The intricate relationship between RNA-binding proteins (RBPs) and circular RNAs (circRNAs) has rapidly ascended as a focal point in molecular oncology, offering transformative insights into cancer’s underlying mechanisms. Traditionally overshadowed by linear RNAs, circRNAs have emerged as versatile regulators within cells, particularly through their dynamic interactions with RBPs. This molecular dialogue governs not only gene expression but also cellular behaviors fundamental to tumor proliferation, metastasis, therapeutic resistance, and immune system evasion. Understanding this complex circRNA-RBP network unveils a promising frontier for innovative cancer diagnostics and targeted therapies.
CircRNAs are a distinct class of endogenous RNA molecules, characterized by their covalently closed-loop structures produced through a noncanonical splicing mechanism known as back-splicing. Unlike linear RNAs, circRNAs lack free 5′ and 3′ termini, conferring exceptional stability against exonucleases. Initially dismissed as splicing artifacts, advancements in high-throughput sequencing and bioinformatics have redefined circRNAs as critical players in the post-transcriptional regulation of gene expression. These circular molecules act as molecular sponges that sequester microRNAs and RBPs, thereby modulating signaling pathways pivotal to oncogenesis and tumor progression.
Central to the biogenesis and functional regulation of circRNAs are the RNA-binding proteins, a diverse group of proteins that recognize specific RNA motifs and structures. RBPs influence the fate of circRNAs at multiple levels, including their maturation from precursor mRNAs, cellular localization, and interaction dynamics. Proteins such as Quaking (QKI), fused in sarcoma (FUS), specificity protein 1 (SP1), adenosine deaminase acting on RNA 1 (ADAR1), and DExH-box helicase 9 (DHX9) have been identified as key modulators of circRNA formation. These factors employ mechanistic finesse to either promote or suppress circularization, impacting downstream oncogenic pathways.
Specifically, RBPs like QKI enhance circRNA formation by binding intronic sequences flanking circularized exons, thereby facilitating the back-splicing reaction. Similarly, FUS directly interacts with circRNAs, creating feedback loops that sustain the aberrant expression of oncogenic circRNAs, amplifying tumor growth signals. Conversely, ADAR1 mediates adenosine-to-inosine RNA editing events that can disrupt complementary base pairing necessary for circularization, effectively decreasing circRNA abundance. DHX9 operates as an RNA helicase unwinding RNA duplexes, thus impeding the back-splicing machinery and altering circRNA landscapes. This fine balance between promotion and inhibition orchestrated by RBPs profoundly shapes tumor biology.
Recent findings emphasize the role of the tumor microenvironment (TME) in modulating the circRNA-RBP interface. Hypoxic conditions commonly found within solid tumors alter the expression profiles and activities of specific RBPs, thereby affecting circRNA biogenesis. Hypoxia-inducible factors (HIFs) can induce or repress RBPs, indirectly regulating circRNA pools that contribute to adaptive responses such as angiogenesis and metabolic reprogramming. Furthermore, N6-methyladenosine (m6A), the most prevalent internal RNA modification, has been implicated in modifying circRNA structure and function. m6A marks on circRNAs influence their stability, translation potential, and affinity toward RBPs, integrating another regulatory layer within cancer pathogenesis.
The regulatory versatility of circRNAs, modulated by RBPs and epigenetic marks like m6A, elevates the circRNA-RBP nexus as a potential therapeutic target. Contemporary RNA-based technologies, including RNA interference (RNAi), site-directed RNA editing, and the CRISPR/Cas system, are being adapted to manipulate this network. RNAi approaches aim to silence oncogenic RBPs or circRNAs, while CRISPR-Cas13 systems offer programmable RNA targeting capabilities to disrupt deleterious circRNA-RBP interactions precisely. Additionally, strategies utilizing ADAR-mediated RNA editing enable the correction or modulation of RNA transcripts without permanent genomic alterations, promising enhanced safety profiles for clinical applications.
These pioneering techniques allow for tailored modulation of cancer-driving RNA networks with promising specificity and efficacy. By selectively perturbing the circRNA-RBP axis, researchers envision not only halting tumor progression but also overcoming resistance mechanisms limiting current therapies. This approach could reinvigorate immune recognition of tumor cells and reverse malignant phenotypes, carving new paths toward personalized oncology.
Beyond therapeutic potentials, the circRNA-RBP interaction landscape serves as an invaluable biomarker reservoir. The stability of circRNAs in bodily fluids and their tumor-specific expression profiles coupled with RBP signatures offer avenues for non-invasive diagnostics and prognostics. Liquid biopsy platforms detecting circRNA snippets or RBP expression patterns may significantly enhance early cancer detection and monitoring treatment response, heralding a new era of precision medicine.
Overall, the revelation of circRNAs as functional entities, meticulously regulated by RBPs and modulated by the tumor milieu and epitranscriptomic modifications, underscores a profound paradigm shift in understanding RNA biology in cancer. Ongoing research aims to decode the full spectrum of circRNA-RBP interactions and their mechanistic implications across various cancer types, fostering a deeper understanding of tumor heterogeneity and evolution.
As the field advances, integrating multi-omics approaches and single-cell analyses will elucidate how circRNA-RBP networks dynamically respond to genetic and environmental cues in cancer cells. These insights are expected to catalyze the development of next-generation RNA-targeted therapeutics with high precision, reduced toxicity, and improved patient outcomes.
Such comprehensive exploration also demands addressing technical challenges, including efficient delivery systems for RNA therapeutics, avoiding off-target effects, and ensuring long-term safety in clinical settings. Collaborative efforts bridging molecular biology, bioengineering, and clinical oncology are pivotal for translating these promising molecular mechanisms into tangible cancer therapies.
In conclusion, the expanding knowledge surrounding the circRNA-RBP axis not only deepens our comprehension of cancer biology but also catalyzes innovation in molecular therapeutics. Targeting this axis holds the promise of revolutionizing cancer treatment paradigms and opens new horizons for combating one of humanity’s most formidable diseases.
Subject of Research:
Regulation of circRNA generation and function by RNA-binding proteins in cancer biology and therapeutic applications.
Article Title:
Expanded insights into the mechanisms of RNA-binding protein regulation of circRNA generation and function in cancer biology and therapy
News Publication Date:
2025
Web References:
http://dx.doi.org/10.1016/j.gendis.2024.101383
References:
Lixia Li, Chunhui Wei, Yu Xie, Yanyu Su, Caixia Liu, Guiqiang Qiu, Weiliang Liu, Yanmei Liang, Xuanna Zhao, Dan Huang, Dong Wu. Genes & Diseases, Volume 12, Issue 4, 2025, 101383.
Image Credits:
Genes & Diseases
Keywords:
RNA-binding proteins, circular RNAs, cancer biology, tumor proliferation, metastasis, drug resistance, immune evasion, back-splicing, RNA interference, CRISPR-Cas13, RNA editing, epitranscriptomic modification, N6-methyladenosine.
