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Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review)

  • Authors:
    • Xiangjun Dong
    • Yinwei Che
    • Yuzhuo Jiao
    • Hao Dong
    • Qingchao Ren
    • Huashan Sun
    • Tao Zhao
  • View Affiliations / Copyright

    Affiliations: Department of Central Laboratory, Shandong Provincial Key Medical and Health Laboratory of Perioperative Precise Anesthesia and Organ Protection Mechanism Research, Rizhao Key Laboratory of Basic Research on Anesthesia and Respiratory Intensive Care, The People's Hospital of Rizhao, Rizhao, Shandong 276826, P.R. China
    Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 302
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    Published online on: August 28, 2025
       https://doi.org/10.3892/mmr.2025.13667
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Abstract

 As a class of endogenous non‑coding RNAs, circular RNAs (circRNAs) are produced by an event known as back‑splicing. Although circRNAs were initially considered to be the product of abnormal splicing events, increasing evidence has shown their vital role in the development of various diseases, especially malignant tumors. Tumor metastasis is the leading cause of tumor deterioration and cancer‑associated mortality, and involves biological changes to malignant cells. A number of circRNAs can mediate tumor progression, especially tumor metastasis. Furthermore, due to their unique structural features, circRNAs are highly stable in body fluids, and have temporal and tissue specificity, making them potentially ideal non‑invasive biomarkers for sensitive monitoring of tumor changes. The present review focuses on circRNAs associated with tumor metastasis and discusses their functional mechanisms. Furthermore, the current review summarizes advances regarding circRNAs as biomarkers and detection strategies.
View Figures

Figure 1

Biogenesis of circular RNAs. EcRNAs
and EIciRNAs are conventionally formed in three ways:
Circularization caused by exon skipping, intron pairing-driven
circularization and RBP interaction-mediated circularization. ciRNA
forms a lariat structure through splicing by relying on a conserved
motif, thereby evading debranching. ciRNA, intron-derived circular
RNA; EcRNA, exonic circular RNA; EIciRNA, exon-intron circular RNA;
RBP, RNA-binding protein.

Figure 2

Functions of circRNAs. (A) CircRNAs
function mainly through four direct mechanisms of action: Sponging
miRNAs, interacting with RBPs, regulating host genes and coding
proteins or peptides. (B) CircRNAs can be encapsulated into
exosomes and serve a role in regulating tumor metastasis through
transport and release. (C) CircRNAs interact with endothelial
cells, immune cells, tumor-derived fibroblasts and ECM in the tumor
immune microenvironment to affect immune function, and then affect
tumor progression. (D) CircRNAs can regulate transcription factors
such as ZEB and TWIST, signaling pathways such as the TGF-β and Wnt
pathways, and the tumor immune microenvironment through various
direct action modes, influencing the epithelial-mesenchymal
transition process. (E) Metabolism-related circRNAs regulate tumor
metastasis by influencing glucose, fatty acid and amino acid
metabolism, and autophagy processes through enzymes, transcription
factors and signaling pathways. Ago2, argonaute RISC catalytic
component 2; AMPK, AMP-activated protein kinase; ATG, autophagy
related protein; CAF, cancer-associated fibroblast; circRNA,
circular RNA; E-Cad, E-cadherin; ECM, extracellular matrix; HIF,
hypoxia-inducible factor; hVPS15, vacuolar protein sorting 15;
IRES, internal ribosome entry site; JAK, Janus kinase; LC3-PE,
microtubule-associated proteins 1A/1B light chain
3-phosphatidylethanolamine complex; m6A,
N6-methyladenosine; miRNA, microRNA; N-Cad, N-cadherin;
NK, natural killer; RBP, RNA-binding protein; RNA pol II, RNA
polymerase II; TAM, tumor-associated macrophage; TIMP, tissue
inhibitor of metalloproteinase; TME, tumor microenvironment; TWIST,
twist family bHLH transcription factor; ULK1, unc-51 like autophagy
activating kinase 1; YTHDF, YTH domain-containing family protein 1;
ZEB, zinc finger E-box binding homeobox.

Figure 3

Overview of circRNAs in various types
of cancer metastases. CircRNA/circ, circular RNA.
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Copy and paste a formatted citation
Spandidos Publications style
Dong X, Che Y, Jiao Y, Dong H, Ren Q, Sun H and Zhao T: Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review). Mol Med Rep 32: 302, 2025.
APA
Dong, X., Che, Y., Jiao, Y., Dong, H., Ren, Q., Sun, H., & Zhao, T. (2025). Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review). Molecular Medicine Reports, 32, 302. https://doi.org/10.3892/mmr.2025.13667
MLA
Dong, X., Che, Y., Jiao, Y., Dong, H., Ren, Q., Sun, H., Zhao, T."Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review)". Molecular Medicine Reports 32.5 (2025): 302.
Chicago
Dong, X., Che, Y., Jiao, Y., Dong, H., Ren, Q., Sun, H., Zhao, T."Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review)". Molecular Medicine Reports 32, no. 5 (2025): 302. https://doi.org/10.3892/mmr.2025.13667
Copy and paste a formatted citation
x
Spandidos Publications style
Dong X, Che Y, Jiao Y, Dong H, Ren Q, Sun H and Zhao T: Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review). Mol Med Rep 32: 302, 2025.
APA
Dong, X., Che, Y., Jiao, Y., Dong, H., Ren, Q., Sun, H., & Zhao, T. (2025). Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review). Molecular Medicine Reports, 32, 302. https://doi.org/10.3892/mmr.2025.13667
MLA
Dong, X., Che, Y., Jiao, Y., Dong, H., Ren, Q., Sun, H., Zhao, T."Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review)". Molecular Medicine Reports 32.5 (2025): 302.
Chicago
Dong, X., Che, Y., Jiao, Y., Dong, H., Ren, Q., Sun, H., Zhao, T."Circular RNAs: Fundamental mechanisms in tumor metastasis and detection strategies (Review)". Molecular Medicine Reports 32, no. 5 (2025): 302. https://doi.org/10.3892/mmr.2025.13667
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