Jul 2026· Frontiers in Cell and Developmental Biology· Vol 14· 0 citations· 147 references
Medicine
TL;DR
This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication.
Abstract
Cancer remains a major global health burden, with its incidence and mortality rates persistently high despite advances in treatment. Despite therapeutic innovations, malignant tumors continue to pose a formidable challenge to global health. Against this backdrop, the crosstalk between long non-coding RNAs (lncRNAs) and the Notch signaling pathway has emerged as a pivotal driver of tumorigenesis and progression. However, the complex regulatory network and a comprehensive mechanistic framework of this axis await systematic elucidation. This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication. The discussion encompasses various malignancies, spanning the digestive, respiratory, urogenital, nervous, and hematologic systems. The lncRNA-Notch regulatory axis is identified as a ubiquitous and functionally central oncogenic network. It orchestrates critical malignant phenotypes—such as such as stemness maintenance, epithelial-mesenchymal transition, metabolic shifts, drug resistance, and immune evasion—through intricate bidirectional crosstalk. Functional studies confirm that targeting key nodes of this axis can effectively reverse drug resistance and suppress tumor growth. Although challenges remain in its clinical translation, future research integrating single-cell multi-omics, nanotechnology, and other innovative strategies will undoubtedly open new avenues for precision diagnosis and cancer therapy.
Gastric Cancer (GC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer-related mortality worldwide. The aggressive nature of GC, coupled with late clinical presentation and limited therapeutic options, underscores the urgent need for a deeper molecular understanding of its pathogenesis. In the past, microRNAs (miRNAs)-evolutionarily conserved, 19-25-nucleotide, non-protein-coding RNAs-have emerged as pivotal post- transcriptional regulators that simultaneously modulate dozens of messenger RNAs through seed-sequence-mediated binding to 3' untranslated regions. In GC, the most intensively studied axes include Notch, Wnt/β-catenin, Hippo, Hedgehog, TGF-β, MAPK, PI3K-AKT-mTOR, and JAK/STAT. Importantly, these pathways do not operate in isolation; instead, they form interconnected networks wherein a single miRNA can create feed-forward or feedback loops that amplify or attenuate oncogenic signaling. Decoding such miRNA-orchestrated crosstalk is not merely an academic exercise; it offers tangible translational opportunities. Restoration of tumor-suppressive miRNAs using synthetic mimics delivered by lipid nanoparticles, or selective silencing of oncomiRs with antagomirs locked by 2'-O-methoxyethyl modifications, has already shown synergistic efficacy with chemotherapy, HER2-targeted agents, and immune checkpoint blockade in preclinical GC models. Moreover, circulating exosomal miRNA signatures that reflect pathway activation states are being vigorously pursued as minimally invasive biomarkers for early detection, molecular subtyping, and real-time monitoring of therapeutic response. In this comprehensive review, we therefore synthesize current mechanistic insights into miRNA- mediated regulation of the aforementioned signaling highways, highlight context-dependent controversies arising from tumor heterogeneity and microbial influence, and outline rational combinatorial strategies that may accelerate the development of next-generation, highly selective, low-toxicity interventions against gastric cancer.
Liu-Shan Wei, Jia Yu, Yan Hu et al.· Current Cancer Drug Targets· 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
Metastasis and therapeutic resistance remain the principal causes of cancer-related mortality, reflecting the failure of current therapies to eradicate disseminated and treatment-refractory tumor cells. Long non-coding RNAs, once considered transcriptional noise, have now emerged as pivotal regulators of cancer progression, acting through diverse mechanisms to modulate signaling pathways, transcriptional programs, tumor metabolism, and the tumor microenvironment. Accumulating evidence demonstrates that lncRNAs orchestrate epithelial-mesenchymal transition, metabolic reprogramming, and immune evasion, thereby enabling metastatic dissemination and fostering resistance to chemotherapy. Moreover, recent discoveries have revealed that certain lncRNAs can encode functional micropeptides, further expanding their biological and therapeutic relevance. In this review, we systematically summarize current advances in lncRNA-mediated regulation of cancer metastasis and drug resistance, with particular emphasis on their roles in oncogenic signaling cascades, transcriptional control, immune cell reprogramming, and metabolic remodeling. we also discuss emerging therapeutic strategies targeting lncRNAs, including antisense oligonucleotides, CRISPR-based approaches, and lncRNA-encoded micropeptides interventions. Finally, we highlight key challenges, including context-dependent lncRNA functions, tumor heterogeneity, delivery, off-target effects, and biomarker standardization, and discuss multi-omics, single-cell, and spatial approaches may facilitate the translation of lncRNA biology into precision oncology.
Dong Liang, Jing-Wen Zheng, Zheng-Dan Gao et al.· Biochimica et biophysica act...· 0 citations
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of tumor-immune interactions, bridging epigenetic, transcriptional, and post-transcriptional control of immune signaling networks. Recent multi-omics analyses reveal that lncRNAs shape the tumor immune microenvironment (TIME) by influencing immune-cell differentiation, activation, and exhaustion, as well as cytokine, chemokine, and immune-checkpoint pathways. Acting through molecular scaffolding, chromatin remodeling, and competing endogenous RNA (ceRNA) mechanisms, lncRNAs orchestrate the recruitment and functional polarization of lymphoid and myeloid populations, thereby dictating the balance between antitumor immunity and immune suppression. Integrative evidence further links specific lncRNA signatures to PD-1/PD-L1 checkpoint regulation, metabolic reprogramming, and therapeutic resistance. Here, we synthesize current discoveries defining the lncRNA-TIME nexus and highlight advances in high-throughput sequencing, single-cell transcriptomics, and computational modeling that enable the mapping of these complex networks. We discuss the translational promise of targeting lncRNAs as biomarkers and therapeutic nodes to enhance immunotherapy efficacy. Collectively, these integrative insights position lncRNAs as critical molecular interfaces connecting tumor genomics with immune regulation and open new avenues for precision immuno-oncology.
Juwon Lee, Revathy Nadhan, Yong-Sang Song et al.· Genomics, Proteomics & Bioin...· 0 citations
Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults and remains associated with poor clinical outcomes despite advances in surgical resection, radiotherapy, and temozolomide-based chemotherapy. Its remarkable molecular heterogeneity, highly immunosuppressive tumor microenvironment, and intrinsic therapeutic resistance continue to limit the effectiveness of current treatment strategies. Long non-coding RNAs (lncRNAs), transcripts exceeding 200 nucleotides in length that lack protein-coding capacity, have emerged as critical regulators of GBM biology through transcriptional, post-transcriptional, and epigenetic mechanisms. Acting as competing endogenous RNAs, chromatin modifiers, molecular scaffolds, and regulators of RNA-binding proteins, lncRNAs orchestrate key oncogenic pathways controlling proliferation, invasion, angiogenesis, stemness, metabolic reprogramming, immune evasion, and resistance to chemotherapy and radiotherapy. This review provides a comprehensive overview of lncRNA biogenesis, classification, and mechanisms of action, followed by an updated synthesis of oncogenic and tumor-suppressive lncRNAs implicated in GBM progression. Particular emphasis is placed on emerging evidence demonstrating how immunophenotype-related lncRNAs regulate immune cell infiltration, immune checkpoint signaling, and the immunosuppressive glioblastoma microenvironment, highlighting their potential to improve patient stratification and guide immunotherapeutic approaches. We also discuss the growing clinical utility of lncRNAs as diagnostic, prognostic, and predictive biomarkers, including circulating lncRNAs and lncRNA-based molecular signatures. Finally, we examine current and emerging therapeutic strategies targeting lncRNAs, including nanoparticle-mediated delivery systems designed to overcome the blood-brain barrier. Advances in single-cell and spatial transcriptomic technologies are further expanding our understanding of lncRNA-mediated regulatory networks and intratumoral heterogeneity, supporting the development of precision medicine strategies. Collectively, lncRNAs represent promising biomarkers and therapeutic targets with significant potential to improve the diagnosis, prognosis, and treatment of glioblastoma.
N. Elemam, Jana H. Sweillam, Youssef A. El-Sherif et al.· Frontiers in Immunology· 1 citation
Lung cancer is characterized by profound molecular and clinical heterogeneity and remains the leading cause of cancer-related mortality worldwide. Its initiation and progression are shaped by complex genetic and epigenetic alterations that perturb key biological processes, including cell proliferation, apoptosis, metabolic reprogramming, invasion, metastasis, and immune evasion. Increasing evidence indicates that dysregulated alternative splicing (AS) represents a critical post-transcriptional regulatory mechanism involved in lung cancer pathogenesis. Although AS abnormalities are not the sole drivers of tumorigenesis, they contribute to malignant transformation, tumor progression, therapeutic resistance, and phenotypic plasticity, providing opportunities for biomarker development and therapeutic targeting. This review summarizes the multifaceted roles of AS in lung cancer biology, highlighting its contributions to tumor evolution, metastatic dissemination, and treatment resistance. Furthermore, subtype-specific AS landscapes between major lung cancer subtypes are discussed to elucidate their distinct molecular mechanisms and therapeutic implications. Representative AS-generated isoforms, including cluster of differentiation 44 variants (CD44v), are further discussed as examples of how aberrant splicing events regulate cancer stemness, tumor progression, and therapeutic responses. The regulatory mechanisms underlying CD44v generation, including upstream splicing factors and downstream signaling pathways, are also summarized. Collectively, this review highlights the emerging role of aberrant AS regulation in lung cancer and emphasizes its potential implications for biomarker discovery and precision therapeutic strategies targeting splicing dysregulation.
Lingrui Shang, Nannan Wang, Qianqian Liu et al.· International Journal of Mol...· 0 citations
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