EP425 - ECE_2237 - Molecular and functional characterization of aminoacyl-tRNA synthetases in hepatocellular carcinoma

Le résumé fourni par la source

Abstract Introduction Nutrient availability and amino acid homeostasis are central regulators of metabolic and endocrine function in the liver. Alterations in amino acid sensing and utilization contribute to metabolic reprogramming in metabolic dysfunction–associated steatotic liver disease (MASLD), a major driver of liver-related morbidity. Increasing evidence suggests that protein synthesis and translational control link nutrient excess to cellular dysfunction. Aminoacyl-tRNA synthetases (ARSs), which connect amino acid metabolism with translation and exert additional regulatory roles, may act as key mediators of disease progression. Therefore, we aimed to characterize the expression landscape and functional relevance of ARSs during chronic liver disease progression to hepatocellular carcinoma (HCC). Materials and Methods We performed an extensive transcriptomic analysis encompassing 27 cytosolic and mitochondrial ARSs across 16 independent in silico cohorts. These datasets included a wide spectrum of chronic liver disease stages and HCC. Following the identification of the most consistently dysregulated genes, mitochondrial HARS2 and PARS2 were selected as top candidates for functional characterization due to their robust expression patterns. For functional studies, we employed CRISPR/Cas9-mediated gene editing to generate knockout (KO) models in two distinct HCC cell lines: Hep3B and SNU-387. The functional impact of these ARSs on the malignant phenotype was rigorously assessed through a battery of assays, including cell proliferation, wound-healing migration, colony formation, and tumorsphere formation to evaluate their role in HCC. Results Transcriptomic analysis revealed a widespread significant dysregulation of ARSs in HCC. Mitochondrial ARSs, specifically HARS and PARS2, emerged as the most robust biomarkers, significantly discriminating between tumor and adjacent non-tumoral tissue across multiple cohorts. In the Hep3B cell line, a HARS2-KO was successfully generated with 95% efficiency. Functional assays demonstrated that HARS2 depletion led to a significant reduction in cell proliferation, migratory capacity, colony-forming units, and tumorsphere volume, suggesting a pro-tumorigenic role in HCC. Conclusions Our findings reveal a profound dysregulation of ARSs in the progression from chronic liver disease to HCC. Specifically, mitochondrial HARS2 acts as a key driver of tumorigenicity, highlighting its potential as a novel therapeutic target and diagnostic biomarker within the metabolic-oncological axis. Funding ISCIII (PI23/00652; co-funded by the EU), MINECO (FPU20/03957), JdA (PI-0046-2024, BIO-0139), FSEEN, and CIBERobn/ehd.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.