Endocrine Abstracts

Hormonal signalling plays a key role in the progression of metabolic (dysfunction)-associated fatty liver disease (MAFLD) to hepatocellular carcinoma (HCC). However, the role of somatostatin (SST), cortistatin (CORT), neuronostatin (NST) and ghrelin systems in MAFLD-HCC progression has not yet been elucidated. We characterized the role of SST/CORT/NST and ghrelin systems in chronic liver disease and evaluated their clinical potential. The expression of the components of the SST/CORT/NST/ghrelin systems (ligands, receptors and accessory proteins) was analysed in different mouse models of MAFLD/non-alcoholic steatohepatitis (NASH)/cirrhosis, in two retrospective human cohorts [cohort 1: HCC vs. adjacent (n=93); cohort 2: HCC vs. adjacent (n=58), cirrhosis (n=39), and healthy livers (n=5)], in different in silico MAFLD and HCC human cohorts (mRNA/protein), and in three liver-derived cell lines (HepG2, Hep3B and SNU-387). Proliferation after treatment with natural (SST/CORT/NST) and synthetic (Lanreotide, Ocreotide, Pasireotide) peptides was evaluated in cell lines and human liver primary cultures. Our results revealed that MAFLD mouse models showed a damage-dependent differential expression pattern of SST/CORT/NST components. Indeed, early MAFLD stages were characterized by a decreased expression of Cort, Sstr1, Sstr2, Sstr3 and the truncated Sstr5 md3 receptor, while there was a marked increase in the expression of Sstr3, Sstr4, Sstr5 and Sstr5 md3 in advanced stages. Some of these observations were validated in a human in silico cohort of MAFLD (i.e. SSTR5 overexpression and CORT downregulation), confirming CORT dysregulation as an early event in MAFLD. In tumoral stages, retrospective cohorts revealed a decreased expression of CORT, SSTR1, SSTR2 and ghrelin receptor and the overexpression of SSTR5 and the NST receptor (GPR107) in tumoral tissues. These alterations were validated in in silico cohorts of HCC. Besides, the decreased expression of CORT was associated with the dedifferenciation of the tissue while GPR107 overexpression was associated with key aggresiveness parameters (survival, recurrence, tumoral diameter, etc.) in the retrospective and in silico cohorts. In vitro assays revealed a decreased proliferation after treatment with SST, CORT, NST and the synthetic analogues, which was dependent on the expression of the receptors. Specifically, NST reduced proliferation of the most aggresive cell lines, Hep3B and SNU-387. Altogether, this study demonstrates an profound alteration in the expression levels of the SST/CORT/NST and ghrelin systems in human, animal, and cellular models of chronic liver disease, and suggests a potential prognostic and therapeutic role of certain components of these hormonal systems in chronic liver disease.

Fundings

ISCIII (PI20/01301), JdA (PEMP-0036-2020, BIO-0139), FSEEN and CIBERobn.