Non-coding RNA Research最新文献_第6页

miRNA-195-5p modulates cell proliferation and stemness by targeting the Wnt signalling network in breast cancer miRNA-195-5p通过靶向Wnt信号网络调节乳腺癌细胞增殖和干细胞性

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-01 Epub Date: 2025-09-13 DOI: 10.1016/j.ncrna.2025.09.001

Sanjeev Kumar , Neeru Saini

Cancer stem cells (CSCs) are a specific subpopulation of cells within the tumour characterised by self-renewal, proliferation and tumorigenic potential. Heterogeneity in the CSCs population and their ability to rewire the signalling networks make it difficult to target cancer by single gene inhibition. This study investigates the regulatory role of miR-195-5p in modulating CSC properties and associated signalling pathways in breast cancer. Previously shown to inhibit proliferation, invasion, and metastasis, miR-195-5p is now revealed to downregulate stemness markers (OCT4, SOX2, NANOG, and CD44). The prevalence of heterogeneity of stemness markers in MCF-7 and MDA-MB-231 cell lines is a novel advancement of this study. In MCF-7, SOX2-and CD44-overexpressing cells were found to be distinct, non-overlapping populations, as confirmed by immunofluorescence colocalisation analysis. SOX2-positive nuclei comprised ∼30 % of the MCF-7 population and were significantly reduced following miR-195-5p overexpression. Mechanistically, this downregulation of stemness correlated with decreased expression of β-catenin and its upstream regulators GSK3β and FZD6, were validated as direct targets of miR-195-5p using a luciferase reporter assay. miR-195-5p also inhibited TCF/LEF transcriptional activity, indicating suppression of canonical Wnt/β-catenin signalling. Functionally, miR-195-5p overexpression led to a reduced proliferation zone in CFSE-prestained 3D spheres derived from MCF-7 cells over seven days. To further dissect its mechanism, Wnt signalling was perturbed using siRNA against GSK3β, β-catenin and ICG-001 (a CBP/β-catenin interaction inhibitor), and their combination. GSK3β knockdown led to increased β-catenin expression, nuclear localisation, and enhanced 3D sphere proliferation, while β-catenin inhibition upregulated protein expression of GSK3β and suppressed proliferation of cancer cells. Combined inhibition of GSK3β and CBP/β-catenin interaction downregulated expression of β-catenin, supporting the role of miR-195-5p in CSC suppression. This study identifies miR-195-5p as a potent regulator of CSCs and proliferation, and modulator of the Wnt signalling cascade. Co-inhibition of GSK3β and CBP/β-catenin through miR-195-5p highlights its therapeutic potential in combating stemness and proliferation in breast cancer.

肿瘤干细胞（CSCs）是肿瘤内具有自我更新、增殖和致瘤潜能的特定细胞亚群。CSCs群体的异质性及其重新连接信号网络的能力使其难以通过单基因抑制靶向癌症。本研究探讨了miR-195-5p在乳腺癌中调节CSC特性和相关信号通路中的调节作用。先前显示miR-195-5p抑制增殖、侵袭和转移，现在发现miR-195-5p下调干性标记（OCT4、SOX2、NANOG和CD44）。干细胞标记在MCF-7和MDA-MB-231细胞系中异质性的普遍存在是本研究的一个新进展。免疫荧光共定位分析证实，在MCF-7中，sox2和cd44过表达细胞是不同的、不重叠的群体。sox2阳性细胞核占MCF-7群体的30%，并且在miR-195-5p过表达后显著减少。在机制上，这种干性下调与β-catenin及其上游调节因子GSK3β和FZD6的表达降低相关，通过荧光素酶报告基因试验证实了它们是miR-195-5p的直接靶点。miR-195-5p还抑制了TCF/LEF的转录活性，表明抑制了典型的Wnt/β-catenin信号传导。在功能上，miR-195-5p过表达导致MCF-7细胞衍生的cfse染色3D球在7天内增殖区减少。为了进一步分析其机制，使用siRNA干扰GSK3β、β-catenin和ICG-001（一种CBP/β-catenin相互作用抑制剂）及其组合，干扰Wnt信号。GSK3β敲低导致β-catenin表达增加，核定位增加，3D球增殖增强，而β-catenin抑制上调GSK3β蛋白表达，抑制癌细胞增殖。联合抑制GSK3β和CBP/β-catenin相互作用下调β-catenin的表达，支持miR-195-5p在CSC抑制中的作用。本研究确定miR-195-5p是CSCs和增殖的有效调节剂，也是Wnt信号级联的调节剂。通过miR-195-5p共同抑制GSK3β和CBP/β-catenin，突出了其在对抗乳腺癌干细胞和增殖方面的治疗潜力。

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引用次数: 0

AutoML identification of microRNA biomarkers in high-risk pediatric acute lymphoblastic leukemia 高危儿童急性淋巴细胞白血病microRNA生物标志物的AutoML鉴定

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-01 Epub Date: 2025-08-20 DOI: 10.1016/j.ncrna.2025.08.003

Ioannis Kyriakidis , Zacharias Papadovasilakis , Georgios Papoutsoglou , Iordanis Pelagiadis , Helen A. Papadaki , Charalampos Pontikoglou , Eftichia Stiakaki

Despite significant advancements in overall survival rates for childhood acute lymphoblastic leukemia (ALL), relapse continues to pose a major challenge. MicroRNAs have proven valuable for improving diagnosis, treatment, and survival outcomes, establishing themselves as key biomarkers. Using RNA-seq data from 123 ALL patients and employing predictive modeling via automated machine learning (AutoML) alongside causal-inspired biomarker discovery, we identified highly predictive microRNA signatures linked to high-risk strata and clinical features in unfavorable cases. We further identified predictive signatures for each genetic subtype of childhood ALL, highlighting shared miRNAs throughout the study. A thorough literature review of the relationships between miRNA differential expression and key high-risk features in childhood ALL [immunophenotype, elevated white blood cell counts at diagnosis, central nervous system involvement, measurable residual disease (MRD), and chemoresistance] confirmed the signatures generated in this study. Our results revealed a highly predictive signature distinguishing B- and T-ALL, associated with apoptosis, confirming the reported difference between the two immunophenotypes. Additionally, miR-223 emerged as crucial for high-risk stratification and chemoresistant MRD-positive cases. These findings demonstrate the potential of AutoML tools to reveal novel biological insights in pediatric ALL, driving future advancements.

尽管儿童急性淋巴细胞白血病（ALL）的总生存率有了显著进步，但复发仍然是一个重大挑战。MicroRNAs已被证明对改善诊断、治疗和生存结果有价值，并成为关键的生物标志物。利用来自123名ALL患者的RNA-seq数据，并通过自动机器学习（AutoML）和因果启发的生物标志物发现采用预测建模，我们确定了与高危层和不利病例临床特征相关的高预测性microRNA特征。我们进一步确定了儿童ALL的每个遗传亚型的预测特征，突出了整个研究中共享的mirna。对儿童ALL中miRNA差异表达与关键高危特征（免疫表型、诊断时白细胞计数升高、中枢神经系统受累、可测量残留病（MRD）和化疗耐药）之间关系的全面文献综述证实了本研究中产生的特征。我们的研究结果显示，区分B- all和T-ALL的高度预测性特征与细胞凋亡有关，证实了两种免疫表型之间的差异。此外，miR-223对于高风险分层和耐药mrd阳性病例至关重要。这些发现表明，AutoML工具有潜力揭示儿科ALL的新生物学见解，推动未来的进展。

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引用次数: 0

The mechanism of plasma exosome miR-15a-5p targeting the CF-modified protein IGF1R to regulate alveolar epithelial autophagy and influence pulmonary interstitial fibrosis 血浆外泌体miR-15a-5p靶向cf修饰蛋白IGF1R调控肺泡上皮自噬并影响肺间质纤维化的机制

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-12-01 Epub Date: 2025-07-03 DOI: 10.1016/j.ncrna.2025.07.001

Yina Li , Nan Wang , Jinying Hu, Minlan Luo, Na Zhang, Lili Gao

Aims

This study investigates how plasma exosomal miRNAs regulate core fucosylation (CF)-modified targets to influence autophagy and fibrosis in idiopathic pulmonary fibrosis (IPF), aiming to identify novel therapeutic strategies targeting dysregulated alveolar epithelial cell (AEC) autophagy.

Materials and methods

Plasma exosomes from IPF patients and healthy controls were isolated via ultracentrifugation, validated by TEM, nanoparticle tracking analysis (NTA), and Western blot (CD9/CD81). Exosomal miRNA profiling employed high-throughput sequencing, with TargetScan/miRanda predicting target genes. A549 and MLE-12 cells assessed exosome uptake (PKH67 labeling) and miRNA-mRNA interactions (dual-luciferase assays). CF modification was analyzed via immunoprecipitation/Western blot. In vivo validation used bleomycin (BLM)-induced fibrosis models in alveolar epithelial-specific FUT8-knockout (CKO) mice.

Key findings

IPF plasma exosomes suppressed autophagy and exacerbated fibrosis in AECs. miR-15a-5p was markedly downregulated in IPF exosomes. Overexpression of miR-15a-5p reversed BLM-induced autophagy inhibition and fibrosis. Mechanistically, miR-15a-5p directly targeted IGF1R, a CF-modified protein. Reduced miR-15a-5p elevated IGF1R expression, activating PI3K/AKT to inhibit autophagy and promote fibrosis.

Significance

This study identifies miR-15a-5p as a critical regulator of CF-modified IGF1R in IPF pathogenesis. Its downregulation drives PI3K/AKT-mediated autophagy suppression, accelerating fibrosis. Restoring miR-15a-5p or targeting IGF1R/PI3K/AKT signaling may offer novel therapeutic avenues for IPF.

本研究探讨血浆外泌体mirna如何调节核心聚焦化（CF）修饰的靶点影响特发性肺纤维化（IPF）的自噬和纤维化，旨在确定针对失调肺泡上皮细胞（AEC）自噬的新治疗策略。材料和方法采用超离心分离IPF患者和健康对照的血浆外泌体，通过TEM、纳米颗粒跟踪分析（NTA）和Western blot （CD9/CD81）进行验证。外泌体miRNA分析采用高通量测序，TargetScan/miRanda预测靶基因。A549和MLE-12细胞评估外泌体摄取（PKH67标记）和miRNA-mRNA相互作用（双荧光素酶测定）。通过免疫沉淀/Western blot分析CF修饰。在肺泡上皮特异性fut8敲除（CKO）小鼠中使用博来霉素（BLM）诱导的纤维化模型进行体内验证。关键发现sipf血浆外泌体抑制aec的自噬并加重纤维化。miR-15a-5p在IPF外泌体中明显下调。过表达miR-15a-5p可逆转blm诱导的自噬抑制和纤维化。在机制上，miR-15a-5p直接靶向IGF1R，一种cf修饰的蛋白。miR-15a-5p降低，IGF1R表达升高，激活PI3K/AKT抑制自噬，促进纤维化。本研究发现miR-15a-5p在IPF发病机制中是cf修饰的IGF1R的关键调节因子。其下调驱动PI3K/ akt介导的自噬抑制，加速纤维化。恢复miR-15a-5p或靶向IGF1R/PI3K/AKT信号通路可能为IPF提供新的治疗途径。

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引用次数: 0

Serum lncRNAs NEAT1, PVT1 and H19 as novel biomarkers for sarcopenia diagnosis and treatment response 血清lncrna NEAT1、PVT1和H19作为肌少症诊断和治疗反应的新生物标志物

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-06-23 DOI: 10.1016/j.ncrna.2025.06.003

Paula Aparicio , Tresa López-Royo , David Navarrete-Villanueva , Alba María Gómez Cabello , Marcela González-Gross , Ignacio Ara , Germán Vicente-Rodríguez , Rosario Osta , Raquel Manzano

Sarcopenia, the loss of muscle mass and function generally associated to age, leads to increased dependence and mortality in older adults. Despite its clinical significance, unclear molecular mechanisms hinder the development of universal diagnostic and therapeutic monitoring methods. Recent research suggests long non-coding RNAs (lncRNAs) as potential biomarkers for muscle damage and sarcopenia. This study investigates the role of six specific lncRNAs as biomarkers for diagnosing and monitoring sarcopenia following physical training. For this purpose, an initial cohort of participants was divided into two experiments: Trial 1, a cross-sectional study comprising 54 sarcopenic patients and 29 robust controls, both including men and women; Trial 2, a non-randomized controlled trial, where the same sarcopenic patients from Trial 1 were divided in two groups: a Control Group (CG, n = 15); and a Trained Group (TG, n = 22). RNA was extracted from serum samples for all the participants, and the expression of 6 lncRNA (PVT1, HOTAIR, MALAT1, NEAT1, GAS5, H19), selected from the literature, was quantified by RT-PCR and compared between the different groups. Statistical evaluation uncovered four lncRNAs with significantly distinct expression in Trial 1: PVT1 (LOG2FC = 1.194), GAS5 (LOG2FC = 0.8224), NEAT1 (LOG2FC = 1.497) and H19 (LOG2FC = −0.9958) and three lncRNA significantly different between TG and CG in Trial 2 (PVT1 (LOG2FC = −1.796), MALAT1 (LOG2FC = 2.834) and H19 (LOG2FC = 1.355). Among them, NEAT 1 stands aout as promissing diagnostic marker ans PVT1 and H19 may serve as both diagnosis and treatment monitoring, altough further validation in larger cohorts is needed to confirm these results.

骨骼肌减少症，肌肉质量和功能的丧失，通常与年龄有关，导致老年人对药物的依赖性和死亡率增加。尽管具有临床意义，但不清楚的分子机制阻碍了通用诊断和治疗监测方法的发展。最近的研究表明，长链非编码rna （lncRNAs）是肌肉损伤和肌肉减少症的潜在生物标志物。本研究探讨了六种特异性lncrna作为诊断和监测运动后肌肉减少症的生物标志物的作用。为此，最初的参与者队列被分为两个实验：试验1是一项横断面研究，包括54名肌肉减少症患者和29名健全对照，包括男性和女性；试验2是一项非随机对照试验，试验1中相同的肌肉减少症患者被分为两组：对照组（CG, n = 15）；训练组（TG, n = 22）。从所有参与者的血清样本中提取RNA，并从文献中选择6种lncRNA （PVT1、HOTAIR、MALAT1、NEAT1、GAS5、H19）进行RT-PCR定量表达，并在不同组间进行比较。统计分析发现，试验1中有4个lncRNA表达差异显著：PVT1 （LOG2FC = 1.194）、GAS5 （LOG2FC = 0.8224）、NEAT1 （LOG2FC = 1.497）和H19 (LOG2FC = - 0.9958)；试验2中有3个lncRNA在TG和CG中表达差异显著(PVT1 （LOG2FC = - 1.796）、MALAT1 （LOG2FC = 2.834）和H19 （LOG2FC = 1.355）。其中，NEAT 1被认为是有希望的诊断标志物，PVT1和H19可能同时用作诊断和治疗监测，尽管这些结果需要在更大的队列中进一步验证。

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引用次数: 0

Exosome-derived hsa_circ_0007132 promotes lenvatinib resistance by inhibiting the ubiquitin-mediated degradation of NONO 外泌体衍生的hsa_circ_0007132通过抑制泛素介导的NONO降解来促进lenvatinib耐药性

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-05-15 DOI: 10.1016/j.ncrna.2025.05.007

Mingbo Cao , Yuxuan Li , Xiaorui Su , Yongchang Tang , Feng Yuan , Yupeng Ren , Meihai Deng , Zhicheng Yao

Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor, with its incidence showing a troubling upward trend over the past decade. Lenvatinib is one of the first-line medications for treating advanced HCC, however, the development of resistance significantly undermines its potential to improve patient prognosis. In recent years, exosomal circRNAs have been implicated in the resistance mechanisms of various cancers, yet their role in mediating lenvatinib resistance (LR) remains largely unexplored. In this study, we identified hsa_circ_0007132, which is upregulated in the serum exosomes of HCC patients exhibiting progressive disease (PD) following lenvatinib treatment. Subsequently, we employed LR cell lines to conduct both in vitro and in vivo experiments, which provided compelling evidence that hsa_circ_0007132 significantly promotes LR in HCC. Mechanistically, hsa_circ_0007132 interacts with the NONO protein, impairing its ubiquitination and leading to increased stability and upregulation of NONO expression, thereby enhancing NONO-mediated nuclear export of ZEB1 mRNA and elevating ZEB1 protein expression, which ultimately contributes to LR. In summary, our findings unveil a critical mechanism through which HCC mediates tumor progression and LR via exosomal hsa_circ_0007132, while also emphasizing that targeting NONO may represent a promising therapeutic strategy to overcome LR.

肝细胞癌（HCC）是一种高度异质性的实体肿瘤，其发病率在过去十年中呈现出令人不安的上升趋势。Lenvatinib是治疗晚期HCC的一线药物之一，然而耐药的发展显著削弱了其改善患者预后的潜力。近年来，外泌体环状rna与各种癌症的耐药机制有关，但它们在介导lenvatinib耐药（LR）中的作用仍未被广泛探索。在这项研究中，我们发现hsa_circ_0007132在lenvatinib治疗后出现进展性疾病（PD）的HCC患者的血清外泌体中表达上调。随后，我们利用LR细胞系进行了体外和体内实验，提供了令人信服的证据，证明hsa_circ_0007132在HCC中显著促进LR。从机制上讲，hsa_circ_0007132与NONO蛋白相互作用，损害其泛素化，导致NONO表达的稳定性增强和上调，从而增强NONO介导的ZEB1 mRNA的核输出，提高ZEB1蛋白的表达，最终导致LR。总之，我们的研究结果揭示了HCC通过外泌体hsa_circ_0007132介导肿瘤进展和LR的关键机制，同时也强调靶向NONO可能是克服LR的一种有希望的治疗策略。

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引用次数: 0

NSUN2-mediated m5C hypermethylation of hsa_circ_0004516 promotes breast cancer brain metastasis by activating AKT signaling nsun2介导的m5C高甲基化hsa_circ_0004516通过激活AKT信号通路促进乳腺癌脑转移

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-08-29 DOI: 10.1016/j.ncrna.2025.08.009

Min Li , Jiawei Li , Hongbo Wen , Jun Li , Song Wang , Jianran Guo , Dongyan Zhang , Anqi Zhang , Chuanyou Cui , Rong Fu , Meng An , Wei Zhang , Bo Fu

Breast cancer brain metastasis (BCBM) remains fatal with elusive mechanisms. Here, we unveil the first circRNA m5C methylation landscape in BCBM through MeRIP-seq (methylated RNA immunoprecipitation next-generation sequencing) identifying 7465 BCBM-specific m5C peaks versus 5929 in primary breast cancer (BC). A total of 48 hypermethylated and 128 hypomethylated m5C sites in BCBM (231-BR) were identified compared to BC. Bioinformatics enrichment analysis revealed hypermethylated circRNAs enriched in ERBB/VEGF signaling pathways. Among 8 validated differentially methylated circRNAs, hsa_circ_0004516 was consistently upregulated in BCBM tissues/cells and exhibited NSUN2-dependent m5C modification. Mechanistically, NSUN2-mediated m5C methylation enhanced hsa_circ_0004516 stability, evidenced by significantly shortened half-life upon NSUN2 depletion. Crucially, catalytic mutant NSUN2 (C271A/C321A) abolished this effect. Functional assays demonstrated that hsa_circ_0004516 knockdown in 231-BR cells suppressed proliferation, migration, and invasion by reducing p-AKT (Ser473) levels. The AKT activator SC79 reversed these phenotypic impairments, definitively linking hsa_circ_0004516-driven metastasis to AKT signaling activation. Our study establishes the NSUN2-m5C-hsa_circ_0004516-AKT axis as a novel therapeutic target and biomarker for BCBM.

乳腺癌脑转移（BCBM）仍然是致命的，其机制尚不清楚。在这里，我们通过MeRIP-seq（甲基化RNA免疫沉淀下一代测序）揭示了BCBM中第一个circRNA m5C甲基化图谱，鉴定了原发性乳腺癌（BC）中7465个BCBM特异性m5C峰和5929个m5C峰。与BC相比，BCBM中共有48个高甲基化位点和128个低甲基化位点（231-BR）。生物信息学富集分析显示，高甲基化的环状rna富集于ERBB/VEGF信号通路中。在8个验证的差异甲基化circrna中，hsa_circ_0004516在BCBM组织/细胞中持续上调，并表现出nsun2依赖性m5C修饰。在机制上，NSUN2介导的m5C甲基化增强了hsa_circ_0004516的稳定性，在NSUN2耗尽后，半衰期显著缩短。关键是，催化突变体NSUN2 （C271A/C321A）消除了这种效应。功能分析表明，231-BR细胞中hsa_circ_0004516敲低通过降低p-AKT （Ser473）水平抑制增殖、迁移和侵袭。AKT激活剂SC79逆转了这些表型损伤，明确地将hsa_circ_0004516驱动的转移与AKT信号激活联系起来。我们的研究确定了NSUN2-m5C-hsa_circ_0004516-AKT轴是BCBM的一个新的治疗靶点和生物标志物。

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引用次数: 0

LncPTEN1, a long non-coding RNA generated from PTEN, suppresses lung cancer metastasis through the regulation of EMT progress LncPTEN1是由PTEN产生的长链非编码RNA，通过调控EMT进程抑制肺癌转移

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-05-24 DOI: 10.1016/j.ncrna.2025.05.011

Zichu Shen , Ailin Zhong , Chun Zhang , Xiaowei Tang , Xuyang Zhao , Zhiyuan Hou , Hui Liang , Yuxin Yin

Lung cancer is among the most frequently observed and lethal malignancies globally, and metastasis represents a critical determinant of patient outcomes. PTEN, a well-established tumor suppressor, has emerged as an important regulator in lung cancer progression. However, the molecular mechanism of PTEN gene suppressing lung cancer metastasis lacks deeper exploration. In this research, we identify and characterize LncPTEN1, a novel long non-coding RNA generated from PTEN gene. We show that YTHDC1 promotes the alternative splicing of LncPTEN1, resulting in significantly elevated LncPTEN1 expression in normal lung cells. Clinical analyses across multiple patient cohorts demonstrate that low LncPTEN1 expression strongly correlates with poor patient survival and increased metastasis, indicating its potential as a prognostic biomarker. Mechanistically, LncPTEN1 facilitates the interaction between Trim16 and Vimentin, promoting the ubiquitination and proteasomal degradation of Vimentin, thereby suppressing EMT-driven metastasis. The collective evidence from our investigation demonstrates that LncPTEN1 represents a novel tumor-suppressive lncRNA which inhibits lung cancer metastasis through promoting the degradation of Vimentin and inhibiting the EMT progress.

肺癌是全球最常见和最致命的恶性肿瘤之一，转移是患者预后的关键决定因素。PTEN是一种公认的肿瘤抑制因子，已成为肺癌进展的重要调节因子。然而，PTEN基因抑制肺癌转移的分子机制缺乏更深入的探索。在本研究中，我们鉴定并鉴定了一种由PTEN基因产生的新型长链非编码RNA LncPTEN1。我们发现YTHDC1促进LncPTEN1的选择性剪接，导致LncPTEN1在正常肺细胞中的表达显著升高。多个患者队列的临床分析表明，LncPTEN1低表达与患者生存差和转移增加密切相关，表明其作为预后生物标志物的潜力。机制上，LncPTEN1促进Trim16与Vimentin的相互作用，促进Vimentin的泛素化和蛋白酶体降解，从而抑制emt驱动的转移。我们的研究表明，LncPTEN1是一种新型的肿瘤抑制lncRNA，通过促进Vimentin的降解和抑制EMT的进展来抑制肺癌转移。

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引用次数: 0

Alternative transcription increases isoform complexity in Long Non-Coding RNAs and alters their functions in cancer 选择性转录增加了长链非编码rna的异构体复杂性，并改变了它们在癌症中的功能

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-05-03 DOI: 10.1016/j.ncrna.2025.04.008

Max Bone , Gareth J. Inman

Transcriptional start and end variance, a less-explored aspect of lncRNA biology, is a critical determinant of isoform diversity in human RNA. While alternative splicing (AS) has been extensively studied as a mechanism of isoform generation, differences in transcriptional start and termination site usage—whether from distinct promoters or varying initiation events at the same core promoter—contribute more to isoform diversity than alternative splicing. In the context of long non-coding RNAs (lncRNAs), even subtle alterations to transcriptional start and end sites can induce significant changes in the structural and functional capacities of individual lncRNA isoforms.

This review highlights the underappreciated realm of transcriptional start and end variance in lncRNAs, exploring its pivotal role in shaping the diversity of lncRNA transcripts. In cancer, where lncRNAs are increasingly recognised as key players in tumorigenesis, understanding the ramifications of transcriptional start and end variance is crucial. With single nucleotide alterations capable of influencing the folding energy, shape, stability, and function of a lncRNA molecules, significant changes to transcriptional regulation may lead to aberrant isoforms with implications for cancer initiation, progression, and potentially, its treatment.

As lncRNAs emerge as therapeutic targets, particularly with the advancement of antisense oligonucleotide (ASO) technologies, it becomes crucial to understand the regulatory landscape of transcriptional variation among lncRNA isoforms, to ensure selective targeting of oncogenic transcripts while sparing those with normal physiological functions. By highlighting the significance of transcriptional start and end site variation as major contributors to lncRNA diversity, the potential exploitation for precision therapeutic interventions in the field of non-coding RNA cancer research can be expanded.

转录起始和结束变异是lncRNA生物学中较少探索的一个方面，是人类RNA同工异构体多样性的关键决定因素。虽然选择性剪接（AS）作为异构体产生的一种机制已经被广泛研究，但转录起始位点和终止位点的使用差异——无论是来自不同的启动子还是来自同一核心启动子的不同起始事件——比选择性剪接更能促进异构体多样性。在长链非编码rna （lncRNA）的背景下，即使转录起始位点和结束位点的细微改变也会导致单个lncRNA亚型的结构和功能能力发生重大变化。这篇综述强调了lncRNA转录起始和结束变异的未被充分认识的领域，探讨了其在塑造lncRNA转录物多样性中的关键作用。在癌症中，lncrna越来越被认为是肿瘤发生的关键角色，理解转录起始和结束变异的后果至关重要。由于单核苷酸的改变能够影响lncRNA分子的折叠能量、形状、稳定性和功能，转录调控的重大变化可能导致异常异构体，从而影响癌症的发生、进展，并可能影响其治疗。随着lncRNA成为治疗靶点，特别是随着反义寡核苷酸（ASO）技术的进步，了解lncRNA亚型之间转录变异的调控格局变得至关重要，以确保选择性靶向致癌转录物，同时保留那些具有正常生理功能的转录物。通过强调转录起始位点和结束位点变异作为lncRNA多样性的主要贡献者的重要性，可以扩大对非编码RNA癌症研究领域精确治疗干预的潜在开发。

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引用次数: 0

MiR-92a-1-5p contributes to cellular proliferation and survival in chronic myeloid leukemia and its inhibition enhances imatinib efficacy MiR-92a-1-5p参与慢性髓性白血病细胞增殖和存活，抑制MiR-92a-1-5p可增强伊马替尼的疗效

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-05-21 DOI: 10.1016/j.ncrna.2025.05.008

Joanne Peters , Emeline Bollaert , Anne-Sophie Cloos , Melissa Claus , Ahmed Essaghir , Sandrine Lenglez , Pascale Saussoy , Guillaume Dachy , Pierre Autin , Jean-Baptiste Demoulin , Violaine Havelange

Tyrosine kinase inhibitors (TKI), such as imatinib, have revolutionized chronic myeloid leukemia (CML) treatment. Despite this success, TKI intolerance and resistance remain significant clinical challenges. A promising therapeutic approach is to simultaneously target the BCR::ABL1 oncogene and other oncogenic drivers. The polycistronic miR-17-92 cluster is known to contribute to CML development and progression, but the specific roles of miR-92a-1-5p within this cluster remain unclear. In this study, we assess the roles of this microRNA and evaluate the therapeutic potential of combining microRNA inhibition with imatinib to improve treatment outcome. Our results show that miR-92a-1-5p is downregulated by imatinib in myeloid cell lines harboring BCR::ABL1 and in CML patient samples. Inhibition of miR-92a-1-5p reduces proliferation and enhances imatinib-induced cell death, while its overexpression increases proliferation and counteracts the effects of imatinib on cell death. This decrease in proliferation caused by miR-92a-1-5p inhibition is rescued after simultaneous inhibition of two newly identified target genes: BNIP3L (NIX) and TP53INP1. We confirm that miR-92a-1-5p regulates proliferation and cell cycle by targeting TP53INP1 and decreases autophagy by targeting BNIP3L. Our data suggest that miR-92a-1-5p plays a role in CML progression, and its inhibition enhances imatinib anti-leukemic efficacy, making it a potential therapeutic target.

酪氨酸激酶抑制剂（TKI），如伊马替尼，已经彻底改变了慢性髓性白血病（CML）的治疗。尽管取得了这一成功，TKI不耐受和耐药仍然是重大的临床挑战。一种有希望的治疗方法是同时靶向BCR::ABL1癌基因和其他致癌驱动因子。已知多顺反性miR-17-92簇有助于CML的发生和进展，但miR-92a-1-5p在该簇中的具体作用尚不清楚。在本研究中，我们评估了这种microRNA的作用，并评估了将microRNA抑制与伊马替尼联合使用以改善治疗结果的治疗潜力。我们的研究结果表明，在BCR::ABL1的髓系和CML患者样本中，miR-92a-1-5p被伊马替尼下调。抑制miR-92a-1-5p可减少增殖并增强伊马替尼诱导的细胞死亡，而其过表达可增加增殖并抵消伊马替尼对细胞死亡的影响。抑制miR-92a-1-5p导致的增殖减少在同时抑制两个新发现的靶基因：BNIP3L （NIX）和TP53INP1后得到挽救。我们证实miR-92a-1-5p通过靶向TP53INP1调节增殖和细胞周期，并通过靶向BNIP3L减少自噬。我们的数据表明，miR-92a-1-5p在CML进展中发挥作用，其抑制作用增强了伊马替尼抗白血病的疗效，使其成为潜在的治疗靶点。

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引用次数: 0

Dual role of lncRNA OTUD6B-AS1 in immune evasion and ferroptosis resistance: A prognostic and therapeutic biomarker in breast cancer lncRNA OTUD6B-AS1在免疫逃避和铁垂症抵抗中的双重作用：乳腺癌的预后和治疗生物标志物

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-10-01 Epub Date: 2025-06-17 DOI: 10.1016/j.ncrna.2025.06.002

Jia-Ning Zhang , Zi-Lu Yi , Xi-Rui Zhou , Sha-sha Liu , Hong Liu

Background

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators in tumorigenesis and therapeutic resistance. This study investigates the prognostic significance and dual biological functions of lncRNA OTUD6B-AS1 in breast cancer (BC), focusing on its roles in immune evasion and ferroptosis resistance.

Methods

Multi-omics data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and lncRNA databases (AnnoLnc2, LncACTdb 3.0) were integrated to analyze OTUD6B-AS1 expression, clinical relevance, and molecular networks. Experimental validations included co-culture assays with CD8⁺ T cells, drug sensitivity tests, and ferroptosis marker analysis.

Results

OTUD6B-AS1 exhibited significant overexpression across multiple cancers, particularly in breast cancer (BC), where elevated levels strongly correlated with poor prognosis. Its expression was closely associated with key clinical indicators (T/N/M stage, ER/PR/HER2 status), prompting the development of a nomogram prognostic model with high clinical applicability. Genomic analysis revealed frequent amplification of OTUD6B-AS1 and co-occurrence of PIK3CA mutations. Co-expression and ceRNA networks highlighted its interaction with RNA degradation pathways. Notably, OTUD6B-AS1 was associated with immune evasion by regulating PD-L1 and CD8⁺ T cell activity. Concurrently, high OTUD6B-AS1 expression conferred ferroptosis resistance via GPX4/SLC7A11 modulation.

Conclusion

In conclusion, OTUD6B-AS1 serves as a biomarker in BC, driving immune evasion and ferroptosis resistance. Targeting OTUD6B-AS1 may enhance immunotherapy efficacy and overcome chemoresistance, offering novel therapeutic avenues.

长链非编码rna （lncRNAs）已成为肿瘤发生和治疗耐药的关键调控因子。本研究探讨lncRNA OTUD6B-AS1在乳腺癌（BC）中的预后意义和双重生物学功能，重点研究其在免疫逃避和铁垂症抵抗中的作用。方法整合来自Cancer Genome Atlas （TCGA）、Gene Expression Omnibus （GEO）和lncRNA数据库（AnnoLnc2、LncACTdb 3.0）的多组学数据，分析OTUD6B-AS1的表达、临床相关性和分子网络。实验验证包括与CD8+ T细胞共培养试验、药物敏感性试验和铁下垂标志物分析。结果sotud6b - as1在多种癌症中表现出显著的过表达，特别是在乳腺癌（BC）中，其水平升高与预后不良密切相关。它的表达与关键临床指标（T/N/M分期、ER/PR/HER2状态）密切相关，促进了一种具有较高临床适用性的nomogram预后模型的发展。基因组分析显示OTUD6B-AS1频繁扩增和PIK3CA突变共现。共表达和ceRNA网络强调了其与RNA降解途径的相互作用。值得注意的是，OTUD6B-AS1通过调节PD-L1和CD8+ T细胞活性与免疫逃避相关。同时，高OTUD6B-AS1表达通过GPX4/SLC7A11调节，赋予铁下垂抗性。结论OTUD6B-AS1在BC中发挥生物标志物作用，促进免疫逃避和铁下沉抵抗。靶向OTUD6B-AS1可能提高免疫治疗效果，克服化疗耐药，为治疗提供新的途径。

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引用次数: 0