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A Machine Learning Model Based on microRNAs for the Diagnosis of Essential Hypertension 基于microrna的原发性高血压诊断机器学习模型
Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-25 DOI: 10.3390/ncrna9060064
Amela Jusic, Inela Junuzovic, Ahmed Hujdurovic, Lu Zhang, Mélanie Vausort, Yvan Devaux
Introduction: Hypertension is a major and modifiable risk factor for cardiovascular diseases. Essential, primary, or idiopathic hypertension accounts for 90–95% of all cases. Identifying novel biomarkers specific to essential hypertension may help in understanding pathophysiological pathways and developing personalized treatments. We tested whether the integration of circulating microRNAs (miRNAs) and clinical risk factors via machine learning modeling may provide useful information and novel tools for essential hypertension diagnosis and management. Materials and methods: In total, 174 participants were enrolled in the present observational case–control study, among which, there were 89 patients with essential hypertension and 85 controls. A discovery phase was conducted using small RNA sequencing in whole blood samples obtained from age- and sex-matched hypertension patients (n = 30) and controls (n = 30). A validation phase using RT-qPCR involved the remaining 114 participants. For machine learning, 170 participants with complete data were used to generate and evaluate the classification model. Results: Small RNA sequencing identified seven miRNAs downregulated in hypertensive patients as compared with controls in the discovery group, of which six were confirmed with RT-qPCR. In the validation group, miR-210-3p/361-3p/362-5p/378a-5p/501-5p were also downregulated in hypertensive patients. A machine learning support vector machine (SVM) model including clinical risk factors (sex, BMI, alcohol use, current smoker, and hypertension family history), miR-361-3p, and miR-501-5p was able to classify hypertension patients in a test dataset with an AUC of 0.90, a balanced accuracy of 0.87, a sensitivity of 0.83, and a specificity of 0.91. While five miRNAs exhibited substantial downregulation in hypertension patients, only miR-361-3p and miR-501-5p, alongside clinical risk factors, were consistently chosen in at least eight out of ten sub-training sets within the SVM model. Conclusions: This study highlights the potential significance of miRNA-based biomarkers in deepening our understanding of hypertension’s pathophysiology and in personalizing treatment strategies. The strong performance of the SVM model highlights its potential as a valuable asset for diagnosing and managing essential hypertension. The model remains to be extensively validated in independent patient cohorts before evaluating its added value in a clinical setting.
高血压是心血管疾病的一个主要的可改变的危险因素。原发性、原发性或特发性高血压占所有病例的90-95%。识别新的特异性高血压生物标志物可能有助于理解病理生理途径和开发个性化治疗。我们通过机器学习模型测试了循环microRNAs (miRNAs)和临床危险因素的整合是否可以为原发性高血压的诊断和管理提供有用的信息和新工具。材料与方法:本观察性病例对照研究共纳入174例受试者,其中原发性高血压患者89例,对照组85例。通过对年龄和性别匹配的高血压患者(n = 30)和对照组(n = 30)的全血样本进行小RNA测序进行发现阶段。使用RT-qPCR的验证阶段涉及其余114名参与者。对于机器学习,使用170个具有完整数据的参与者来生成和评估分类模型。结果:小RNA测序发现,与对照组相比,高血压患者中有7个mirna下调,其中6个经RT-qPCR证实。在验证组中,高血压患者中miR-210-3p/361-3p/362-5p/378a-5p/501-5p也下调。包含临床危险因素(性别、BMI、饮酒、当前吸烟者和高血压家族史)、miR-361-3p和miR-501-5p的机器学习支持向量机(SVM)模型能够在测试数据集中对高血压患者进行分类,AUC为0.90,平衡精度为0.87,灵敏度为0.83,特异性为0.91。虽然有5种mirna在高血压患者中表现出显著的下调,但在SVM模型的10个子训练集中,至少有8个子训练集中一致选择了miR-361-3p和miR-501-5p以及临床危险因素。结论:本研究强调了基于mirna的生物标志物在加深我们对高血压病理生理的理解和个性化治疗策略方面的潜在意义。支持向量机模型的强大性能突出了其作为诊断和管理原发性高血压的宝贵资产的潜力。在评估其在临床环境中的附加价值之前,该模型仍需在独立患者队列中进行广泛验证。
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引用次数: 0
Crosstalk between Non-Coding RNAs and Wnt/β-Catenin Signaling in Head and Neck Cancer: Identification of Novel Biomarkers and Therapeutic Agents. 癌症头颈部非编码RNA与Wnt/β-儿茶素信号传导的串扰:新型生物标志物和治疗剂的鉴定。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-17 DOI: 10.3390/ncrna9050063
Anjana Sajeev, Bandari BharathwajChetty, Ravichandran Vishwa, Mohammed S Alqahtani, Mohamed Abbas, Gautam Sethi, Ajaikumar B Kunnumakkara

Head and neck cancers (HNC) encompass a broad spectrum of neoplastic disorders characterized by significant morbidity and mortality. While contemporary therapeutic interventions offer promise, challenges persist due to tumor recurrence and metastasis. Central to HNC pathogenesis is the aberration in numerous signaling cascades. Prominently, the Wnt signaling pathway has been critically implicated in the etiology of HNC, as supported by a plethora of research. Equally important, variations in the expression of non-coding RNAs (ncRNAs) have been identified to modulate key cancer phenotypes such as cellular proliferation, epithelial-mesenchymal transition, metastatic potential, recurrence, and treatment resistance. This review aims to provide an exhaustive insight into the multifaceted influence of ncRNAs on HNC, with specific emphasis on their interactions with the Wnt/β-catenin (WBC) signaling axis. We further delineate the effect of ncRNAs in either exacerbating or attenuating HNC progression via interference with WBC signaling. An overview of the mechanisms underlying the interplay between ncRNAs and WBC signaling is also presented. In addition, we described the potential of various ncRNAs in enhancing the efficacy of chemotherapeutic and radiotherapeutic modalities. In summary, this assessment posits the potential of ncRNAs as therapeutic agents targeting the WBC signaling pathway in HNC management.

头颈癌(HNC)包括一系列以显著发病率和死亡率为特征的肿瘤性疾病。虽然当代的治疗干预措施带来了希望,但由于肿瘤复发和转移,挑战依然存在。HNC发病机制的核心是众多信号级联的异常。值得注意的是,Wnt信号通路与HNC的病因密切相关,这得到了大量研究的支持。同样重要的是,非编码RNA(ncRNA)表达的变化已被确定为调节关键的癌症表型,如细胞增殖、上皮-间质转移、转移潜能、复发和治疗耐药性。这篇综述旨在全面了解ncRNA对HNC的多方面影响,特别强调它们与Wnt/β-连环蛋白(WBC)信号轴的相互作用。我们进一步描述了ncRNA通过干扰WBC信号传导在加重或减弱HNC进展中的作用。还概述了ncRNAs和WBC信号传导之间相互作用的机制。此外,我们还描述了各种ncRNA在增强化疗和放射治疗模式疗效方面的潜力。总之,该评估认为ncRNA在HNC管理中具有作为靶向WBC信号通路的治疗剂的潜力。
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引用次数: 0
The Potential Role of Circulating Long Miscellaneous RNAs in the Diagnosis and Prognosis of Hepatitis C Related Hepatocellular Carcinoma. 循环长杂RNA在丙型肝炎相关肝细胞癌诊断和预后中的潜在作用。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-11 DOI: 10.3390/ncrna9050062
Shimaa Abdelsattar, Sally A Fahim, Hala F M Kamel, Hiba Al-Amodi, Zeinab A Kasemy, Fatma O Khalil, Mahmoud S Abdallah, Hanan M Bedair, Abdel-Naser Abdel-Atty Gadallah, Aliaa Sabry, Mohamed A Sakr, Mahmoud Selim, Eman M Abd El Gayed

Ribonucleic acids (RNAs) are important regulators of gene expression and crucial for the progression of hepatocellular carcinoma (HCC). This study was designed to determine the diagnostic and prognostic utility of the circulating long miscellaneous RNAs; LINC01419, AK021443, and AF070632 in HCV-related HCC patients. Real-time PCR was used to measure their relative expression levels in the plasma of 194 HCV patients, 120 HCV-related HCC patients and 120 healthy controls. LINC01419 and AK021443 expression levels had significantly increasing linear trend estimates while AF070632 was dramatically downregulated in HCC compared to HCV. Interestingly, LINC01419 and AK021443 served as more significant diagnostic biomarkers for HCC than AF070632 and AFP. Multivariate analysis with cox regression revealed that the high expression of AK021443 [HR = 10.06, CI95%: 3.36-30.07], the high expression of LINC01419 [HR 4.13, CI95%: 1.32-12.86], and the low expression of AF070632 [HR = 2.70, CI95%: 1.07-6.81] were significant potential prognostic factors for HCC. Besides, the Kaplan-Meier analysis showed that HCC patients with high LIN01419 and AK021443 and low AF070632 expression levels had shorter OS. The circulating LINC01419 and AK021443 can be used as noninvasive potential biomarkers for diagnosis and prognosis of HCV-related HCC patients than AF070632 providing new targets for limiting the progression of the disease.

核糖核酸(RNA)是基因表达的重要调节因子,对肝细胞癌(HCC)的进展至关重要。本研究旨在确定循环长杂RNA的诊断和预后效用;LINC01419、AK021443和AF070632在HCV相关HCC患者中的应用。采用实时聚合酶链式反应测定194名HCV患者、120名HCV相关HCC患者和120名健康对照者血浆中它们的相对表达水平。LINC01419和AK021443的表达水平具有显著增加的线性趋势估计,而与HCV相比,AF070632在HCC中显著下调。有趣的是,LINC01419和AK021443是比AF070632和AFP更重要的HCC诊断生物标志物。采用cox回归的多因素分析显示,AK021443的高表达[HR=10.06,CI95%:3.36-30.07]、LINC01419的高表达[HR4.13,CI95%1.32-12.86]和AF070632的低表达[HR=2.70,CI95%21.07-6.81]是HCC的重要潜在预后因素。此外,Kaplan-Meier分析显示,具有高LIN01419和AK021443以及低AF070632表达水平的HCC患者具有较短的OS。与AF070632相比,循环的LINC01419和AK021443可作为诊断和预后HCV相关HCC患者的非侵入性潜在生物标志物,为限制疾病进展提供了新的靶点。
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引用次数: 0
A Small De Novo CNV Deletion of the Paternal Copy of FOXF1, Leaving lncRNA FENDRR Intact, Provides Insight into Their Bidirectional Promoter Region. FOXF1的父系拷贝的一个小的De Novo CNV缺失,使lncRNA FENDRR保持完整,提供了对其双向启动子区域的深入了解。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-09 DOI: 10.3390/ncrna9050061
Przemyslaw Szafranski, Paweł Stankiewicz

Pathogenic single-nucleotide variants (SNVs) and copy-number variant (CNV) deletions involving the FOXF1 transcription factor gene or CNV deletions of its distant lung-specific enhancer are responsible for alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a rarely diagnosed lethal lung developmental disorder in neonates. In contrast to SNVs within FOXF1 and CNV deletions involving only the FOXF1 enhancer, larger-sized deletions involving FOXF1 and the adjacent, oppositely oriented lncRNA gene FENDRR have additionally been associated with hypoplastic left heart syndrome and single umbilical artery (SUA). Here, in an ACDMPV infant without any congenital heart defect or SUA, we identified a small 5 kb CNV deletion that removed the paternal allele of FOXF1 and its promoter, leaving FENDRR and its promoter intact. Reporter assay in the IMR-90 fetal cell line implied that the deletion may indeed not have significantly affected FENDRR expression. It also showed a polarization of the FOXF1-FENDRR inter-promoter region consisting of its ability to increase the transcription of FENDRR but not FOXF1. Interestingly, this transcription-stimulating activity was suppressed in the presence of the FOXF1 promoter. Our data shed more light on the interactions between neighboring promoters of FOXF1-FENDRR and possibly other divergently transcribed mRNA-lncRNA gene pairs.

涉及FOXF1转录因子基因的致病性单核苷酸变异株(SNV)和拷贝数变异株(CNV)缺失或其远处肺特异性增强子的CNV缺失是肺泡毛细血管发育不良伴肺静脉错位(ACDMPV)的原因,ACDMPV是一种罕见的新生儿致命性肺发育障碍。与FOXF1内的SNV和仅涉及FOXF1增强子的CNV缺失相反,涉及FOXFl和相邻的反向lncRNA基因FENDRR的较大大小的缺失还与发育不良左心综合征和单脐动脉(SUA)相关。在这里,在一个没有任何先天性心脏缺陷或SUA的ACDMPV婴儿中,我们发现了一个小的5kb CNV缺失,该缺失去除了FOXF1及其启动子的父系等位基因,使FENDRR及其启动子保持完整。IMR-90胎儿细胞系中的报告基因分析表明,缺失可能确实没有显著影响FENDRR的表达。它还显示了FOXF1-FENDRR启动子间区的极化,该极化由其增加FENDRR转录但不增加FOXF1转录的能力组成。有趣的是,这种转录刺激活性在FOXF1启动子存在的情况下被抑制。我们的数据进一步阐明了FOXF1-FENDRR的相邻启动子与可能的其他差异转录的信使核糖核酸基因对之间的相互作用。
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引用次数: 0
Altered Expression of Vitamin D Metabolism Genes and Circulating MicroRNAs in PBMCs of Patients with Type 1 Diabetes: Their Association with Vitamin D Status and Ongoing Islet Autoimmunity. 1型糖尿病患者外周血单个核细胞中维生素D代谢基因和循环微小RNA表达的改变:它们与维生素D状态和持续的胰岛自身免疫的关系。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-07 DOI: 10.3390/ncrna9050060
Hakeemah Al-Nakhle, Ihsan Mohsen, Bashir Elnaem, Abdullah Alharbi, Ibtisam Alnakhli, Shareefa Almoarfi, Jameela Fallatah

Background: The immunomodulatory role of 1,25-Dihydroxy vitamin D3 (1,25(OH)2D3) is exerted through its interaction with the vitamin D receptor (VDR) present on pancreatic and immune cells. While a deficiency in vitamin D has been linked to Type 1 Diabetes Mellitus (T1DM), the exact molecular mechanism driving this down-regulation in T1DM is yet to be fully understood. This study aimed to decipher differences in the expression of genes associated with vitamin D metabolism in T1DM patients and to ascertain if there is a correlation between serum 1,25(OH)2D3 levels and the expression of these genes. We also sought to understand the influence of specific microRNAs (miRNAs) on the expression of vitamin D metabolism genes in peripheral blood mononuclear cells (PBMCs) of T1DM patients. Furthermore, the study delved into the potential implications of altered vitamin D metabolism genes and miRNAs on autoimmune processes.

Methods: Utilizing real-time PCR, we assessed the expression profiles of genes encoding for 1-hydroxylases (CYP27B1) and 24-hydroxylases (CYP24A1), as well as related miRNAs, in PBMCs from 30 T1DM patients and 23 healthy controls. ELISA tests facilitated the measurement of 1,25(OH)2D3, GAD65, and IA-2 levels.

Results: Our findings showcased downregulated CYP27B1 mRNA levels, while CYP24A1 expression remained stable compared to healthy subjects (CYP27B1, p = 0.0005; CYP24A1, p = 0.205, respectively). In T1DM patients, the levels of has-miR-216b-5p were found to be increased, while the levels of has-miR-21-5p were decreased in comparison to the control group. Notably, no correlation was identified between the expression of CYP27B1 in T1DM patients and the levels of has-miR-216b-5p, has-miR-21-5p, and 1,25(OH)2D3. A significant negative correlation was identified between CYP27B1 mRNA levels in PBMCs of T1DM and IA2, but not with GAD65.

Conclusions: The study highlights there were reduced levels of both CYP27B1 mRNA and has-miR-21-5p, along with elevated levels of has-miR-216b-5p in the PBMCs of T1DM. However, the absence of a correlation between the expression of CYP27B1, levels of has-miR-216b-5p, and the status of 1,25(OH)2D3 suggests the possible existence of other regulatory mechanisms. Additionally, the inverse relationship between IA2 autoantibodies and CYP27B1 expression in T1DM patients indicates a potential connection between this gene and the autoimmune processes inherent in T1DM.

背景:1,25-二羟基维生素D3(1,25(OH)2D3)的免疫调节作用是通过其与胰腺和免疫细胞上的维生素D受体(VDR)的相互作用发挥的。虽然维生素D缺乏与1型糖尿病(T1DM)有关,但驱动T1DM这种下调的确切分子机制尚不完全清楚。本研究旨在解读T1DM患者维生素D代谢相关基因表达的差异,并确定血清1,25(OH)2D3水平与这些基因表达之间是否存在相关性。我们还试图了解特定微小RNA(miRNA)对T1DM患者外周血单核细胞(PBMC)中维生素D代谢基因表达的影响。此外,该研究深入探讨了维生素D代谢基因和miRNA改变对自身免疫过程的潜在影响。方法:利用实时PCR,我们评估了30名T1DM患者和23名健康对照的PBMC中编码1-羟化酶(CYP27B1)和24-羟化酶(CYP24A1)的基因以及相关miRNA的表达谱。ELISA测试促进了1,25(OH)2D3、GAD65和IA-2水平的测量。结果:与健康受试者相比,我们的研究结果显示CYP27B1 mRNA水平下调,而CYP24A1的表达保持稳定(CYP27B1,p=0.0005;CYP24A1,p=0.205)。与对照组相比,T1DM患者的has-miR-216b-5p水平升高,而has-miR21-5p水平降低。值得注意的是,在T1DM患者中CYP27B1的表达与has-miR-216b-5p、has-miR21-5p和1,25(OH)2D3的水平之间没有发现相关性。T1DM和IA2的PBMC中CYP27B1 mRNA水平之间存在显著的负相关,但与GAD65无关。结论:该研究强调,T1DM的PBMCs中CYP27B1mRNA和has-miR-21-5p水平均降低,has-miR216b-5p水平升高。然而,CYP27B1的表达、has-miR-216b-5p的水平和1,25(OH)2D3的状态之间缺乏相关性,这表明可能存在其他调节机制。此外,T1DM患者中IA2自身抗体和CYP27B1表达之间的反比关系表明该基因与T1DM固有的自身免疫过程之间存在潜在联系。
{"title":"Altered Expression of Vitamin D Metabolism Genes and Circulating MicroRNAs in PBMCs of Patients with Type 1 Diabetes: Their Association with Vitamin D Status and Ongoing Islet Autoimmunity.","authors":"Hakeemah Al-Nakhle,&nbsp;Ihsan Mohsen,&nbsp;Bashir Elnaem,&nbsp;Abdullah Alharbi,&nbsp;Ibtisam Alnakhli,&nbsp;Shareefa Almoarfi,&nbsp;Jameela Fallatah","doi":"10.3390/ncrna9050060","DOIUrl":"10.3390/ncrna9050060","url":null,"abstract":"<p><strong>Background: </strong>The immunomodulatory role of 1,25-Dihydroxy vitamin D3 (1,25(OH)2D3) is exerted through its interaction with the vitamin D receptor (VDR) present on pancreatic and immune cells. While a deficiency in vitamin D has been linked to Type 1 Diabetes Mellitus (T1DM), the exact molecular mechanism driving this down-regulation in T1DM is yet to be fully understood. This study aimed to decipher differences in the expression of genes associated with vitamin D metabolism in T1DM patients and to ascertain if there is a correlation between serum 1,25(OH)2D3 levels and the expression of these genes. We also sought to understand the influence of specific microRNAs (miRNAs) on the expression of vitamin D metabolism genes in peripheral blood mononuclear cells (PBMCs) of T1DM patients. Furthermore, the study delved into the potential implications of altered vitamin D metabolism genes and miRNAs on autoimmune processes.</p><p><strong>Methods: </strong>Utilizing real-time PCR, we assessed the expression profiles of genes encoding for 1-hydroxylases (<i>CYP27B1</i>) and 24-hydroxylases (<i>CYP24A1</i>), as well as related miRNAs, in PBMCs from 30 T1DM patients and 23 healthy controls. ELISA tests facilitated the measurement of 1,25(OH)2D3, GAD65, and IA-2 levels.</p><p><strong>Results: </strong>Our findings showcased downregulated <i>CYP27B1</i> mRNA levels, while <i>CYP24A1</i> expression remained stable compared to healthy subjects (<i>CYP27B1</i>, <i>p</i> = 0.0005; <i>CYP24A1</i>, <i>p</i> = 0.205, respectively). In T1DM patients, the levels of has-miR-216b-5p were found to be increased, while the levels of has-miR-21-5p were decreased in comparison to the control group. Notably, no correlation was identified between the expression of <i>CYP27B1</i> in T1DM patients and the levels of has-miR-216b-5p, has-miR-21-5p, and 1,25(OH)2D3. A significant negative correlation was identified between <i>CYP27B1</i> mRNA levels in PBMCs of T1DM and IA2, but not with GAD65.</p><p><strong>Conclusions: </strong>The study highlights there were reduced levels of both <i>CYP27B1</i> mRNA and has-miR-21-5p, along with elevated levels of has-miR-216b-5p in the PBMCs of T1DM. However, the absence of a correlation between the expression of <i>CYP27B1</i>, levels of has-miR-216b-5p, and the status of 1,25(OH)2D3 suggests the possible existence of other regulatory mechanisms. Additionally, the inverse relationship between IA2 autoantibodies and <i>CYP27B1</i> expression in T1DM patients indicates a potential connection between this gene and the autoimmune processes inherent in T1DM.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2023-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inverse Modulation of Aurora Kinase A and Topoisomerase IIα in Normal and Tumor Breast Cells upon Knockdown of Mitochondrial ASncmtRNA. 线粒体ASncmtRNA敲除后正常和肿瘤乳腺细胞中Aurora激酶A和拓扑异构酶IIα的反向调节。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-02 DOI: 10.3390/ncrna9050059
Maximiliano F Bendek, Christopher Fitzpatrick, Emanuel Jeldes, Anne Boland, Jean-François Deleuze, Nicole Farfán, Jaime Villegas, Gino Nardocci, Martín Montecino, Luis O Burzio, Verónica A Burzio

Breast cancer is currently the most diagnosed form of cancer and the leading cause of death by cancer among females worldwide. We described the family of long non-coding mitochondrial RNAs (ncmtRNAs), comprised of sense (SncmtRNA) and antisense (ASncmtRNA) members. Knockdown of ASncmtRNAs using antisense oligonucleotides (ASOs) induces proliferative arrest and apoptotic death of tumor cells, but not normal cells, from various tissue origins. In order to study the mechanisms underlying this selectivity, in this study we performed RNAseq in MDA-MB-231 breast cancer cells transfected with ASncmtRNA-specific ASO or control-ASO, or left untransfected. Bioinformatic analysis yielded several differentially expressed cell-cycle-related genes, from which we selected Aurora kinase A (AURKA) and topoisomerase IIα (TOP2A) for RT-qPCR and western blot validation in MDA-MB-231 and MCF7 breast cancer cells, as well as normal breast epithelial cells (HMEC). We observed no clear differences regarding mRNA levels but both proteins were downregulated in tumor cells and upregulated in normal cells. Since these proteins play a role in genomic integrity, this inverse effect of ASncmtRNA knockdown could account for tumor cell downfall whilst protecting normal cells, suggesting this approach could be used for genomic protection under cancer treatment regimens or other scenarios.

癌症是目前诊断最多的癌症,也是全球女性癌症死亡的主要原因。我们描述了长的非编码线粒体RNA(ncmtRNA)家族,由有义(SncmtRNA)和反义(ASNcmtRRNA)成员组成。使用反义寡核苷酸(ASOs)敲除ASNcmtRNA可诱导来自不同组织来源的肿瘤细胞(而非正常细胞)的增殖停滞和凋亡死亡。为了研究这种选择性的潜在机制,在本研究中,我们在用ASncmtRNA-特异性ASO或对照-ASO转染或未转染的MDA-MB-231乳腺癌症细胞中进行了RNAseq。生物信息学分析产生了几个差异表达的细胞周期相关基因,我们从中选择Aurora激酶A(AURKA)和拓扑异构酶IIα(TOP2A)用于MDA-MB-231和MCF7乳腺癌症细胞以及正常乳腺上皮细胞(HMEC)的RT-qPCR和蛋白质印迹验证。我们没有观察到mRNA水平的明显差异,但这两种蛋白质在肿瘤细胞中下调,在正常细胞中上调。由于这些蛋白质在基因组完整性中发挥作用,这种ASncmtRNA敲除的反向作用可能是肿瘤细胞下降的原因,同时保护正常细胞,这表明这种方法可用于癌症治疗方案或其他情况下的基因组保护。
{"title":"Inverse Modulation of Aurora Kinase A and Topoisomerase IIα in Normal and Tumor Breast Cells upon Knockdown of Mitochondrial ASncmtRNA.","authors":"Maximiliano F Bendek,&nbsp;Christopher Fitzpatrick,&nbsp;Emanuel Jeldes,&nbsp;Anne Boland,&nbsp;Jean-François Deleuze,&nbsp;Nicole Farfán,&nbsp;Jaime Villegas,&nbsp;Gino Nardocci,&nbsp;Martín Montecino,&nbsp;Luis O Burzio,&nbsp;Verónica A Burzio","doi":"10.3390/ncrna9050059","DOIUrl":"10.3390/ncrna9050059","url":null,"abstract":"<p><p>Breast cancer is currently the most diagnosed form of cancer and the leading cause of death by cancer among females worldwide. We described the family of long non-coding mitochondrial RNAs (ncmtRNAs), comprised of sense (SncmtRNA) and antisense (ASncmtRNA) members. Knockdown of ASncmtRNAs using antisense oligonucleotides (ASOs) induces proliferative arrest and apoptotic death of tumor cells, but not normal cells, from various tissue origins. In order to study the mechanisms underlying this selectivity, in this study we performed RNAseq in MDA-MB-231 breast cancer cells transfected with ASncmtRNA-specific ASO or control-ASO, or left untransfected. Bioinformatic analysis yielded several differentially expressed cell-cycle-related genes, from which we selected Aurora kinase A (<i>AURKA</i>) and topoisomerase IIα (<i>TOP2A</i>) for RT-qPCR and western blot validation in MDA-MB-231 and MCF7 breast cancer cells, as well as normal breast epithelial cells (HMEC). We observed no clear differences regarding mRNA levels but both proteins were downregulated in tumor cells and upregulated in normal cells. Since these proteins play a role in genomic integrity, this inverse effect of ASncmtRNA knockdown could account for tumor cell downfall whilst protecting normal cells, suggesting this approach could be used for genomic protection under cancer treatment regimens or other scenarios.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Intergenic Type LncRNA (LINC RNA) Faces in Cancer with In Silico Scope and a Directed Lens to LINC00511: A Step toward ncRNA Precision. 癌症基因间型LncRNA(LINC-RNA)的面与硅镜和LINC00511的定向透镜:迈向ncRNA精度的一步。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-25 DOI: 10.3390/ncrna9050058
Shorouk Eldash, Eman F Sanad, Dina Nada, Nadia M Hamdy

Background: Long intergenic non-coding RNA, is one type of lncRNA, exerting various cellular activities, as does ncRNA, including the regulation of gene expression and chromatin remodeling. The abnormal expression of lincRNAs can induce or suppress carcinogenesis.

Main body: LincRNAs can regulate cancer progression through different mechanisms and are considered as potential drug targets. Genetic variations such as single nucleotide polymorphisms (SNPs) in lincRNAs may affect gene expression and messenger ribonucleic acid (mRNA) stability. SNPs in lincRNAs have been found to be associated with different types of cancer, as well. Specifically, LINC00511 has been known to promote the progression of multiple malignancies such as breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, and others, making it a promising cancer prognostic molecular marker.

Conclusion: LincRNAs have been proved to be associated with different cancer types through various pathways. Herein, we performed a comprehensive literature and in silico databases search listing lncRNAs, lincRNAs including LINC00511, lncRNAs' SNPs, as well as LINC00511 SNPs in different cancer types, focusing on their role in various cancer types and mechanism(s) of action.

背景:长基因间非编码RNA是lncRNA的一种,与ncRNA一样发挥各种细胞活性,包括调节基因表达和染色质重塑。lincRNA的异常表达可以诱导或抑制致癌作用。主体:LincRNAs可以通过不同的机制调节癌症的进展,被认为是潜在的药物靶点。lincRNA中的单核苷酸多态性(SNPs)等遗传变异可能影响基因表达和信使核糖核酸(mRNA)的稳定性。lincRNA中的SNPs也被发现与不同类型的癌症有关。具体而言,已知LINC00511可促进多种恶性肿瘤的进展,如乳腺癌症、癌症、癌症、肝细胞癌等,使其成为癌症预后分子标志物。结论:LincRNAs已被证明通过多种途径与不同类型的癌症相关。在此,我们进行了全面的文献和计算机数据库搜索,列出了lncRNA、包括LINC00511在内的lincRNA、lncRNA的SNPs以及不同癌症类型中的LINC00511 SNPs,重点关注它们在各种癌症类型和作用机制中的作用。
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引用次数: 0
Discovery and Comprehensive Characterization of Novel Circular RNAs of the Apoptosis-Related BOK Gene in Human Ovarian and Prostate Cancer Cells, Using Nanopore Sequencing. 应用纳米孔测序技术发现人卵巢和前列腺癌症细胞中凋亡相关BOK基因的新环状RNA并对其进行综合表征。
IF 3.6 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-09-24 DOI: 10.3390/ncrna9050057
Christos K Kontos, Despina Hadjichambi, Maria Papatsirou, Paraskevi Karousi, Spyridon Christodoulou, Diamantis C Sideris, Andreas Scorilas

CircRNAs have become a novel scientific research hotspot, and an increasing number of studies have shed light on their involvement in malignant progression. Prompted by the apparent scientific gap in circRNAs from apoptosis-related genes, such as BOK, we focused on the identification of novel BOK circRNAs in human ovarian and prostate cancer cells. Total RNA was extracted from ovarian and prostate cancer cell lines and reversely transcribed using random hexamer primers. A series of PCR assays utilizing gene-specific divergent primers were carried out. Next, third-generation sequencing based on nanopore technology followed by extensive bioinformatics analysis led to the discovery of 23 novel circRNAs. These novel circRNAs consist of both exonic and intronic regions of the BOK gene. Interestingly, the exons that form the back-splice junction were truncated in most circRNAs, and multiple back-splice sites were found for each BOK exon. Moreover, several BOK circRNAs are predicted to sponge microRNAs with a key role in reproductive cancers, while the presence of putative open reading frames indicates their translational potential. Overall, this study suggests that distinct alternative splicing events lead to the production of novel BOK circRNAs, which could come into play in the molecular landscape and clinical investigation of ovarian and prostate cancer.

CircRNA已成为一个新的科学研究热点,越来越多的研究揭示了它们与恶性进展的关系。由于凋亡相关基因(如BOK)的circRNA存在明显的科学缺口,我们专注于在人类卵巢和前列腺癌症细胞中鉴定新的BOK circRNA。从卵巢和前列腺癌症细胞系中提取总RNA,并使用随机六聚体引物逆转录。利用基因特异性差异引物进行了一系列PCR检测。接下来,基于纳米孔技术的第三代测序,以及广泛的生物信息学分析,发现了23种新的circRNA。这些新的circRNA由BOK基因的外显子区和内含子区组成。有趣的是,在大多数circRNA中,形成背剪接连接的外显子被截短,并且每个BOK外显子都发现了多个背剪接位点。此外,一些BOK circRNA被预测为海绵状微小RNA,在生殖癌症中发挥关键作用,而假定的开放阅读框的存在表明了它们的翻译潜力。总体而言,这项研究表明,不同的选择性剪接事件导致了新的BOK circRNA的产生,这可能在卵巢和前列腺癌症的分子景观和临床研究中发挥作用。
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引用次数: 0
Long Non-Coding RNA TUG1 Gene Polymorphism and TUG1 Expression Level as Molecular Biomarkers of Systemic Lupus Erythematosus and Lupus Nephritis. 作为系统性红斑狼疮和狼疮性肾炎分子生物标志物的长非编码RNA TUG1基因多态性和TUG1表达水平。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-19 DOI: 10.3390/ncrna9050056
Gehan Abd-Elfatah Tawfeek, Heba Kasem, Eman Ali Abdallah, Mohammed Almulhim, Abdullah Almulhim, Mohammed Albarqi, Khaled Mohamed Amin Elzorkany

Long non-coding RNA (lncRNA) TUG1 acts as a proto-oncogene, allowing the proliferation of tumor cells, and it has been related to inflammation. Therefore, we aimed in this study to investigate for the first time the role of TUG1 gene polymorphism and the TUG1 level as biomarkers in systemic lupus erythematosus (SLE) and their link to lupus nephritis 145 SLE. A total of 145 healthy controls were subjected to clinical and laboratory evaluation. The disease activity was assessed by the SLE disease activity index (SLEDAI) score. SLE patients were divided into two subgroups according to the presence of lupus nephritis. The TUG1 gene polymorphisms rs5749201 and rs886471 were determined by Sanger sequencing, and TUG1 expression was assessed by qRT-PCR. There was a significant increase in the risk of SLE AA, TA, dominant genotypes, and the A allele of rs5749201 (p < 0.001) by 4.9-, 10.1-, 6.5-, and 2.5-fold in comparison to the relative control. GG and TG, dominant genotypes and the G allele of rs886471 (p < 0.01) increased the risk by 5.09-, 11.9-, 6.5-, and 2.6-fold. AA, A allele, dominant and recessive rs5749201genotypes increased the risk of lupus nephritis by 16.6-, 7.4-, 7.1-, and 12.2-fold, respectively (p < 0.05). GG, dominant and recessive genotypes, and the G allele of rs886471 increased the risk of lupus nephritis by 17.04-, 7.8-, 9.4-, and 6.08-fold, respectively (p < 0.05). Additionally, the AG haplotype increased the risk of SLE and lupus nephritis by 2.7- and 7.8-fold, respectively. The AA rs5749201 and GG rs886471 variants are significantly associated with more severe disease (p < 0.001). TUG1 expression was significantly higher in SLE than in the control and in the lupus nephritis than in non-lupus nephritis cases (p < 0.05). Interestingly, AA rs5749201 and GG rs886471 were significantly associated with higher TUG1 levels (p < 0.001). It was also found that AA rs5749201 and high SLEDAI were predictors of lupus nephritis. Overall, our findings illustrated for the first time that TUG1 gene rs5749201 and rs886471 variants were associated with increased risk of SLE, more severe disease, and lupus nephritis, and the TUG1 level could be used as a diagnostic biomarker of SLE and lupus nephritis.

长非编码RNA(lncRNA)TUG1作为原癌基因,允许肿瘤细胞增殖,它与炎症有关。因此,我们在本研究中首次探讨了TUG1基因多态性和TUG1水平作为系统性红斑狼疮(SLE)生物标志物的作用及其与狼疮性肾炎145 SLE的关系。共对145名健康对照进行了临床和实验室评估。疾病活动性通过SLE疾病活动性指数(SLEDAI)评分进行评估。根据狼疮性肾炎的存在,将SLE患者分为两个亚组。通过Sanger测序测定TUG1基因多态性rs5749201和rs886471,并通过qRT-PCR评估TUG1的表达。与相对对照相比,SLE AA、TA、显性基因型和rs5749201的a等位基因的风险显著增加了4.9-、10.1-、6.5-和2.5倍(p<0.001)。GG和TG、rs886471的显性基因型和G等位基因(p<0.01)使患狼疮性肾炎的风险增加了5.09、11.9、6.5和2.6倍。AA、A等位基因、显性和隐性rs5749201基因型使患狼疮肾炎的风险分别增加了16.6、7.4、7.1和12.2倍(p<0.05),此外,AG单倍型使SLE和狼疮性肾炎的风险分别增加2.7倍和7.8倍。AA rs5749201和GG rs886471变异体与更严重的疾病显著相关(p<0.001)。TUG1在SLE中的表达显著高于对照组,在狼疮性肾炎中的表达明显高于非狼疮性肾炎(p<0.05)。有趣的是,AA rs5749201和GG rs886471与较高的TUG1水平显著相关(p<0.001)。还发现AA rs574920 1和高SLEDAI是狼疮性肾炎的预测因素。总体而言,我们的研究结果首次表明,TUG1基因rs5749201和rs886471变异与SLE、更严重疾病和狼疮性肾炎的风险增加有关,TUG1水平可作为SLE和狼疮性肾小球肾炎的诊断生物标志物。
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引用次数: 0
Novel Insights into Circular RNAs in Metastasis in Breast Cancer: An Update. 癌症转移中环状RNA的新发现:最新进展。
IF 4.3 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-16 DOI: 10.3390/ncrna9050055
Paola Zepeda-Enríquez, Macrina B Silva-Cázares, César López-Camarillo

Circular RNAs (circRNAs) are single-stranded closed non-coding RNA molecules that are aberrantly expressed and produce tumor-specific gene signatures in human cancers. They exert biological functions by acting as transcriptional regulators, microRNA sponges, and protein scaffolds, regulating the formation of protein-RNA complexes and, ultimately, regulating gene expression. Triple-negative breast cancer (TNBC) is one of the most aggressive cancers of the mammary gland and has a poor prognosis. Studies of circRNAs in TNBC are limited but have demonstrated these molecules' pivotal roles in cell proliferation, invasion, metastasis, and resistance to chemo/radiotherapy, suggesting that they could be potential prognostic biomarkers and novel therapeutic targets. Here, we reviewed the status of actual knowledge about circRNA biogenesis and functions and summarized novel findings regarding their roles in TNBC development and progression. In addition, we discussed recent data about the importance of exosomes in the transport and export of circRNAs in TNBC. Deep knowledge of circRNA functions in metastasis and therapy responses could be an invaluable guide in the identification of novel therapeutic targets for advancing the treatment of TNBC.

环状RNA(circRNA)是单链闭合的非编码RNA分子,在人类癌症中异常表达并产生肿瘤特异性基因特征。它们通过充当转录调节因子、微小RNA海绵和蛋白质支架发挥生物功能,调节蛋白质-RNA复合物的形成,并最终调节基因表达。癌症三阴性(TNBC)是最具侵袭性的乳腺癌之一,预后不良。对circRNAs在TNBC中的研究是有限的,但已经证明了这些分子在细胞增殖、侵袭、转移和化疗/放疗耐药性中的关键作用,这表明它们可能是潜在的预后生物标志物和新的治疗靶点。在这里,我们回顾了关于circRNA生物发生和功能的实际知识现状,并总结了关于它们在TNBC发展和进展中的作用的新发现。此外,我们还讨论了外泌体在TNBC中circRNA转运和输出中的重要性的最新数据。对circRNA在转移和治疗反应中的功能的深入了解可能是确定新的治疗靶点以推进TNBC治疗的宝贵指南。
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引用次数: 0
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Non-Coding RNA
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