Circular RNA in Gastric Cancer
Gastric cancer (GC) is a prevalent malignancy and ranks as the third leading cause of cancer-related deaths globally. Despite advancements in medical science, there remains a lack of simple and effective screening methods for early-stage GC, leading to poor treatment outcomes and prognosis. Recent progress in molecular biology techniques has expanded research on circular RNA (circRNA), a type of non-coding RNA (ncRNA) with unique structural and biological stability. Emerging evidence suggests that circRNA plays a significant role in tumorigenesis, making it a potential biomarker for tumor diagnosis. Studies have demonstrated that circRNA is involved in the proliferation, invasion, metastasis, and apoptosis of GC cells, offering new directions for diagnosis and treatment. This article reviews the structure and function of circRNA, summarizes current research findings, and discusses its potential diagnostic value in GC.
Introduction GC originates from the gastric mucosal epithelium and is a common malignant tumor. According to the World Health Organization’s International Cancer Research Center, GC ranked fifth in global cancer incidence in 2018 and was the third leading cause of cancer-related deaths. Over one million new cases were reported in 2018, with an estimated annual death toll of 783,000. Early diagnosis and prevention are crucial, yet there is no efficient screening method for early-stage GC. The sensitivity and specificity of existing biomarkers need improvement. Advances in molecular biology and high-throughput sequencing have led to the discovery of ncRNAs, including circRNAs. Research has shown that circRNAs play important roles in various cancers, including GC, by acting as oncogenes or tumor suppressor genes. For instance, circLARP4 inhibits GC cell proliferation by sponging miR-424, which interacts with the Hippo signaling pathway. Due to its structural stability, circRNA may become a potential target for disease diagnosis and treatment.
Definition and Characteristics of CircRNA CircRNA is a type of endogenous ncRNA derived from precursor mRNA (pre-mRNA) transcribed by RNA polymerase II. Unlike linear RNA, circRNA lacks a 5′ cap and 3′ poly(A) tail, forming a closed-loop structure that provides greater stability. Discovered over 40 years ago, circRNA was initially considered a by-product of abnormal splicing. However, advancements in molecular purification and high-throughput sequencing have revealed its widespread presence in various tissues, with over 140,000 circRNAs identified. CircRNA can be classified into three categories based on its composition: exonic circRNA (ecRNA), circular intronic RNA (ciRNA), and exon-intron circRNA (EIciRNA). Key characteristics of circRNA include its widespread presence in eukaryotic organisms, tissue-specific expression, resistance to exonuclease degradation, and miRNA sponge effect.
CircRNA Synthesis and Degradation Mechanism CircRNA is synthesized through reverse splicing, where the 5′ and 3′ ends of pre-mRNA are covalently linked to form a circular transcript. Three types of circRNAs are formed through this process: ecRNA, ciRNA, and EIciRNA. EcRNA is produced via exon cyclization, while ciRNA is formed through intron cyclization driven by conserved sequences. EIciRNA contains both exons and introns and is formed when intron sequences are not completely excised. CircRNA is resistant to degradation by ribonuclease R (RNase R) due to its closed-loop structure. However, it can be degraded by miR-671 through the Argonaute protein (AGO) or excreted via extracellular vesicles (EVs).
Function of CircRNA CircRNA regulates gene expression by binding to RNA polymerase II or transcription-related proteins. It also acts as a miRNA sponge, binding to miRNAs and relieving their negative regulation on target genes. For example, ciRS-7 contains multiple miR-7 binding sites and acts as a sponge for miR-7. CircRNA can also interact with RNA-binding proteins (RBPs) to form RNA-protein complexes, regulating gene transcription and protein activity. Additionally, some circRNAs have translational functions, producing functional proteins or peptides. For instance, the circRNA of hepatitis D virus (HDV) encodes pathogenic viral proteins.
Research Methods of CircRNA Various techniques are used to study circRNA, including RNA sequencing, real-time quantitative polymerase chain reaction (RT-PCR), Northern blotting, and RNase R digestion. RNA sequencing has identified abundant circRNA expression in eukaryotic organisms. RT-PCR is used to quantify specific circRNAs, while RNase R digestion helps identify circRNA due to its resistance to degradation. Functional studies involve overexpression or knockdown of circRNA using vectors, siRNA, or small hairpin RNA. Interactions between circRNA and miRNA are studied using dual-luciferase reporter assays and RNA immunoprecipitation (RIP).
Functions of CircRNAs in GC CircRNA is differentially expressed in GC and plays a role in its development and progression. For example, hsa_circ_0074362 is downregulated in GC tissues, while hsa_circ_0000467 is upregulated. CircRNA can serve as a diagnostic marker for GC. For instance, hsa_circ_0000181 is significantly downregulated in GC tissues and plasma, correlating with tumor diameter, lymphatic metastasis, and distant metastasis. CircRNA also inhibits GC proliferation and metastasis. Overexpression of circ_0027599 inhibits GC cell proliferation by sponging miR-101, which regulates the tumor suppressor gene PHLDA1. Conversely, circRNA can promote GC development. For example, circ_0067997 promotes GC by regulating the miR-515-5p/XIAP axis. CircRNA can also be used to analyze GC prognosis. High levels of circPVT1 are associated with poor prognosis, as it acts as a sponge for miR-125, promoting GC cell proliferation. Additionally, circRNA can serve as a therapeutic target. Silencing hsa_circ_0081143 reduces GC cell viability and enhances sensitivity to cisplatin. CircRNA also regulates GC metabolism and the tumor microenvironment. For example, ciRS-7 regulates the PTEN/PI3K/AKT pathway, promoting GC cell proliferation, while circ-104916 inhibits the epithelial-mesenchymal transition (EMT) process in GC cells.
Conclusion CircRNA has shown potential as a biomarker for early diagnosis and treatment of GC. However, further research is needed to fully understand its role in GC development and molecular mechanisms. Multi-center clinical studies are essential to validate its diagnostic and therapeutic potential. In the future, circRNA may become a valuable tool for the screening, diagnosis, and treatment of GC.
doi.org/10.1097/CM9.0000000000000908
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