Hermán-Sánchez Natalia, Del Rio-Moreno Mercedes, Ciria Rubén, Sánchez-Frias Marina E, Fernández-Barrena Maite G, Uriarte Iker, Chicano-Galvez Eduardo, Ortea Ignacio, Peralbo-Molina Ángela, Briceño Javier, Avila Matías A, Rodríguez-Perálvarez Manuel, Luque Raúl M, López-Cánovas Juan L, Gahete Manuel D
Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, Córdoba, 14004, Spain.
Mol Cancer. 2025 Jan 14;24(1):15. doi: 10.1186/s12943-024-02206-5.
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.
肝细胞癌（HCC）的基因/转录组特征已被广泛描述。然而，其蛋白质组学特征尚不完整。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。
对肝脏样本的胞质和核部分进行非靶向定量蛋白质组学分析[HCC与非肿瘤相邻组织（NTAT），n = 42例患者]。在7个计算机模拟HCC队列中证实了变化。在沉默/过表达VARS1和/或MAGI1后，对HCC来源的细胞系评估其功能和分子影响。过表达VARS1的Hep3B细胞用于体内研究[极限稀释分析（ELDA）和原位肿瘤形成]。对过表达VARS1的HCC细胞系进行定量蛋白质组学分析。
定量蛋白质组学揭示了HCC中胞质和核蛋白质组的失调，并定义了两个蛋白质组学HCC亚组，最具侵袭性的亚组与氨酰-tRNA合成酶（ARSs）的失调有关。ARSs失调在计算机模拟HCC队列中得到证实，并与预后不良相关。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-氨酰合成酶（VARS1）是最持续过表达且与侵袭性相关的ARSs。VARS1调节（沉默/过表达）在体外和/或体内改变了肿瘤形成相关参数。对过表达VARS1的细胞进行定量蛋白质组学和挽救实验，确定HCC中的肿瘤抑制因子MAGI1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亚组。ARSs机制在侵袭性亚组中失调，具有作为预后生物标志物的潜力。VARS1通过调节MAGI1促进侵袭性，代表了HCC中一种新的可靶向弱点。
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