Fibroblast growth factor 15 (FGF15), FGF19 in humans, is a gut-derived hormone and a key regulator of bile acids and carbohydratemetabolism. FGF15 also participates in liver regeneration after partial hepatectomy inducing hepatocellular proliferation.FGF19 is overexpressed in a significant proportion of human hepatocellular carcinomas (HCC), and activation of its receptorFGFR4 promotes HCC cell growth. Here we addressed for the first time the role of endogenous Fgf15 in hepatocarcinogenesis.Fgf151/1 and Fgf152/2 mice were subjected to a clinically relevant model of liver inflammation and fibrosis-associated carcinogenesis.Fgf152/2 mice showed less and smaller tumors, and histological neoplastic lesions were also smaller than inFgf151/1 animals. Importantly, ileal Fgf15 mRNA expression was enhanced in mice undergoing carcinogenesis, but at variancewith human HCC it was not detected in liver or HCC tissues, while circulating FGF15 protein was clearly upregulated. Hepatocellularproliferation was also reduced in Fgf152/2 mice, which also expressed lower levels of the HCC marker alphafetoprotein(AFP). Interestingly, lack of FGF15 resulted in attenuated fibrogenesis. However, in vitro experiments showed thatliver fibrogenic stellate cells were not direct targets for FGF15/FGF19. Conversely we demonstrate that FGF15/FGF19 inducesthe expression of the pro-fibrogenic and pro-tumorigenic connective tissue growth factor (CTGF) in hepatocytes. These findingssuggest the existence of an FGF15-triggered CTGF-mediated paracrine action on stellate cells, and an amplification mechanismfor the hepatocarcinogenic effects of FGF15 via CTGF production. In summary, our observations indicate that ileal FGF15 maycontribute to HCC development in a context of chronic liver injury and fibrosis.

Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development

Carotti S;Vespasiani Gentilucci U;Morini S;
2015-01-01

Abstract

Fibroblast growth factor 15 (FGF15), FGF19 in humans, is a gut-derived hormone and a key regulator of bile acids and carbohydratemetabolism. FGF15 also participates in liver regeneration after partial hepatectomy inducing hepatocellular proliferation.FGF19 is overexpressed in a significant proportion of human hepatocellular carcinomas (HCC), and activation of its receptorFGFR4 promotes HCC cell growth. Here we addressed for the first time the role of endogenous Fgf15 in hepatocarcinogenesis.Fgf151/1 and Fgf152/2 mice were subjected to a clinically relevant model of liver inflammation and fibrosis-associated carcinogenesis.Fgf152/2 mice showed less and smaller tumors, and histological neoplastic lesions were also smaller than inFgf151/1 animals. Importantly, ileal Fgf15 mRNA expression was enhanced in mice undergoing carcinogenesis, but at variancewith human HCC it was not detected in liver or HCC tissues, while circulating FGF15 protein was clearly upregulated. Hepatocellularproliferation was also reduced in Fgf152/2 mice, which also expressed lower levels of the HCC marker alphafetoprotein(AFP). Interestingly, lack of FGF15 resulted in attenuated fibrogenesis. However, in vitro experiments showed thatliver fibrogenic stellate cells were not direct targets for FGF15/FGF19. Conversely we demonstrate that FGF15/FGF19 inducesthe expression of the pro-fibrogenic and pro-tumorigenic connective tissue growth factor (CTGF) in hepatocytes. These findingssuggest the existence of an FGF15-triggered CTGF-mediated paracrine action on stellate cells, and an amplification mechanismfor the hepatocarcinogenic effects of FGF15 via CTGF production. In summary, our observations indicate that ileal FGF15 maycontribute to HCC development in a context of chronic liver injury and fibrosis.
2015
fibrosis; fibroblast growth factor 15/19; connective tissue growth factor
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12610/8210
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