Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression
Abstract Background 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....
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2025-01-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02206-5 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Natalia Hermán-Sánchez |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| format | Article |
| id | doaj-art-f421fa066d8c4ee9ab975008888e31e2 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj-art-f421fa066d8c4ee9ab975008888e31e22025-01-19T12:12:32ZengBMCMolecular Cancer1476-45982025-01-0124111610.1186/s12943-024-02206-5Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expressionNatalia Hermán-Sánchez0Mercedes del Rio-Moreno1Rubén Ciria2Marina E. Sánchez-Frias3Maite G. Fernández-Barrena4Iker Uriarte5Eduardo Chicano-Galvez6Ignacio Ortea7Ángela Peralbo-Molina8Javier Briceño9Matías A. Avila10Manuel Rodríguez-Perálvarez11Raúl M. Luque12Juan L. López-Cánovas13Manuel D. Gahete14Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University HospitalMaimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University HospitalHepatology Laboratory, Solid Tumors Program, CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), CIMA, University of Navarra, Instituto de Salud Carlos IIIHepatology Laboratory, Solid Tumors Program, CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), CIMA, University of Navarra, Instituto de Salud Carlos IIIIMIBIC Mass Spectrometry and Molecular Imaging Unit (IMSMI), Reina Sofía University Hospital, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba (UCO)Centro de Investigación en Nanomateriales y Nanotecnología (CINN-CSIC), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)IMIBIC Mass Spectrometry and Molecular Imaging Unit (IMSMI), Reina Sofía University Hospital, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba (UCO)Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University HospitalHepatology Laboratory, Solid Tumors Program, CIBEREHD (Center for Biomedical Network Research in Liver and Digestive Diseases), CIMA, University of Navarra, Instituto de Salud Carlos IIIMaimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University HospitalDepartment of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)Department of Cell Biology, Physiology, and Immunology, University of Córdoba, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn)Abstract Background 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12943-024-02206-5Quantitative proteomicsHepatocellular carcinomaAminoacyl-tRNA synthetasesVARS1MAGI1 |
| spellingShingle | 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 Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression Molecular Cancer Quantitative proteomics Hepatocellular carcinoma Aminoacyl-tRNA synthetases VARS1 MAGI1 |
| title | Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression |
| title_full | Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression |
| title_fullStr | Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression |
| title_full_unstemmed | Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression |
| title_short | Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression |
| title_sort | quantitative proteomic analysis unveils a critical role of vars1 in hepatocellular carcinoma aggressiveness through the modulation of magi1 expression |
| topic | Quantitative proteomics Hepatocellular carcinoma Aminoacyl-tRNA synthetases VARS1 MAGI1 |
| url | https://doi.org/10.1186/s12943-024-02206-5 |
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