Fibroblast growth factor 15 (FGF15), FGF19 in humans, is a gut‐derived hormone and a key regulator of bile acids and carbohydrate metabolism. 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 receptor FGFR4 promotes HCC cell growth. Here we addressed for the first time the role of endogenous
Fgf15
in hepatocarcinogenesis.
Fgf15
+/
+
and
Fgf15
−/−
mice were subjected to a clinically relevant model of liver inflammation and fibrosis‐associated carcinogenesis.
Fgf15
−/−
mice showed less and smaller tumors, and histological neoplastic lesions were also smaller than in
Fgf15
+/
+
animals. Importantly, ileal
Fgf15
mRNA expression was enhanced in mice undergoing carcinogenesis, but at variance with human HCC it was not detected in liver or HCC tissues, while circulating FGF15 protein was clearly upregulated. Hepatocellular proliferation was also reduced in
Fgf15
−/−
mice, which also expressed lower levels of the HCC marker alpha‐fetoprotein (AFP). Interestingly, lack of FGF15 resulted in attenuated fibrogenesis. However,
in vitro
experiments showed that liver fibrogenic stellate cells were not direct targets for FGF15/FGF19. Conversely we demonstrate that FGF15/FGF19 induces the expression of the pro‐fibrogenic and pro‐tumorigenic connective tissue growth factor (CTGF) in hepatocytes. These findings suggest the existence of an FGF15‐triggered CTGF‐mediated paracrine action on stellate cells, and an amplification mechanism for the hepatocarcinogenic effects of FGF15 via CTGF production. In summary, our observations indicate that ileal FGF15 may contribute to HCC development in a context of chronic liver injury and fibrosis.
What's new?
Fibroblast growth factor‐19 (FGF19), in rodents called FGF15, is a gut‐derived hormone recently implicated as a driver gene in liver carcinogenesis. Here, the authors show that
Fgf15
−/−
mice develop less hepatocellular carcinoma and less liver fibrosis as compared to
Fgf15
+/+
littermates, underscoring the important role of the factor in liver damage and cancer development. Interestingly, Fgf15 expression is not detected in injured liver or carcinoma tissue, but is upregulated in the ileum and blood, pointing to a new gut‐liver axis involved in hepatocarcinogenesis.
Hepatocellular carcinoma (HCC) is the most prevalent liver tumor and a deadly disease with limited therapeutic options. Dysregulation of cell signaling pathways is a common denominator in ...tumorigenesis, including hepatocarcinogenesis. The epidermal growth factor receptor (EGFR) signaling system is commonly activated in HCC, and is currently being evaluated as a therapeutic target in combination therapies. We and others have identified a central role for the EGFR ligand amphiregulin (AR) in the proliferation, survival and drug resistance of HCC cells. AR expression is frequently up-regulated in HCC tissues and cells through mechanisms not completely known. Here we identify the beta-catenin signaling pathway as a novel mechanism leading to transcriptional activation of the AR gene in human HCC cells. Activation of beta-catenin signaling, or expression of the T41A beta-catenin active mutant, led to the induction of AR expression involving three specific beta-catenin-Tcf responsive elements in its proximal promoter. We demonstrate that HCC cells expressing the T41A beta-catenin active mutant show enhanced proliferation that is dependent in part on AR expression and EGFR signaling. We also demonstrate here a novel cross-talk of the EGFR system with fibroblast growth factor 19 (FGF19). FGF19 is a recently identified driver gene in hepatocarcinogenesis and an activator of beta-catenin signaling in HCC and colon cancer cells. We show that FGF19 induced AR gene expression through the beta-catenin pathway in human HCC cells. Importantly, AR up-regulation and EGFR signaling participated in the induction of cyclin D1 and cell proliferation elicited by FGF19. Finally, we demonstrate a positive correlation between FGF19 and AR expression in human HCC tissues, therefore supporting in clinical samples our experimental observations. These findings identify the AR/EGFR system as a key mediator of FGF19 responses in HCC cells involving beta-catenin signaling, and suggest that combined targeting of FGF19 and AR/EGFR may enhance therapeutic efficacy.
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