CircRNAs involved in the hallmarks of cancer. a CDR1as and circHIPK3 active cell proliferative through regulating EGFR; (b) Circ-ITCH et al. promote cancer cells evading antigrowth signals by preventing expression or activation of tumor suppressors, such as PTEN and CDK; (c) Hsa_circ_0007534 et al. promote cancer cells evading cell death via regulating cellular apoptosis or autophagy; (d) Has-circ-0020397 limits replicative potential of cancer cell trough regulating TERT; (e) CircRNA-MYLK et al. sustain angiogenesis trough regulating VEGF; (f) Dirc-10,720 et al. regulate the process of EMT and thus tissue invasion and metastasis of cancer
Over the past decade, research on circular RNA (circRNA) has rapidly evolved, shedding light on the significant impact these unique RNA molecules have on cancer biology. The recent review by Conn, Chinnaiyan, and Conn (2024), published in Nature Reviews Cancer, provides a comprehensive overview of the functional roles of circRNAs in oncogenesis, highlighting their potential as both biomarkers and therapeutic targets.
Understanding circRNAs: A Unique RNA Family
CircRNAs are a class of non-coding RNA molecules distinguished by their covalently closed loop structures, which make them more stable than their linear counterparts. Unlike linear RNAs, which have 5' and 3' ends, circRNAs form continuous loops, giving them resistance to exonucleases and thus contributing to their hyperstability in the cellular environment. This stability allows circRNAs to persist in cells longer, making them particularly intriguing in the context of cancer, where RNA stability can have significant effects on gene regulation and cellular behavior (Conn, Chinnaiyan, & Conn, 2024).
CircRNA Diversity and Oncogenesis
The review emphasizes that circRNAs exhibit far greater diversity compared to linear RNAs, with approximately ten times more circRNA variants identified in cells. This diversity enables circRNAs to engage in a wide array of cellular functions, many of which are crucial in the context of cancer. CircRNAs can influence every stage of oncogenesis—from initiation to progression and metastasis—through their interactions with various molecular partners, including proteins, RNA, and DNA.
One of the key insights from Conn and colleagues (2024) is that despite their structural differences, circRNAs can function analogously to their linear mRNA counterparts in terms of gene regulation and protein synthesis. However, their increased stability and diversity equip circRNAs with unique capabilities to modulate cellular processes, making them potent players in cancer development.
Mechanisms of circRNA Function in Cancer
CircRNAs contribute to oncogenesis through several mechanisms. They can act as microRNA (miRNA) sponges, sequestering miRNAs and preventing them from binding to their target mRNAs. This sponging activity can result in the upregulation of oncogenes or the downregulation of tumor suppressors, thereby promoting cancer progression. Additionally, some circRNAs can bind to RNA-binding proteins (RBPs), modulating their activity and altering cellular pathways involved in cell proliferation, apoptosis, and metastasis (Conn et al., 2024).
The review also discusses how mutations in the factors responsible for circRNA biogenesis can lead to aberrant circRNA expression, further contributing to cancer. These mutations may affect the splicing machinery that generates circRNAs, leading to the production of circRNAs with oncogenic properties or the loss of circRNAs that normally suppress tumor development.
CircRNAs as Biomarkers and Therapeutic Targets
Given their stability and specificity, circRNAs hold great promise as biomarkers for cancer diagnosis and prognosis. The review highlights several circRNAs that have been identified as potential biomarkers in specific cancers, such as circHIPK3 in colorectal cancer and circZNF609 in bladder cancer. These circRNAs are present at stoichiometrically valid quantities in cancer cells, making them reliable indicators of disease state and progression (Conn et al., 2024).
Moreover, circRNAs offer exciting possibilities for therapeutic intervention. The review discusses the potential of developing circRNA-based therapies, either by targeting specific circRNAs with antisense oligonucleotides or by leveraging circRNAs to modulate gene expression in cancer cells. Such approaches could provide new avenues for precision medicine in oncology, where treatments are tailored to the molecular profiles of individual tumors.
Conclusion: The Future of circRNA Research in Cancer
Conn, Chinnaiyan, and Conn (2024) conclude that the field of circRNA research is at a pivotal moment, with significant opportunities to expand our understanding of these molecules and their role in cancer. As research continues to uncover the complex functions of circRNAs, their potential as biomarkers and therapeutic agents becomes increasingly clear. This review serves as a foundational resource for scientists and clinicians aiming to explore the therapeutic exploitation of circRNAs, paving the way for novel cancer treatments and improved patient outcomes.
References
Conn, V. M., Chinnaiyan, A. M., & Conn, S. J. (2024). Circular RNA in cancer. Nature Reviews Cancer, 24(597–613). https://doi.org/10.1038/s41568-024-00498-0
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