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• W4381125424 abstract "<h3>Introduction</h3> Hepatocellular carcinoma (HCC) is a leading cause of cancer related death worldwide, with underlying liver cirrhosis (LC) the best recognised risk factor. Fibroblast growth factor 21 (FGF21) is a key metabolic regulator through binding tyrosine kinase receptors FGFR1, 2 and 3 alongside co-receptor beta klotho (KLB), it leads to positive metabolic outcomes weight loss and improved glycaemic control. Animals lacking FGF21 develop HCC at an accelerated rate. We aim to define expression of FGFRs and KLB in human non-diseased liver (NL), LC and HCC at gene and protein level. <h3>Methods</h3> Archived frozen and paraffin-embedded human liver tissue (NL, LC, HCC) was accessed via Grampian Biorepository (ethics no TR00161/196). Gene expression was assessed by qPCR using Sybr Green assays (n=16, 8, 9) and protein by immunohistochemistry (IHC) on a newly generated liver cancer tissue microarray (n=11, 25, 33). Quantification of IHC staining was performed using QuPath-0.3.2 software to generate an intensity of staining ‘H’ score or negative vs positive. Figures were created in GraphPad Prism 8. Data is presented as mean±S.E.M. and analysed using Kruskal-Wallis or ANOVA. <h3>Results</h3> At a gene level there was no significant difference seen in receptor or KLB ΔCT values between NL, LC and HCC groups. FGFR1 had stronger intensity of staining compared to FGFR2 and 3 (% positive: 100 vs 5.9 vs 22.7). Both FGFR1 and KLB had significant reduction in protein expression in HCC (NL, LC, HCC: FGFR1: 250±10.4, 219±8.6, 186±7.3; p<0.0001 and KLB: 266+/- 8.5; 234±13.0; 203±8.8 p=0.0002). In HCC, FGFR1 showed greater nuclear location (nucleus:cytoplasm ratio 0.97±0.03, 1.11±0.05, 1.38±0.08 p<0.0001). <h3>Conclusions</h3> As seen in our cohort, the reduced expression of FGFR1 and KLB could explain that despite increased circulating FGF21 levels reported in liver disease, tissues appear to be less responsive. The discrepancy between gene and protein changes, particularly FGFR1 and KLB, suggest the presence of additional pathways such as; post-translational modifications or accelerated degradation of these proteins in HCC compared to cirrhosis and non-diseased. Internalisation of FGFR1 may contribute to reduced sensitivity to FGF21. Further work to understand the mechanisms behind the receptor expression, localisation and responsiveness to FGF21 in human hepatocyte models of HCC will assist in identifying if this may be a target of interest in the prevention and treatment of HCC." @default.
• W4381125424 created "2023-06-19" @default.
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• W4381125424 date "2023-06-01" @default.
• W4381125424 modified "2023-09-27" @default.
• W4381125424 title "O25 FGF21 sensitivity in hepatocellular carcinoma could be impaired through reduction in FGFR1 and KLB expression" @default.
• W4381125424 doi "https://doi.org/10.1136/gutjnl-2023-bsg.24" @default.
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