MiR-423-5p通过MALAT-1和线粒体相互作用在肝细胞癌中发挥代谢和生长调节作用。

IF 12.8 1区 医学 Q1 ONCOLOGY
Marco Bocchetti, Alessia Maria Cossu, Manuela Porru, Maria Grazia Ferraro, Carlo Irace, Rossella Tufano, Giovanni Vitale, Gabriella Misso, Nicola Amodio, Marianna Scrima, Ines Simeone, Michele Ceccarelli, Ugo Chianese, Lucia Altucci, Vincenzo Desiderio, Tarik Regad, Michele Caraglia, Silvia Zappavigna
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引用次数: 0

摘要

背景:MicroRNAs (miRNAs)和长链非编码rna (lncRNAs)是基因表达的关键调控因子,在癌症进展中起着至关重要的作用。最近的研究强调了miR-423-5p作为肝细胞癌(HCC)的潜在调节剂,特别是在对索拉非尼治疗有反应的患者中。已经假设了与致癌lncRNA MALAT-1的功能相互作用,这表明可能存在影响肿瘤侵袭性的调节机制。方法:为了研究这种相互作用,我们分析了硅芯片患者数据集,将miR-423-5p和MALAT-1表达与总生存期(OS)和无病生存期(DFS)联系起来。利用慢病毒转导系统,在HCC细胞系(HepG2、Hep3B和SNU387)中实现了miR-423-5p和MALAT-1的稳定过表达。进行功能测定以评估增殖、迁移、侵袭和克隆潜能。通过RNA免疫沉淀(RIP)确认miR-423-5p和MALAT-1之间的相互作用,然后使用下一代测序(NGS)进行转录组学分析。采用海马Mito应激测试评估线粒体活性,以测量氧气消耗率(OCR)和ATP产量。在原位小鼠模型中进行体内实验以评估肿瘤生长情况。结果:患者数据分析显示,miR-423-5p高表达与侵袭性较低的肿瘤表型和生存率提高相关,而MALAT-1与预后较差相关。在体外,miR-423-5p过表达降低了MALAT-1水平,并显著损害了增殖、迁移和侵袭。NGS分析确定了与肿瘤进展和代谢转变相关的转录组变化。海马Mito应激测试显示miR-423-5p过表达后细胞呼吸和ATP产生减少。在体内,与对照组相比,来自过表达mir -423-5p的细胞和ASO GapmeR下调MALAT-1的肿瘤均表现出显著的生长降低。结论:这些发现首次表明,miR-423-5p在HCC中通过下调MALAT-1作为肿瘤抑制因子影响线粒体代谢。这个调控轴代表了肝癌精准医学方法的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MiR-423-5p is a metabolic and growth tuner in hepatocellular carcinoma via MALAT-1 and mitochondrial interaction.

Background: MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are key regulators of gene expression and play a crucial role in cancer progression. Recent studies have highlighted miR-423-5p as a potential modulator in hepatocellular carcinoma (HCC), especially in patients responding to sorafenib treatment. A functional interaction with the oncogenic lncRNA MALAT-1 has been hypothesized, suggesting a regulatory mechanism that may influence tumor aggressiveness.

Methods: To investigate this interaction, we analyzed in silico patient datasets to correlate miR-423-5p and MALAT-1 expression with overall survival (OS) and disease free survival (DFS). Stable overexpression of miR-423-5p and MALAT-1 was achieved in HCC cell lines (HepG2, Hep3B, and SNU387) using a lentiviral transduction system. Functional assays were performed to assess proliferation, migration, invasion, and clonogenic potential. The interaction between miR-423-5p and MALAT-1 was confirmed by RNA immunoprecipitation (RIP), followed by transcriptomic analysis using next-generation sequencing (NGS). Mitochondrial activity was evaluated using the Seahorse Mito Stress Test to measure oxygen consumption rate (OCR) and ATP production. In vivo experiments in orthotopic mouse models were performed to assess tumor growth.

Results: Patient data analysis revealed that high miR-423-5p expression correlated with a less aggressive tumor phenotype and improved survival, while MALAT-1 was associated with poorer prognosis. In vitro, miR-423-5p overexpression reduced MALAT-1 levels and significantly impaired proliferation, migration, and invasion. NGS analysis identified transcriptomic changes linked to tumor progression and metabolic shift. The Seahorse Mito Stress Test demonstrated decreased cellular respiration and ATP production upon miR-423-5p overexpression. In vivo, both tumors derived from miR-423-5p-overexpressing cells and MALAT-1 downregulation by ASO GapmeR evidenced a significantly reduced growth compared to controls.

Conclusion: These findings suggest, for the first time, that miR-423-5p acts as a tumor suppressor affecting mitochondrial metabolism through MALAT-1 downregulation in HCC. This regulatory axis represents a potential therapeutic target for precision medicine approaches in liver cancer.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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