Endocrine Abstracts

Metabolic associated fatty liver disease (MAFLD) is rapidly becoming a major aetiology for the development of hepatocellular carcinoma (HCC, the most common liver cancer) in the context of chronic liver disease. Current therapeutical options for MAFLD (dietetic/lifestyle intervention and/or pharmacological approaches) are still insufficient and the cellular and molecular mechanisms underlying this disease are yet to be fully understood. Our group previously reported that the neuronostatin (NST)/GPR107 system could be used as a potential biomarker in prostate cancer progression and aggressiveness. Therefore, we aimed to explore the role of NST and its putative receptor GPR107 in the MAFLD-HCC spectrum. For this purpose, GPR107 expression was analysed in 2 internal retrospective cohorts with chronic liver disease samples [cohort 1: HCC vs adjacent tissue (n=93)/cohort 2: HCC vs adjacent (n=58), cirrhotic (n=39) and healthy tissue (n=5)], 13 external validation cohorts (6 with HCC and 7 with MAFLD) and 3 liver cancer cell lines (HepG2, Hep3B and SNU-387). Functional assays (proliferation, wound healing, colony and hepatosphere formation) were also implemented in liver cancer cells to evaluate the impact of NST application and/or GPR107 expression modulation (overexpression/silencing). Overexpression of GPR107 in tumour samples was observed in cohort 1 and validated in 5 out of 6 external HCC cohorts. Moreover, GPR107 expression levels positively correlated with key cancer aggressiveness biomarkers (e.g. MKI67, CDK1, RB, C-MYC), and were associated with microvascular invasion. In 4 out of 7 external MAFLD cohorts, we detected a gradual increase in GPR107 expression through the MAFLD-HCC progression, suggesting a role in hepatocarcinogenesis. Regarding GPR107 expression in cell lines, it was primarily detected in Hep3B, followed by SNU-387, and was not detected in HepG2. Functional assays revealed a decrease in cell proliferation in response to NST in all studied cell lines. On the other hand, GPR107 overexpression in Hep3B and SNU-387 increased, while its silencing decreased, cell proliferation. Lastly, combined NST administration and GPR107 overexpression reduced Hep3B and SNU-387 proliferation vs GPR107 overexpression alone, whereas the combination of NST application and GPR107 silencing showed no significant difference from GPR107 silencing. Altogether, our data demonstrate that GPR107 is overexpressed in the MAFLD progression towards HCC, suggesting that the NST/GPR107 system might be a novel vulnerability in chronic liver disease, and that could be exploited as a diagnostic and prognostic biomarker and a therapeutic target in MAFLD-HCC.