Non-coding RNA Research最新文献_第4页

LncRNA-EME1 enhances BRCA1 recruitment and alters repair of DNA damage in cervical cancer radioresistance LncRNA-EME1增强BRCA1募集并改变宫颈癌放射抵抗中DNA损伤的修复

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-09-19 DOI: 10.1016/j.ncrna.2025.09.006

Qing Li, Zhenyu Zhou, Xiaoying Li, Qiongyu Lan

Background

Cervical cancer is a significant cause of mortality in women globally, and radioresistance limits the effectiveness of standard radiotherapy treatment. Exploring the molecular mechanisms that contribute to radioresistance is vital for improving therapies. This study focuses on the role of lncRNA in influencing the radioresistance of cervical cancer.

Methods

We identified lncRNA-EME1 as a candidate regulator of cervical cancer radioresistance through transcriptomic sequencing and RT-qPCR. Its function was explored by silencing or overexpressing lncRNA-EME1, followed by proliferation (MTT), clonogenic survival, apoptosis, and ROS assays. Effects on BRCA1 expression and DNA damage response were examined by WB, γ-H2AX focus analysis, and the I-SceI-mediated homologous recombination assay. Mechanistic insights were obtained using RNA pull-down and RIP assays. Finally, a xenograft model with subsequent TUNEL and immunohistochemical analyses was used to validate the role of lncRNA-EME1 in regulating BRCA1 and mediating radioresistance in vivo.

Results

Our findings indicate that lncRNA-EME1 is overexpressed in radioresistant cervical cancer cells. Silencing lncRNA-EME1 enhances radiosensitivity in HeLa-IR and SiHa-IR cells, suppresses malignant phenotypes, and increases apoptosis and ROS levels. This effects corresponds with reduced BRCA1 expression and alterations in DNA damage repair markers, highlighting its role in the radiation response. The positive association between lncRNA-EME1 and BRCA1 further supports its involvement in DNA damage repair, thereby regulating cervical cancer cells' sensitivity to radiation therapy. In vivo xenograft experiments further confirmed that lncRNA-EME1 promotes BRCA1 expression and contributes to cervical cancer radioresistance.

Conclusion

This study sheds light on the role of lncRNA-EME1 in regulating BRCA1 activity and contributing to cervical cancer radioresistance. Our data reveals that decreasing lncRNA-EME1 expression could potentially boost radiosensitivity in cervical cancer cells.

宫颈癌是全球妇女死亡的重要原因之一，放射耐药限制了标准放射治疗的有效性。探索导致放射耐药的分子机制对改善治疗至关重要。本研究的重点是lncRNA在影响宫颈癌放射耐药中的作用。方法通过转录组测序和RT-qPCR鉴定lncRNA-EME1是宫颈癌放射耐药的候选调控因子。通过沉默或过表达lncRNA-EME1，随后进行增殖（MTT）、克隆存活、细胞凋亡和ROS检测来探索其功能。通过WB、γ-H2AX聚焦分析和i - scei介导的同源重组实验检测BRCA1表达和DNA损伤反应的影响。通过RNA下拉和RIP测定获得机制见解。最后，采用异种移植物模型进行TUNEL和免疫组织化学分析，验证lncRNA-EME1在体内调节BRCA1和介导放射耐药中的作用。结果lncRNA-EME1在宫颈癌放射耐药细胞中过表达。沉默lncRNA-EME1可增强HeLa-IR和SiHa-IR细胞的放射敏感性，抑制恶性表型，增加细胞凋亡和ROS水平。这种影响与BRCA1表达减少和DNA损伤修复标记的改变相对应，突出了其在辐射反应中的作用。lncRNA-EME1与BRCA1之间的正相关进一步支持其参与DNA损伤修复，从而调节宫颈癌细胞对放射治疗的敏感性。体内异种移植实验进一步证实，lncRNA-EME1促进BRCA1表达，参与宫颈癌放射耐药。结论本研究揭示了lncRNA-EME1在调控BRCA1活性和促进宫颈癌放射耐药中的作用。我们的数据显示，lncRNA-EME1表达的降低可能会潜在地提高宫颈癌细胞的放射敏感性。

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引用次数: 0

Long non-coding RNAs in B-cell acute lymphoblastic leukemia: Disease implication, challenges and therapeutic opportunities b细胞急性淋巴细胞白血病中的长链非编码rna：疾病含义、挑战和治疗机会

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-09-16 DOI: 10.1016/j.ncrna.2025.09.005

Devesh Srivastava, Ashish Misra

B-cell acute lymphoblastic leukemia (B-ALL) manifests as an abnormal proliferation of neoplastic B-cell lymphocytes, adversely affecting both children and adults. Despite the advancements in cancer research, B-ALL cure remains challenging due to the complexity of the disease and immense subtype heterogeneity. Better understanding of the molecular mechanisms driving B-ALL pathogenesis is imperative to identify the novel therapeutic markers that can impede disease progression. Genomic and transcriptomic studies involving patient samples have underscored the emerging role of long non-coding RNAs (lncRNAs) in the diverse B-ALL landscape. Their dysregulation has been linked to malignant proliferation, metastasis, and varying patient survival outcomes. Gaining detailed mechanistic insights into the role of lncRNAs in B-ALL pathophysiology is pivotal for understanding their contributions to disease progression and developing new therapeutics. Herein, we have comprehensively discussed B-ALL and its diverse subtypes, focusing on the pivotal role played by various lncRNAs in fine-tuning signaling pathways, disease heterogeneity and progression. We have also explored recent advances in our understanding of the diverse classes of lncRNA inhibitors, evaluating their potential as B-ALL therapeutics and challenges associated with their development.

b细胞急性淋巴细胞白血病（B-ALL）表现为肿瘤b细胞淋巴细胞的异常增殖，对儿童和成人都有不良影响。尽管癌症研究取得了进步，但由于疾病的复杂性和巨大的亚型异质性，B-ALL的治愈仍然具有挑战性。更好地了解驱动B-ALL发病机制的分子机制对于确定能够阻止疾病进展的新型治疗标记物至关重要。涉及患者样本的基因组和转录组学研究强调了长链非编码rna （lncrna）在不同B-ALL环境中的新兴作用。它们的失调与恶性增殖、转移和不同的患者生存结果有关。深入了解lncrna在B-ALL病理生理中的作用机制，对于理解它们对疾病进展的贡献和开发新的治疗方法至关重要。在此，我们全面讨论了B-ALL及其不同亚型，重点讨论了各种lncrna在微调信号通路、疾病异质性和进展中发挥的关键作用。我们还探索了我们对不同种类lncRNA抑制剂的理解的最新进展，评估了它们作为B-ALL治疗药物的潜力以及与它们的发展相关的挑战。

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引用次数: 0

AQUARIUM_HB: a bioinformatics pipeline for human blood circular RNA analysis AQUARIUM_HB：用于人血液环状RNA分析的生物信息学管道

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-09-15 DOI: 10.1016/j.ncrna.2025.09.004

Shaoxun Yuan , Xue Bai , Linwei Li , Wanjun Gu

Accurately identifying and quantifying human blood circular RNAs (circRNAs) from RNA-seq data is a critical bioinformatics challenge in biomarker discovery for human diseases. In this study, we present AQUARIUM-HB, a comprehensive bioinformatics pipeline for identifying, quantifying, annotating, and analyzing circRNAs from human blood transcriptomes. AQUARIUM-HB includes three functional modules. First, it identifies and annotates circRNAs from rRNA-depleted RNA-seq datasets of human blood samples. Second, it performs an in-depth expression analysis of blood circRNAs. Third, it constructs a reference set of full-length blood circRNAs. We demonstrate the application of AQUARIUM-HB using a human blood RNA-seq dataset from COVID-19 patients, showcasing its potential for improving the accuracy and depth of circRNA biomarker discovery.

从RNA-seq数据中准确鉴定和定量人类血液环状rna （circRNAs）是发现人类疾病生物标志物的关键生物信息学挑战。在这项研究中，我们提出了水族馆- hb，一个全面的生物信息学管道，用于鉴定、定量、注释和分析来自人类血液转录组的环状rna。水族馆hb包括三个功能模块。首先，它从人类血液样本的rrna耗尽的RNA-seq数据集中识别和注释环状rna。其次，对血液环状rna进行深入的表达分析。第三，构建全长血环rna参考集。我们使用来自COVID-19患者的人类血液RNA-seq数据集展示了AQUARIUM-HB的应用，展示了其在提高circRNA生物标志物发现的准确性和深度方面的潜力。

引用次数: 0

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 : 2025-09-13 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

Circadian rhythm-related miR-6883-5p suppresses enzalutamide-resistant prostate cancer 与昼夜节律相关的miR-6883-5p抑制恩杂鲁胺耐药前列腺癌

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-09-12 DOI: 10.1016/j.ncrna.2025.09.002

Wenchang Yue , Chao Li , Tao Wang , Jiawei You , Jiale Sun , Jiapeng Liu , Ashutosh K. Tewari , Kyprianou Natasha , Mariana G. Figueiro , Jianquan Hou , Babu J. Padanilam

The increasing incidence of prostate cancer (PCa), particularly the emergence of treatment-resistant castration-resistant prostate cancer (CRPC), has intensified research efforts to address this lethal disease. Circadian rhythm gene alterations have been identified as critical factors influencing PCa progression and treatment resistance, warranting further investigation into their roles in PCa biology.

In this study, we identified a significant downregulation of PER1 and its associated miRNA, miR-6883-5p, in PCa cells and clinical samples, suggesting their potential clinical relevance. Functional analyses demonstrated that miR-6883-5p suppresses the proliferation of enzalutamide-resistant PCa cells both in vitro and in vivo by directly targeting AR-V7. Furthermore, we delineated the regulatory functions of the transcription factors BMAL1 and CLOCK in promoting the expression of PER1 and miR-6883-5p, while miR-6883-5p negatively regulates CLOCK expression, thereby impacting the transcription-translation feedback loop (TTFL) of circadian genes.

Collectively, these findings uncover a regulatory axis involving circadian rhythm components, miR-6883-5p, AR-V7, and PCa progression, providing new mechanistic insights into treatment resistance in CRPC and highlighting the circadian clock as a potential therapeutic target.

前列腺癌（PCa）发病率的增加，特别是治疗抵抗性去势抵抗性前列腺癌（CRPC）的出现，加强了对这一致命疾病的研究努力。昼夜节律基因改变已被确定为影响前列腺癌进展和治疗耐药性的关键因素，需要进一步研究其在前列腺癌生物学中的作用。在这项研究中，我们在PCa细胞和临床样本中发现了PER1及其相关miRNA miR-6883-5p的显著下调，这表明它们可能具有临床相关性。功能分析表明，miR-6883-5p通过直接靶向AR-V7，在体外和体内抑制enzalutamide耐药PCa细胞的增殖。此外，我们描述了转录因子BMAL1和CLOCK在促进PER1和miR-6883-5p表达方面的调节功能，而miR-6883-5p负调控CLOCK表达，从而影响昼夜节律基因的转录-翻译反馈回路（TTFL）。总的来说，这些发现揭示了一个涉及昼夜节律成分、miR-6883-5p、AR-V7和PCa进展的调控轴，为CRPC治疗耐药提供了新的机制见解，并突出了生物钟作为潜在的治疗靶点。

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引用次数: 0

Non-coding RNAs in congenital heart disease and placental development: Bridging molecular mechanisms to clinical biomarkers and therapies 先天性心脏病和胎盘发育中的非编码rna：连接临床生物标志物和治疗的分子机制

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-09-01 DOI: 10.1016/j.ncrna.2025.08.006

Haoxuan Wang , Xinzhe Chen , Yinghui Li , Shudan Xiao , Tianqi Teng , Sumin Yang , Kun Wang , Meihua Zhang

Non-coding RNAs (ncRNAs) have emerged as pivotal regulators of gene expression, orchestrating embryonic development and disease pathogenesis. This review synthesizes current knowledge on the origin, biogenesis, and functional diversity of ncRNAs, with a focus on their regulatory crosstalk in congenital heart disease (CHD) and placental development. The fetal heart-placenta axis, a bidirectional signaling network essential for cardiogenesis and placental morphogenesis, is spatiotemporally modulated by ncRNAs through epigenetic and post-transcriptional mechanisms. Through precise regulation of cardiac cell differentiation, angiogenesis, and trophoblast invasion, ncRNAs maintain developmental homeostasis, whereas their dysregulation disrupts these processes, contributing to CHD pathogenesis and positioning them as promising biomarkers. Collectively, this review establishes ncRNAs as molecular bridges between the fetal heart-placenta axis and clinical translation, underscoring their dual utility as diagnostic biomarkers for CHD and modifiable targets to correct placental maldevelopment, thereby advancing precision therapies for congenital disorders.

非编码rna （ncRNAs）已成为基因表达的关键调控因子，协调胚胎发育和疾病发病机制。本文综述了目前关于ncrna的起源、生物发生和功能多样性的知识，重点介绍了它们在先天性心脏病（CHD）和胎盘发育中的调控串扰。胎儿心脏-胎盘轴是一个对心脏发生和胎盘形态发生至关重要的双向信号网络，ncrna通过表观遗传和转录后机制对其进行时空调节。通过对心脏细胞分化、血管生成和滋养细胞侵袭的精确调控，ncrna维持了发育稳态，而它们的失调破坏了这些过程，促进了冠心病的发病机制，并将它们定位为有前途的生物标志物。总的来说，本综述确立了ncrna作为胎儿心脏-胎盘轴和临床翻译之间的分子桥梁，强调了它们作为冠心病诊断生物标志物和纠正胎盘发育不良的可修饰靶点的双重用途，从而推进先天性疾病的精确治疗。

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引用次数: 0

Exosome-like nanovesicles from Dunaliella salina efficient sequential Co-delivery of anti-PDL1 and miR-375 for enhancing gene/immune therapy 来自盐杜氏藻的外泌体样纳米囊泡有效地先后递送抗pdl1和miR-375以增强基因/免疫治疗

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-09-01 DOI: 10.1016/j.ncrna.2025.08.007

Zhaoyi Wei , Mengxi Zhu , Shan Li , Junling An , Yiwen Liu , Shuying Feng , Tingting Yang , Shegan Gao , Gaofeng Liang

Background

Esophageal cancer is one of the common malignant tumors of digestive system. Despite many advances in the treatment of esophageal cancer, many challenges remain. As an endogenous extracellular vesicle, exosomes are increasingly presenting their immense potential in drug delivery. However, it remains a bottleneck to obtain a large quantity of uniform, stable, and multi-component controllable exosomes with low cost and time.

Methods

A novel targeted drug delivery system based on exosome-like nanovesicles has been developed using the natural Marine single-celled salt Dunaliella salina (DENV) to conjugate c (RGDyK) peptide on its surface to achieve targeted drug delivery to esophageal cancer cells. In addition, miR-375 was loaded into cRGD-DENV by electroporation and aPD-L1 was coupled to its surface by matrix metalloproteinase-2 (MMP-2). Characterizations were performed to confirm the successful preparation of engineered exosomes. The effects of engineered exosomes on tumor cell viability, migration, invasion and apoptosis were examined in vitro and the effects of engineered exosomes on esophageal cancer cells were further verified in vivo.

Results

The engineered DENV delivery system was prepared and characterized. It exhibited a uniform particle diameter (approximately 150 nm) with in vitro sustained release features in the presence of MMP-2/9. Importantly, the cRGD-DENV was effective, promoted selective delivery of cargoes to the tumor site, and reduced nonspecific uptake of the DENV cargoes, significantly inhibiting tumor growth in vitro. In vivo results showed that cRGD-DENV-aPDL1/miR375 significantly inhibited tumor growth and affected the proliferation, migration and invasion of esophageal cancer cells by regulating YWHAZ.

Conclusions

The potential of Dunaliella salina exosome-like nanovesicle carrier delivery system in cancer therapy and can provide a very promising platform for the rapid and large-scale generation of functionalized exosome-like nanovesicles.

食管癌是消化系统常见的恶性肿瘤之一。尽管食管癌的治疗取得了许多进展，但仍存在许多挑战。外泌体作为一种内源性细胞外囊泡，在药物传递方面越来越显示出巨大的潜力。然而，如何以较低的成本和时间获得大量均匀、稳定、多组分可控的外泌体仍然是一个瓶颈。方法利用天然海洋单细胞盐Dunaliella salina （DENV）在其表面偶联c （RGDyK）肽，构建一种基于外泌体样纳米囊泡的靶向给药系统，实现对食管癌细胞的靶向给药。此外，通过电穿孔将miR-375加载到cRGD-DENV中，并通过基质金属蛋白酶-2 （MMP-2）将aPD-L1偶联到其表面。进行表征以确认工程外泌体的成功制备。在体外研究了工程外泌体对肿瘤细胞活力、迁移、侵袭和凋亡的影响，并在体内进一步验证了工程外泌体对食管癌细胞的作用。结果制备了工程化的DENV输送系统，并对其进行了表征。其颗粒直径均匀（约150 nm），在MMP-2/9存在下具有体外缓释特性。重要的是，cRGD-DENV是有效的，促进了肿瘤部位的选择性递送，减少了DENV货物的非特异性摄取，在体外显著抑制肿瘤生长。体内实验结果显示，cRGD-DENV-aPDL1/miR375通过调控YWHAZ显著抑制肿瘤生长，影响食管癌细胞的增殖、迁移和侵袭。结论盐杜氏藻外泌体样纳米囊泡载体系统在肿瘤治疗中的应用潜力巨大，为快速、大规模制备功能化外泌体样纳米囊泡提供了良好的平台。

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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 : 2025-08-29 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

Aerobic exercise alleviates allergic airway inflammation by suppressing circMETTL9-mediated formation of macrophage extracellular traps 有氧运动通过抑制circmetl9介导的巨噬细胞胞外陷阱的形成来减轻过敏性气道炎症

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-08-29 DOI: 10.1016/j.ncrna.2025.08.008

Haixia Wang , Ting Gao , Bin Ma , Yuanmin Jia , Hui Wei , Danyang Li , Junlian Gu , Ou Chen , Shouwei Yue

Emerging evidence suggests that aerobic exercise exerts beneficial effects on asthma. Previous studies have demonstrated that cell communication can drive the formation of macrophage extracellular traps (METs). However, the potential of aerobic exercise to mediate communication between airway epithelial cells and macrophages, thereby influencing MET formation, remains unexplored. Our data reveal that the upregulation of circular RNA METTL9 (circMETTL9), derived from methyltransferase-like protein 9 (METTL9) in airway epithelial cells, promotes the formation of METs. Notably, aerobic exercise was found to downregulate the expression of circMETTL9, thereby facilitating communication between airway epithelial cells and macrophages and inhibiting METs formation. Mechanistically, circMETTL9 and insulin-like growth factor binding protein 3 (IGFBP3) compete for binding to the DEXDc domain of eukaryotic translation initiation factor 4A3 (EIF4A3), which regulates METs via the C-X-C motif chemokine ligand 12(CXCL12) -C-X-C chemokine receptor type 4(CXCR4) signaling axis. This study provides robust molecular evidence supporting aerobic exercise as a foundational pulmonary rehabilitation strategy for lung protection in asthma. Targeting circMETTL9, mimicking this exercise-mediated pathway, represents a promising therapeutic approach. These insights offer a direct mechanistic rationale for refining exercise-based rehabilitation protocols and developing novel targeted therapies.

越来越多的证据表明，有氧运动对哮喘有有益的作用。先前的研究表明，细胞通讯可以驱动巨噬细胞胞外陷阱（METs）的形成。然而，有氧运动介导气道上皮细胞和巨噬细胞之间的通讯从而影响MET形成的潜力仍未被探索。我们的数据显示，在气道上皮细胞中，甲基转移酶样蛋白9 （METTL9）衍生的环状RNA METTL9 （circMETTL9）的上调促进了METs的形成。值得注意的是，有氧运动被发现下调circMETTL9的表达，从而促进气道上皮细胞和巨噬细胞之间的交流，抑制METs的形成。在机制上，circMETTL9和胰岛素样生长因子结合蛋白3 （IGFBP3）竞争结合真核翻译起始因子4A3 （EIF4A3）的DEXDc结构域，EIF4A3通过C-X-C基序趋化因子配体12(CXCL12) -C-X-C趋化因子受体4型（CXCR4）信号轴调控METs。本研究提供了强有力的分子证据，支持有氧运动作为哮喘患者肺保护的基础肺康复策略。靶向circMETTL9，模拟这种运动介导的途径，代表了一种有希望的治疗方法。这些见解为完善基于运动的康复方案和开发新的靶向治疗提供了直接的机制基础。

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引用次数: 0

miR-129-1-3p down-regulation promotes BAG cochaperone 3 (BAG3)-driven pro-fibrotic processes in primary fibroblasts from patients with recessive dystrophic epidermolysis bullosa miR-129-1-3p下调可促进隐性营养不良大疱性表皮松解症患者的原代成纤维细胞中BAG cochaperone 3 （BAG3）驱动的促纤维化过程

IF 4.7 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research

Pub Date : 2025-08-22 DOI: 10.1016/j.ncrna.2025.08.005

Rebecca Nobili , Cristina Barbagallo , Marco Ragusa , Jasmine Genovese , Valentina D'Agostino , Andrea Diociaiuti , Daniele Castiglia , Teresa Odorisio , Giovanna Zambruno , May El Hachem , Angelo Giuseppe Condorelli

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and severe skin fragility disease due to loss-of-function mutations in the COL7A1 gene. RDEB patients suffer from relentless mucocutaneous blisters that evolve into chronic wounds with inflammation and progressive fibrosis, which heavily impacts the disease course. RDEB-associated fibrosis is the result of a complex dialogue among different cell types, signalling pathways and epigenetic players that are still poorly characterized. The expression levels of over 750 mature microRNAs were investigated in primary fibroblasts from patients with RDEB (RDEB-FBs) and healthy donors using TaqMan Low-Density Arrays. Among deregulated molecules, only the miR-129-1-3p was down-regulated in RDEB-FBs. Therefore, the role of miR-129-1-3p in regulating the fibrotic features of RDEB-FBs was explored by biochemical and functional assays in cells transfected with a miR-129-1-3p mimic or a small interfering RNA specific for BAG3 (BAG cochaperone 3), a newly identified miR-129-1-3p target. BAG3 expression levels were significantly increased in RDEB-FBs grown under basal conditions and reduced in response to their transfection with a miR-129-1-3p mimic. In RDEB-FBs, the over-expression of miR-129-1-3p or BAG3 silencing markedly impaired cell contractility, a typical feature of activated/pro-fibrotic fibroblasts, decreased phospho-AKT (Ser473) levels, and reduced the ability to synthetize and deposit collagen in the extracellular matrix. Treatment of patients' fibroblasts with the AKT inhibitor perifosine (KRX-0401) recapitulated the effects observed with the mimic molecule of miR-129-1-3p and BAG3 silencing. Our results highlight the role of the miR-129-1-3p/BAG3/AKT axis in RDEB pathogenesis, complementing and expanding the knowledge on non-coding RNAs involved in fibrosis-related processes. Taken together, these findings may contribute to enlarge the toolkit of molecules and pathways that can be exploited as therapeutic targets in skin fibrosis.

隐性营养不良大疱性表皮松解症（RDEB）是一种罕见且严重的皮肤脆弱性疾病，由COL7A1基因的功能缺失突变引起。RDEB患者患有持续的粘膜皮肤水泡，并演变为慢性伤口，伴有炎症和进行性纤维化，严重影响病程。rdeb相关纤维化是不同细胞类型、信号通路和表观遗传参与者之间复杂对话的结果，而这些对话的特征仍然很差。使用TaqMan低密度阵列研究了来自RDEB患者（RDEB- fbs）和健康供者的原代成纤维细胞中750多种成熟microrna的表达水平。在脱调控分子中，只有miR-129-1-3p在rdeb - fb中下调。因此，通过在转染了miR-129-1-3p模拟物或BAG3特异性小干扰RNA (BAG cochaperone 3)（新发现的miR-129-1-3p靶点）的细胞中进行生化和功能检测，探索miR-129-1-3p在调节RDEB-FBs纤维化特征中的作用。在基础条件下生长的RDEB-FBs中，BAG3表达水平显著升高，转染miR-129-1-3p模拟物后，BAG3表达水平降低。在RDEB-FBs中，miR-129-1-3p或BAG3沉默的过表达显著损害了细胞收缩性，这是活化/促纤维化成纤维细胞的典型特征，降低了磷酸化akt （Ser473）水平，降低了合成和沉积细胞外基质胶原的能力。AKT抑制剂perifosine （KRX-0401）治疗患者成纤维细胞的效果与miR-129-1-3p和BAG3沉默的模拟分子相似。我们的研究结果强调了miR-129-1-3p/BAG3/AKT轴在RDEB发病机制中的作用，补充和扩展了参与纤维化相关过程的非编码rna的知识。综上所述，这些发现可能有助于扩大可作为皮肤纤维化治疗靶点的分子和途径的工具包。

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