EP1077 - ECE_2070 - Novel insights on the role of putative neuronostatin receptor GPR107 in liver pathophysiology

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Abstract Our understanding of the somatostatin (SST) endocrine system, which is a well-established source of biomarkers and therapeutic targets in neuroendocrine and pituitary tumours, has been lately expanded through the discovery of neuronostatin (NST), a SST-alternative peptide; the identification of its putative receptor, GPR107; and the extensive research on their role in metabolic regulation and prostate and breast cancer. Liver cancer, particularly hepatocellular carcinoma (HCC), is increasingly associated to underlying metabolic disorders, namely metabolic dysfunction-associated steatotic liver disease (MASLD), which challenge current tumour management strategies. In this study, we investigated the NST-GPR107 system in the MASLD-HCC progression to characterise its potential contribution and exploitability in these diseases. GPR107 expression was evaluated in 2 internal chronic liver disease (CLD)-HCC retrospective cohorts (R1 [n = 93], R2 [n = 102]), 7 MASLD in silico cohorts (n = [45-109]/cohort), 6 HCC in silico cohorts (n = [65-369]/cohorts) and 4 human liver cell lines (THLE-2, HepG2, Hep3B, SNU-387). NST expression was assayed using ELISA in an additional internal MASLD-CLD-HCC plasma cohort (n = 88). In a subset of R1 (n = 25), immunohistochemistry (IHC) for GPR107 was performed. Gene set enrichment analysis (GSEA) were employed to link GPR107 expression with hallmark gene sets, metabolic pathways (KEGG, Reactome) and biological processes (GO). In cell lines, the impact of NST application and GPR107 silencing and overexpression was assessed through functional assays (proliferation, wound healing, colony and hepatosphere formation). The expression of NST and GPR107 was progressively increased in the MASLD-HCC progression, wherein GPR107 was associated with key HCC aggressiveness features (lower portal hypertension and survival, higher microvascular invasion, recurrence and expression of proliferative biomarkers). IHC demonstrated GPR107 cytosolic and membranous presence in HCC cells, where the proliferative tumour borders showed the highest staining. GSEA directly linked GPR107 expression with global expression of cell cycle genes in HCC samples. Accordingly, GPR107 overexpression enhanced, while GPR107 silencing blunted, cancer traits, such as cell proliferation, in HCC cell lines. Moreover, NST showed antiproliferative effects on liver cancer cells, with no effect on healthy hepatocytes (THLE-2). NST addition counteracted the protumoral effects of GPR107 overexpression, whereas the combination of NST and GPR107 silencing enhanced the antitumoral effects. Altogether, these results support the direct association between GPR107 expression and HCC in a metabolic context through cell cycle modulation, which could be exploited for diagnosis, staging and potential treatment in the rapidly evolving field of liver diseases.

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