Somatostatin and ghrelin systems characterization and therapeutic potential in liver diseases

N. Herman-Sánchez*^a (Ms), A. García-Estrada^a (Mr), JL. López-Cánovas^a (Dr), P. Sáez-Martínez^a (Mr), J. Córdoba-Chacón^b (Dr), A. Sarmento-Cabral^a (Dr), M. Rodríguez-Perálvarez^a (Dr), RM. Luque^a (Prof), MD. Gahete^a (Dr)

^a Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, SPAIN ; ^b Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Illinois, UNITED STATES

* nataliahermansan@gmail.com

The components of the somatostatin (SST), cortistatin (CORT), neuronostatin (NST) and ghrelin systems are useful biomarkers in different endocrine and neuroendocrine cancers and their synthetic analogues are valuable tools for their clinical management. However, the role of SST, CORT, NST and ghrelin signalling in liver diseases is poorly known. For that reason, we characterised the presence of the components of the SST/CORT/NST and ghrelin systems and evaluated their clinical potential in metabolic dysfunction-associated fatty liver disease (MAFLD) and hepatocellular carcinoma (HCC). The expression of these components (ligands and receptors) was analysed 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 three liver-derived cell lines (HepG2, Hep3B, SNU-387), in mouse models of MAFLD, and on in silico MAFLD and HCC cohorts. Cell proliferation in response to natural (SST/CORT/NST) and synthetic (Lanreotide, Ocreotide, Pasireotide, BIM-23926) peptides was evaluated in human liver cells (cell lines and primary cultures).

In mouse models, early MAFLD stages were characterised by a decreased expression of Cort, Sstr1, Sstr2 and Sstr3 receptors and the truncated Sstr5md3 receptor, while in advanced stages there was a marked increase in the expression of Sstr3, Sstr4, Sstr5 and Sstr5md3. SSTR5 overexpression and CORT downregulation were validated in a human in silico cohort of MAFLD, suggesting that CORT dysregulation could be an early event in MAFLD. In tumour human tissues, decreased expression of CORT, SSTR2 and ghrelin receptor and overexpression of SSTR5 and GPR107 (the NST receptor) were observed. Interestingly, GPR107 overexpression was associated with tumour aggressiveness (survival, recurrence, tumour diameter, etc.) in different human cohorts. In vitro assays revealed a decreased proliferation after treatment with SST, CORT, NST and the synthetic analogues, which was strongly dependent on the expression of the receptors.

This study demonstrates an ample alteration of SST/CORT/NST and ghrelin systems in liver pathologies, and suggests the prognostic and therapeutic potential of certain components of these hormonal systems (i.e. GPR107) and of SST-analogues for their clinical management.

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

The author has declared no conflict of interest.