeting of drugs[1]. For instance, using lipid nanoparticles to combine circRNAs with anti-cancer drugs can significantly enhance drug accumulation in tumor cells and improve anti-tumor effects[9]. Additionally, the application of circRNAs as drug delivery carriers can also reduce drug side effects and enhance treatment safety and efficacy, opening new avenues for the treatment of digestive system tumors.

CircRNAs can regulate the tumor microenvironment

The tumor microenvironment is pivotal in the initiation and progression of tumors. CircRNAs influence tumor advancement through the regulation of immune cells, stromal cells, and angiogenesis within the tumor microenvironment[4]. For instance, circRNAs can facilitate tumor immune evasion and metastatic processes by modulating the functionality of tumor-associated macrophages[10]. CircRNAs can also interact with other non-coding RNAs, forming complex regulatory networks that further affect the biological behavior of tumors[40]. Consequently, investigating the function of circRNAs within the tumor microenvironment is anticipated to unveil novel therapeutic targets for the management of digestive system malignancies.

Development and application of circRNA vaccines

CircRNA vaccines, as an emerging immunotherapy, show promising application prospects. CircRNA vaccines can effectively activate the immune system, inducing specific T cell responses, thereby enhancing immune surveillance against tumors[41]. For instance, circRNA vaccines targeting gastric cancer have shown good anti-tumor effects in mouse models, significantly inhibiting tumor growth and metastasis[42]. Moreover, the stability and long-lasting effects of circRNA vaccines make them powerful tools for cancer immunotherapy, providing new insights for the treatment of digestive system tumors.

Application of circRNAs in chimeric antigen receptor T-cell therapy

Chimeric antigen receptor (CAR)-T cell therapy has become an effective means for cancer treatment, and the application of circRNAs in this field is gradually receiving attention. Experiments have shown that circRNAs can enhance the anti-tumor activity of CAR-T cells and improve their persistence and specificity[43]. For example, circRNAs can alleviate T cell exhaustion by modulating T cell metabolism and function, thereby enhancing their ability to kill tumor cells[44]. Therefore, incorporating circRNAs into CAR-T cell therapy holds the promise of improving therapeutic outcomes and prognoses for patients with digestive system tumors.

CircRNAs can regulate tumor metabolic reprogramming

The metabolic reprogramming observed in tumor cells is a fundamental aspect of their proliferation and metastasis. CircRNAs influence tumor progression by regulating key metabolic enzymes and affecting metabolic pathways in tumor cells[45]. CircRNAs can enhance the invasiveness of tumor cells by influencing metabolic pathways such as glycolysis and fatty acid oxidation[46]. Therefore, studying the role of circRNAs in tumor metabolic reprogramming provides novel targets for the treatment of digestive system tumors.

Combination therapy with circRNAs

Combination therapy is an important strategy to improve cancer treatment efficacy. The combined application of circRNAs with other treatment methods can produce synergistic effects, enhancing anti-tumor effects. For instance, using circRNAs in conjunction with chemotherapy drugs or immune checkpoint inhibitors can effectively overcome tumor resistance and improve treatment efficacy[47]. Additionally, combination therapy strategies involving circRNAs can also enhance immune responses by modulating the tumor microenvironment, further improving treatment outcomes for digestive system tumors. Thus, combination therapy strategies involving circRNAs provide new directions for the treatment of digestive system tumors.

CONCLUSION

As research continues to deepen on circRNAs in digestive system tumors, recent findings are showing their potential for clinical applications. Recent studies have not only elucidated the molecular mechanisms underlying tumorigenesis and progression but have also facilitated the identification of new biomarkers and therapeutic targets. Many researchers have made numerous discoveries and perspectives through in-depth studies of circRNAs, forming a series of research outcomes. For example, some studies have indicated that specific circRNAs are significantly upregulated or downregulated in digestive system tumors, and these circRNAs may have important impacts on tumor development by regulating gene expression[48]. However, research results regarding the role of circRNAs in different types of digestive system tumors are not entirely consistent, leading to varying opinions on their clinical applications[49,50]. To address this phenomenon, future research needs to be more systematic and standardized. On the one hand, large-scale clinical sample analyses can further validate the expression patterns and biological functions of circRNAs in various digestive system tumors. On the other hand, exploring the crosstalk between circRNAs and other molecules (miRNAs, long non-coding RNAs, etc.), as well as their role in the tumor microenvironment, will help construct a more comprehensive network model of the emergence and progression of digestive system tumors.

Multi-center studies and interdisciplinary collaborations, such as the integration of molecular biology, clinical medicine, and bioinformatics, can provide broader perspectives and deeper analytical tools for circRNA research. This can not only promote the progress of circRNAs research in digestive system tumors but also facilitate its application in clinical practice. Overall, research on circRNAs in digestive system tumors is at a rapidly developing stage. We should focus on revealing the functional mechanisms of circRNAs, clarifying their roles in tumor biology, and promoting their translation into clinical applications through clinical validation and multi-center research. With the deepening of research, circRNAs are expected to provide new ideas and methods for the early diagnosis and personalized treatment of digestive system tumors, ultimately improving patient prognosis and quality of life.