Aug 2026· International Journal of Molecular Sciences· 0 citations· 121 references
TL;DR
This review explores how isomiR generation, miRNA strand selection, arm switching, and epitranscriptomic regulation expand the functional diversity of miRNAs in gynecologic cancers.
Abstract
MicroRNAs (miRNAs) are key regulators of gene expression that act primarily by binding to target messenger RNAs (mRNAs). However, the biology of miRNAs is more complex than initially thought, with functional complexity extending beyond canonical sequences. A multilayered miRNA regulatory landscape involving isomiR generation, altered 5p/3p strand usage, arm switching, A-to-I RNA editing, and epitranscriptomic RNA modifications operates in eukaryotic cells to regulate miRNA function. Collectively, these mechanisms expand the functional diversity of miRNAs by regulating their biogenesis, stability, strand selection, and target specificity, increasing their functional plasticity and contributing to regulatory heterogeneity found in cells. IsomiRs arise from alternative Drosha/Dicer processing, terminal nucleotide additions, RNA editing, and genetic variation, producing functionally distinct isoforms. Arm switching alters gene regulatory outputs through context-dependent changes in predominant 5p/3p strand usage. In addition, epitranscriptomic RNA modifications, such as m6A and m5C, together with A-to-I RNA editing, represent an additional layer of miRNA regulation. These mechanisms can act directly on miRNAs or their precursors, or indirectly by modifying circRNAs and lncRNAs, thereby altering miRNA availability and function. Together, these processes form a dynamic regulatory network that influences key cancer hallmarks, including cell proliferation, apoptosis, epithelial–mesenchymal transition, metastasis, immune evasion, and therapy resistance. However, the contribution of these non-canonical regulatory layers to tumor-specific miRNA function remains poorly understood. In this review, we explore how isomiR generation, miRNA strand selection, arm switching, and epitranscriptomic regulation expand the functional diversity of miRNAs in gynecologic cancers.
Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies.
N6-methyladenosine (m6A) is a major epitranscriptomic modification of RNA that plays a crucial role in regulating RNA metabolism and function, thereby participating in diverse biological processes such as cellular homeostasis and stress responses. The dynamic regulation of m6A is orchestrated by three classes of proteins: methyltransferases that install the modification, demethylases that remove it, and m6A-binding proteins that recognize modified transcripts and mediate downstream effects. Accumulating evidence has shown that dysregulation of m6A is critically involved in the initiation and progression of various malignancies. Hepatocellular carcinoma (HCC), a primary liver malignancy with high mortality and poor prognosis, has also been closely linked to m6A-mediated RNA regulation. In this review, we summarize the molecular mechanisms by which m6A regulates both coding and noncoding RNAs in HCC, highlight the functional roles of key m6A regulators in hepatocarcinogenesis, and discuss the therapeutic potential of targeting the m6A machinery in HCC.
Xinning Luo, Cuiying Qin, Yi Feng et al.· Discover Oncology· 0 citations
BACKGROUND
Long non-coding RNAs and N6-methyladenosine RNA methylation represent two pivotal layers of gene regulation. Their extensive crosstalk forms a sophisticated bidirectional network that is fundamentally rewired in cancer.
MAIN BODY
This review synthesizes current knowledge to elucidate the principles and consequences of this synergistic axis. We detail how m6A modification dictates long non-coding RNA stability, splicing, localization, and function through recruitment of distinct "reader" proteins, with one "reader" family primarily mediating decay while another promotes stabilization. Conversely, we examine how long non-coding RNAs act as scaffolds, guides, and decoys to modulate the activity and specificity of the m6A machinery, establishing powerful feedforward and feedback loops. This reciprocal regulation converges on multiple cancer hallmarks, including proliferation, metabolic reprogramming, immune evasion, stemness, and therapeutic resistance. We critically discuss experimental strategies to establish causal relationships, including site-directed mutagenesis, CRISPR-based editing, and rescue assays. We also evaluate current methodological limitations in m6A detection, from antibody-dependent approaches to emerging nanopore sequencing, and highlight how single-cell and spatial transcriptomic technologies can resolve cell-state-specific networks within the tumor microenvironment. From a translational perspective, we compare small molecule inhibitors targeting m6A "writers" with RNA-based therapies, addressing their respective delivery challenges and toxicity concerns. Finally, we outline how m6A-related long non-coding RNA signatures serve as prognostic biomarkers and liquid biopsy tools for non-invasive cancer monitoring.
CONCLUSION
By integrating molecular mechanisms with clinical perspectives, this review charts a roadmap for targeting the epitranscriptomic-long non-coding RNA circuit in precision oncology.
Ziqiang Wang, Tianzi Li, Kun Li· Journal of Translational Med...· 1 citation
N6-methyladenosine (m6A) is the most widespread, abundant, and conserved post-transcriptional modification in eukaryotic RNA, and it participates in the regulation of various biological processes, especially playing a crucial role in tumorigenesis and progression. During tumor progression, abnormal expression of m6A regulatory proteins often leads to dysregulation of m6A modification levels, thereby affecting tumor pathophysiology. Recent studies have shown that in various tumor types, m6A modifications on target mRNAs and non-coding RNA transcripts can regulate the activity of various oncogenic signaling pathways; moreover, m6A modifications can also regulate the tumor glycolysis process through multiple molecular mechanisms, thereby affecting the proliferation, invasion, and metastasis of tumor cells and other biological behaviors. Most existing reviews focus only on the unidirectional regulatory relationships among m6A modification, oncogenic signaling, and glycolysis, while overlooking the crosstalk among the three. To address this gap, this review systematically summarizes the regulatory effects of m6A modifications on key glycolytic enzymes and various cancer signaling pathways, examines in depth the molecular mechanisms by which the three cooperatively participate in tumorigenesis and progression, comprehensively dissects the bidirectional crosstalk among the three core functional modules within this network, and further proposes a self-stabilizing “m6A–signaling–glycolysis closed-loop regulatory network,” and provides future research directions for this field. It offers theoretical references for related basic research and clinical diagnosis and treatment.
Yonggang Guo, Ruilong Kou, Zhizhong Huang et al.· Frontiers in Cell and Develo...· 0 citations
RNA modifications act as crucial post-transcriptional regulators that fine-tune gene expression to modulate cell function. Among these, N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotic cells, regulating several RNA metabolism pathways including RNA splicing, nuclear export, stability, and translation. These processes are particularly important in rapidly responding immune cells such as T cells, which require dynamic changes in gene expression to support differentiation and effector function. This review focuses on the interplay between immunity and epitranscriptomics and explores the direct and indirect effects of m6A modification on T cells. Specifically, we discuss the role of different writers, erasers, and readers in modulating CD4+ and CD8+ T cell homeostasis, differentiation, and function. In addition, we summarize current evidence linking m6A regulators to anti-tumor T cell responses. Finally, we discuss the recent advances in the field of m6A and immunotherapy by highlighting the potential of pharmacological modulation of m6A regulators in augmenting the efficacy of existing immune therapies. Collectively, by integrating emerging mechanistic and translational insights, this review highlights the pivotal role of m6A regulation in T cell biology and underscores its potential to optimize next-generation immunotherapies.
Yumna A. Butt, Nordin D. Zandhuis, I. Foskolou· Immuno· 0 citations
Cervical cancer progression is driven not only by persistent high-risk human papillomavirus infection but also by multilayered post-transcriptional regulatory networks that reshape tumor cell behavior and the tumor microenvironment. Among these regulators, circular RNAs (circRNAs) have emerged as pivotal modulators of oncogenic signaling. Initially characterized as competing endogenous RNAs (ceRNAs), circRNAs were shown to promote cervical cancer growth, invasion, and chemoresistance by derepressing key oncogenic targets. However, recent evidence expands this paradigm, revealing that circRNAs are subject to epitranscriptomic modification and function as dynamic scaffolds integrating RNA-binding proteins, translational machinery, inflammatory signaling, and metabolic pathways. In cervical cancer, m6A-dependent regulation and reader-mediated translational control enhance circRNA stability and amplify oncogenic outputs, linking RNA modification to metabolic reprogramming and hypoxia adaptation. Concurrently, circRNAs modulate inflammatory cascades such as IL6/JAK/STAT3 and NF-κB, contributing to immune suppression and tumor microenvironment remodeling. These tumor-intrinsic and immune-extrinsic mechanisms converge on metastatic reprogramming, enabling lipid metabolic flexibility, lymphangiogenesis, autophagy activation, and therapeutic resistance. This review synthesizes current evidence to propose a unified regulatory landscape in which circRNAs function as central nodes connecting ceRNA circuits, epitranscriptomic modulation, immune signaling, and metabolic plasticity. Unlike previous reviews that primarily summarized circRNA-mediated ceRNA networks, canonical oncogenic pathways, or biomarker potential, this review adopts a systems-level perspective and critically integrates epitranscriptomic regulation, RNA-binding protein interactions, immune-inflammatory signaling, metabolic plasticity, and metastatic reprogramming. We further distinguish directly validated cervical cancer mechanisms from emerging or hypothetical regulatory layers, thereby providing a clearer conceptual framework for future mechanistic and translational studies.
Heying Huang, Lifeng Liu, Yuemei Cui et al.· Frontiers in Immunology· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
MIT News · Artificial Intelligence· news.mit.eduAug 17, 2026
