Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-01-14 DOI:10.1186/s12943-024-02206-5

Natalia Hermán-Sánchez, Mercedes del Rio-Moreno, Rubén Ciria, Marina E. Sánchez-Frias, Maite G. Fernández-Barrena, Iker Uriarte, Eduardo Chicano-Galvez, Ignacio Ortea, Ángela Peralbo-Molina, Javier Briceño, Matías A. Avila, Manuel Rodríguez-Perálvarez, Raúl M. Luque, Juan L. López-Cánovas, Manuel D. Gahete

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Abstract

Hepatocellular carcinoma (HCC) genetic/transcriptomic signatures have been widely described. However, its proteomic characterization is incomplete. We performed non-targeted quantitative proteomics of HCC samples and explored its clinical, functional, and molecular consequences. Non-targeted quantitative proteomics were performed on cytosolic and nuclear fractions of liver samples [HCC vs. non-tumour adjacent tissue (NTAT), n = 42 patients]. Changes were confirmed in 7 in silico HCC cohorts. Functional and molecular implications were evaluated on HCC-derived cell lines after silencing/overexpressing VARS1 and/or MAGI1. VARS1-overexpressing Hep3B cells were used for in vivo studies [Extreme Limiting Dilution Assay (ELDA) and orthotopic tumour formation]. Quantitative proteomics were performed on VARS1-overexpressing HCC cell lines. Quantitative proteomics revealed the dysregulation of the cytosolic and nuclear proteomes in HCC, and defined two proteomic HCC subgroups, the most aggressive associated to the dysregulation of the aminoacyl-tRNA synthetases (ARSs). ARSs dysregulation was corroborated in in silico HCC cohorts and associated to poor prognosis. Patients with ARSs upregulation had genomic/transcriptomic characteristics of the proliferative HCC. Valine tRNA-aminoacyl synthetase (VARS1) was the ARSs most consistently overexpressed and associated to aggressiveness. VARS1 modulation (silencing/overexpression) altered tumour establishment-associated parameters in vitro and/or in vivo. Quantitative proteomics on cells overexpressing VARS1 and rescue experiments identified the downregulation of MAGI1, a tumour suppressor in HCC, as a mediator of VARS1 function. Quantitative proteomics defines two prognosis-related proteomic HCC subgroups. ARSs machinery is dysregulated in the aggressive subgroup, bearing potential as prognostic biomarkers. VARS1 promotes aggressiveness through the modulation of MAGI1, representing a novel targetable vulnerability in HCC.

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定量蛋白质组学分析揭示了VARS1通过调节MAGI1表达在肝细胞癌侵袭性中的关键作用

肝细胞癌（HCC）的基因/转录组特征已被广泛描述。然而，其蛋白质组学特征还不完整。我们对 HCC 样本进行了非靶向定量蛋白质组学研究，并探讨了其临床、功能和分子后果。我们对肝脏样本（HCC 与非肿瘤邻近组织（NTAT），n = 42 例患者）的细胞膜和细胞核部分进行了非靶向定量蛋白质组学研究。在 7 个硅学 HCC 队列中证实了这些变化。在沉默/外表达 VARS1 和/或 MAGI1 后，对 HCC 衍生细胞系的功能和分子影响进行了评估。VARS1 外表达的 Hep3B 细胞被用于体内研究[极限稀释试验（ELDA）和正位肿瘤形成]。对 VARS1 基因缺失的 HCC 细胞系进行了定量蛋白质组学研究。定量蛋白质组学揭示了 HCC 细胞膜和细胞核蛋白质组的失调，并定义了两个蛋白质组学 HCC 亚群，其中最具侵袭性的亚群与氨基酰-tRNA 合成酶（ARSs）的失调有关。ARSs的失调在硅学HCC队列中得到了证实，并与不良预后有关。ARSs上调的患者具有增殖性HCC的基因组/转录组特征。缬氨酸 tRNA- 氨基酰合成酶（VARS1）是持续过表达最多的 ARSs，与侵袭性相关。VARS1的调控（沉默/高表达）改变了体外和/或体内与肿瘤形成相关的参数。对过表达 VARS1 的细胞进行定量蛋白质组学研究和拯救实验发现，MAGI1（一种 HCC 肿瘤抑制因子）的下调是 VARS1 功能的介导因素。定量蛋白质组学定义了两个与预后相关的蛋白质组学 HCC 亚群。在侵袭性亚组中，ARSs机制失调，有可能成为预后生物标志物。VARS1 通过调节 MAGI1 促进侵袭性，代表了一种新的 HCC 靶向脆弱性。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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