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
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.
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
Current discoveries defining the lncRNA-TIME nexus are synthesized and advances in high-throughput sequencing, single-cell transcriptomics, and computational modeling that enable the mapping of these complex networks are highlighted.
Juwon Lee, Revathy Nadhan, Yong-Sang Song et al.· Genomics, Proteomics & Bioin...· 0 citations
New 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.
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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