细胞外囊泡来源的microrna作为慢性HCV感染患者肝纤维化的非侵入性标志物：一项初步研究

IF 5.9 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Non-coding RNA Research Pub Date : 2025-03-05 DOI:10.1016/j.ncrna.2025.03.004

Victoria Cairoli , Daniel Valle-Millares , Pablo Ryan , Lourdes Dominguez , Luz Martín-Carbonero , Ignacio De los Santos , Elena De Matteo , Beatriz Ameigeiras , Marcela De Sousa , Verónica Briz , María V. Preciado , Amanda Fernández-Rodriguez , Pamela Valva

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引用次数: 0

摘要

细胞外囊泡（EVs）是一种越来越有前途的肝脏液体活检工具。丙型肝炎病毒（HCV）感染，单独或与人类免疫缺陷病毒（HIV）感染一起显著影响类似慢性丙型肝炎（CHC）进展的microRNA (miRNA) ev含量。该研究的目的是深入研究不同肝纤维化分期的CHC患者复杂的ev - mirna谱，旨在确定能够区分显著纤维化的非侵入性标志物。50例CHC患者（HCV+和HCV+/HIV+）血浆ev - mirna分层无显著差异(F <；2)和显著（F≥2）纤维化，进行大规模测序。采用一般线性模型（GLM）根据肝纤维化分期(F≥2和F <；2).随后对以下组的失调生物学途径进行计算机分析：i)所有患者；(二)丙肝病毒+;iii) HCV+/HIV+。采用多序logistic回归分析建立评分，以识别F≥2的病例。采用ROC曲线分析评估SDE mirna和评分的诊断潜力。对于所有CHC患者，鉴定出两个SDE mirna (hsa-miR-122-5p和hsa-miR-92a-3p)，它们调节与细胞骨架组织相关的基因。在区分F≥2的诊断性能方面，两种mirna分别表现出可接受的诊断价值。然而，它们在新评分中的联合使用提高了它们的诊断性能（AUROC = 0.833）。在HCV+亚组中，识别出8种SDE mirna (hsa-miR-122-5p, hsa-miR-320c, hsa-miR-3615, hsa-miR-320a-3p, hsa-miR-374b-5p, hsa-let-7a-3p, hsa-miR-199a-5p, hsa-miR-142-5p)，它们调节巨噬细胞活性和细胞生长/死亡调节。其中，hsa-miR-3615对判别F≥2的诊断效能最高（AUROC = 0.936）。对于HCV+/HIV+， 18个SDE miRNAs （hsa-miR-4508, hsa-miR-122-5p, hsa-miR-451a, hsa-miR-1290, hsa-miR-1246, hsa-miR-107, hsa-miR-15b-5p, hsa-miR-194-5p, hsa-miR-22-5p, hsa-miR-20b-5p, hsa-miR-142-5p, hsa-miR-328-3p, hsa-miR-335-3p, hsa-miR-125a-5p, hsa-miR-423-3p, hsa- mir -7d-3p, hsa-miR-128-3p, hsa-miR-10a-5p）被确认调节RNA沉默过程。在这种情况下，hsa-miR-423-3p和hsa-miR-128-3p表现出出色的诊断性能(AUROC >；0.900)。在不同肝纤维化分期的患者中，无论是在整个CHC队列中，还是在HCV+和HCV+/HIV+亚组中，都发现了不同的ev - mirna谱。这些特定的miRNA特征将有助于阐明临床进化的潜在机制，并确定不利进展的特定生物标志物，可能用于诊断小组。此外，开发的评分证明了在CHC组中区分具有显著纤维化的个体的能力，而不管其HIV感染状态如何。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Extracellular vesicles derived microRNAs as non-invasive markers of liver fibrosis in chronically infected HCV patients: a pilot study

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Extracellular vesicles derived microRNAs as non-invasive markers of liver fibrosis in chronically infected HCV patients: a pilot study

Extracellular vesicles (EVs) are an increasingly promising tool for liquid biopsy in liver diseases. Hepatitis C Virus (HCV) infection, alone or together with Human Immunodeficiency Virus (HIV) infection significantly impacts on the microRNA (miRNA) EVs content resembling chronic hepatitis C (CHC) progression. The objective of the study was to delve into the intricate EVs-miRNA profiles in CHC patients with different liver fibrosis stages, aiming to pinpoint non-invasive markers capable of distinguishing significant fibrosis.

Plasma EV-miRNAs from 50 CHC patients (HCV+ and HCV+/HIV+) stratified in no significant (F < 2) and significant (F ≥ 2) fibrosis, were massively sequenced. General linear models (GLM) were used to identify significantly differential expressed (SDE) miRNAs according to liver fibrosis stages (F ≥ 2 and F < 2). Dysregulated biological pathways were subsequently analyzed in silico for the following groups: i) all patients; ii) HCV+; and iii) HCV+/HIV+. Multiple-ordered logistic regression analysis was performed to develop a score to identify F ≥ 2 cases. The diagnostic potential of both the SDE miRNAs and the developed score was assessed using ROC curve analysis.

With respect to all CHC patients, two SDE miRNAs (hsa-miR-122-5p and hsa-miR-92a-3p) were identified which regulate genes related to cytoskeleton organization. Regarding their diagnostic performance to discriminate F ≥ 2, both miRNAs individually demonstrated acceptable diagnostic values. However, their combined use in a new score enhanced their diagnostic performance (AUROC = 0.833).

In the HCV+ subgroup, 8 SDE miRNAs (hsa-miR-122-5p, hsa-miR-320c, hsa-miR-3615, hsa-miR-320a-3p, hsa-miR-374b-5p, hsa-let-7a-3p, hsa-miR-199a-5p, hsa-miR-142-5p), which regulate macrophage activity and cell growth/death regulation, were recognized. Among them, hsa-miR-3615 displayed the highest diagnostic performance to discriminate F ≥ 2 (AUROC = 0.936).

With respect to HCV+/HIV+, 18 SDE miRNAs (hsa-miR-4508, hsa-miR-122-5p, hsa-miR-451a, hsa-miR-1290, hsa-miR-1246, hsa-miR-107, hsa-miR-15b-5p, hsa-miR-194-5p, hsa-miR-22-5p, hsa-miR-20b-5p, hsa-miR-142-5p, hsa-miR-328-3p, hsa-miR-335-3p, hsa-miR-125a-5p, hsa-miR-423-3p, hsa-let-7d-3p, hsa-miR-128-3p, hsa-miR-10a-5p) were recognized that regulate RNA silencing processes. In this case, hsa-miR-423-3p and hsa-miR-128-3p showed outstanding diagnostic performances (AUROC > 0.900).

Distinct EVs-miRNA profiles were identified in patients with varying liver fibrosis stages, both in the overall CHC cohort and within HCV+ and HCV+/HIV+ subgroups. These specific miRNA signatures would allow the elucidation of potential mechanisms involved in clinical evolution and identification of specific biomarkers of unfavorable progression, plausible to be used in a diagnostic panel. Furthermore, the developed score demonstrates the ability to discriminate within the CHC group those individuals with significant fibrosis regardless of their HIV infection status.

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来源期刊

Non-coding RNA Research Medicine-Biochemistry (medical)

CiteScore

7.70

自引率

6.00%

发文量

审稿时长

49 days

期刊介绍： Non-coding RNA Research aims to publish high quality research and review articles on the mechanistic role of non-coding RNAs in all human diseases. This interdisciplinary journal will welcome research dealing with all aspects of non-coding RNAs-their biogenesis, regulation and role in disease progression. The focus of this journal will be to publish translational studies as well as well-designed basic studies with translational and clinical implications. The non-coding RNAs of particular interest will be microRNAs (miRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs), U-RNAs/small nuclear RNAs (snRNAs), exosomal/extracellular RNAs (exRNAs), Piwi-interacting RNAs (piRNAs) and long non-coding RNAs. Topics of interest will include, but not limited to: -Regulation of non-coding RNAs -Targets and regulatory functions of non-coding RNAs -Epigenetics and non-coding RNAs -Biological functions of non-coding RNAs -Non-coding RNAs as biomarkers -Non-coding RNA-based therapeutics -Prognostic value of non-coding RNAs -Pharmacological studies involving non-coding RNAs -Population based and epidemiological studies -Gene expression / proteomics / computational / pathway analysis-based studies on non-coding RNAs with functional validation -Novel strategies to manipulate non-coding RNAs expression and function -Clinical studies on evaluation of non-coding RNAs The journal will strive to disseminate cutting edge research, showcasing the ever-evolving importance of non-coding RNAs in modern day research and medicine.