Abstract
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy and ranks 6th and 3rd in terms of frequency and cancer mortality, respectively. Overexpression of FGF19 is a common event in human HCC and compounds targeting FGF19 or its receptor tyrosine kinase in the liver (Fibroblast Growth Factor Receptor 4 FGFR4) are being investigated. Studies in mice have shown that long term exposure to high levels of FGF19 causes hepatic tumorigenesis. In addition, FGF19 exerts numerous metabolic effects resulting in protection against insulin resistance. Thus, FGF19 analogs are under evaluation for treatment of metabolic diseases, such as non-alcoholic steatohepatitis (NASH). The aim of our study was to further characterize the oncogenic and metabolic effects of FGF19 in an immunocompetent mouse model.Using the technique of hydrodynamic gene transfer, we obtained C57Bl6/J mice with persistent hepatic expression of FGF19, displaying supra-physiological circulating concentrations of the hormone, associated with inhibition of the bile acid synthesis pathway. We discovered that these mice display a phenotype of diabetes insipidus, characterized by polydipsia and urine dilution persisting over time. This effect resembles that already described for FGF21, a molecule belonging to the same family as FGF19. However, the effect of FGF19 is independent of FGF21 and is also present when a tumor overexpressing FGF19 is injected orthotopically.Furthermore, FGF19 expression, alone or with simultaneous invalidation of p53 by CRISPR-Cas9 technology, gives rise to well-differentiated HCC after 9-12 months. The combination of FGF19 with C-Myc overexpression, with or without the invalidation of p53, induces the development of large, moderately differentiated tumors appearing after only 2-3 weeks. Comparison with tumorigenesis triggered by C-Myc alone or by C-Myc/ CRISPR-p53, reveals oncogenic cooperation between Myc and FGF19, resulting in a very significant acceleration of oncogenesis by FGF19. Transcriptomic and histological analyses of these tumors show that FGF19 stimulates neoangiogenesis. Finally, in a NASH-inducing diet model, tumor expression of FGF19 exerts a paradoxical effect: while accelerating tumor growth, it is accompanied by histological improvement of NASH.