Endocrine Abstracts

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease and is the leading cause of liver-related morbidity and mortality. MASLD is rapidly becoming a major aetiology for the development of hepatocellular carcinoma (HCC), the most common liver cancer. As the incidence of MASLD continues to rise, it is crucial to understand the molecular alterations that lead to HCC. Previous studies have revealed a significant alteration of the mechanisms controlling RNA processing and metabolism in MASLD-related HCC. However, the implication of the RNA-Exosome machinery, which is crucial for RNA processing, degradation, and quality control, is still to be fully defined. This work aims to elucidate the alteration of the RNA–Exosome components in MASLD and MASLD-related HCC, and its correlation with clinical parameters, in order to identify early biomarkers and new therapeutic opportunities. Therefore, we analyzed in silico the mRNA and/or protein expression levels of RNA-Exosome components in MASLD, MASLD-related HCC, Metabolic Dysfunction Associated Steatohepatitis (MASH), HCC and control (healthy and/or non-tumor) samples from fourteen cohorts: two retrospectives (n=94 and n=62 respectively) and twelve in silico (Zhou, GSE63067, Roessler 2, Mas, GSE135251, Wurmbach, TGCA, GSE147304, GSE167523 GSE185051, Arendt and Pinyol). Different bioinformatics approaches were performed, using software such as R, MetaboAnalyst, Gene Set Enrichment Analysis (GSEA) and Single-sample GSEA (ssGSEA). The results revealed a heterogeneous pattern of dysregulation in gene/protein expression of most of the RNA-Exosome components, with percentages of altered elements ranging from 7,7% (retrospective cohort) to 76,7% (Zhou cohort). The most consistently altered elements in MASLD cohorts were EXOSC10, ZFC3H1, PABPN1, EXOSC8, EXOSC4 and EXOSC9; standing out PABPN1, EXOSC4 and ZFC3H1, as they were also the most dysregulated genes in HCC patients. Expression of these components was associated with the enrichment in oncogenic traits (e.g., DNA repair pathway and expression of MYC targets), smggesting important clinical implications. In conclusion, analysis of gene expression dysregulation patterns in RNA-Exosome elements reveal a strong dysregulation in MASLD and MASLD-related HCC samples, which were associated with clinical parameters and with the dysregulation of oncogenic pathways.

Fundings: ISCIII (PI20/01301, PI23/00652; co-funded by the European Union), MINECO (FPU20/03957), JdA (PEMP-0036-2020, BIO-0139), FSEEN and CIBERobn/ehd.