A unified regulatory landscape in which circRNAs function as central nodes connecting ceRNA circuits, epitranscriptomic modulation, immune signaling, immune signaling, metabolic plasticity, and metastatic reprogramming is proposed.
Abstract
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.
This review examines how different types of ncRNAs contribute to cancer initiation, progression, and treatment resistance, and assesses their potential as diagnostic markers, prognostic factors, and therapeutic targets.
Akanksha Samuel, G. Calin· Carcinogenesis· 0 citations
Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, limiting the applicability of endocrine and HER2-targeted therapies. Clinically, TNBC exhibits marked molecular heterogeneity, aggressive behavior, early metastatic dissemination, and poor prognosis relative to other breast cancer subtypes. Increasing evidence indicates that the tumor microenvironment (TME) plays a central role in TNBC progression and therapeutic resistance, with exosomes serving as key mediators of intercellular communication. Exosomes, extracellular vesicles measuring 30–150 nm in diameter, are enriched in non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which regulate interconnected signaling pathways governing proliferation, apoptosis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, immune evasion, metabolic reprogramming, and therapy resistance. This review synthesizes current evidence on how exosomal ncRNAs orchestrate immune-metabolic networks that shape TNBC evolution and highlights their emerging clinical applications as liquid biopsy biomarkers for diagnosis, prognostic stratification, and therapeutic monitoring, as well as their potential as therapeutic targets via antisense oligonucleotides (ASOs), antagomirs, and engineered exosome-based delivery platforms. Finally, we discuss current translational challenges, including exosome heterogeneity, analytical standardization, and clinical validation, and outline future directions for integrating exosomal ncRNAs into precision management strategies for TNBC.
Hui-Xin Chen, Rong Luo, Jiakang Ma et al.· Cancer Biome and Targeted Th...· 0 citations
Abstract Lung cancer remains the leading cause of cancer-related mortality worldwide, with chemoresistance being a major challenge in its treatment. Long non-coding RNAs (lncRNAs), a class of transcripts longer than 200 nucleotides without protein-coding potential, have emerged as critical regulators in tumour progression and drug resistance. This review systematically summarizes the multifaceted mechanisms through which lncRNAs influence chemoresistance across major lung cancer subtypes, particularly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), including regulation of cell proliferation, cell cycle progression, migration, invasion, apoptosis, pyroptosis, necroptosis, and autophagy. Some key lncRNAs function as competing endogenous RNAs (ceRNAs) to sponge microRNAs, modulate chromatin architecture, or alter key signalling pathways (eg, PI3K/Akt, Wnt/β-catenin, and JAK2/STAT3), ultimately promoting survival and chemoresistance of lung cancer cells under chemotherapeutic stress. Clarification of these mechanisms provides novel insights into the development of early diagnostic markers and therapeutic targets. Future research should focus on elucidating specific lncRNA interactions, developing lncRNA-based therapeutics, and exploring their roles in tumour microenvironments and drug-resistant subpopulations to overcome chemoresistance.
Maodan Hou, Jiangyu Chen, Peng Yi et al.· Cancer Management and Resear...· 0 citations
An overview of current understanding of ncRNAs regulating PD-L1 in breast cancer, specifically their molecular mechanisms, therapeutic potential, and clinical relevance as biomarkers and/or therapeutic targets are provided.
Amirhossein Mardi, Sajjad Rajabi Moghaddam, Ali Roohi Motlagh et al.· Clinical and Experimental Me...· 0 citations
Hepatocellular carcinoma (HCC) is a malignant neoplasm characterized by high incidence and mortality rates globally. Its pathogenesis and progression are intricate and multifaceted, necessitating comprehensive analysis and elucidation. Recent studies have demonstrated that non-coding RNAs (such as long non-coding RNAs, circular RNAs, and microRNAs) and alternative splicing, which are central to post-transcriptional regulation, engage in extensive regulatory interactions. These interactions form a complex regulatory network that significantly influences the malignant properties such as stemness, proliferation, invasion, metastasis, metabolic reprogramming, tumor microenvironment, and drug sensitivity in liver cancer cells. This review systematically explores the molecular mechanisms underlying the interactions between non-coding RNAs and alternative splicing events, highlighting the role of this regulatory network in modulating the expression of oncogenes and tumor suppressor genes in HCC. Additionally, this review investigates the prospective application of pivotal molecules within this regulatory network as novel diagnostic biomarkers and therapeutic targets. It also analyzes the challenges and obstacles encountered in the clinical translation process, thereby providing new insights for research on the precision diagnosis and treatment of HCC.
Immune checkpoint inhibitors (ICIs) have revolutionized lymphoma treatment, yet resistance driven by complex regulatory networks remains a major hurdle. Circular RNAs (circRNAs) have emerged as central signaling hubs that integrate metabolic, inflammatory, and oncogenic cues to fine-tune immune checkpoints such as PD-L1 and CD47 in lymphoma. Here, we systematically dissect the molecular mechanisms by which circRNAs govern immune checkpoints in lymphoma, including nuclear transcriptional control, interactions with RNA-binding proteins (RBPs), competitive endogenous RNA (ceRNA) networks, and micropeptide translation. We differentiate between cell-extrinsic, exosome-mediated reprogramming of the tumor microenvironment and cell-intrinsic circRNA circuits within lymphoma cells spatially. Subtype-specific investigations demonstrate the importance of Epstein-Barr virus (EBV)-encoded circRNAs in immune evasion and the synergistic interactions between 9p24.1 amplification and circRNAs in classical Hodgkin lymphoma (cHL). While therapeutic approaches including antisense oligonucleotides, CRISPR-Cas13, and nanodelivery technologies demonstrate preclinical synergy with ICIs, circulating circRNAs show potential as dynamic indicators for predicting ICI responses. We also critically examine ongoing discussions about the flaws of current model systems, the technological constraints of current validation techniques, and the physiological significance of the ceRNA hypothesis. Positioning circRNAs as multimodal regulatory hubs, this review provides a theoretical framework for developing circRNA-based immunotherapies to overcome resistance in lymphoma.
Jingjing Liu, Tianhua Zhao, Yanning Wu et al.· Frontiers in Immunology· 0 citations