Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

Abstract

Mice with hepatocyte-specific deletion ofautophagy-related 7(Atg7ΔHepmice) develop hepatoma, suggesting that autophagy deficiency could be a factor in the initiation of tumorigenesis. We have shown that FGF21 is induced as a ‘mitokine’ whenAtg7is disrupted in insulin target tissues such as the liver, which could affect systemic metabolism through endocrine activity. Since FGF21 or other endocrine FGF such as FGF19 can affect tumor growth, we hypothesized that FGF21 produced byAtg7-knockout (KO) hepatocytes may affect the behavior ofAtg7-KO hepatoma in an autocrine manner. We, thus, crossedAtg7ΔHepmice with systemicFgf21-KO (Fgf21−/−) mice to generateAtg7ΔHepFgf21−/−mice. The number and size of hepatoma ofAtg7ΔHepmice were significantly increased by additionalFgf21KO. The proliferation ofAtg7-KO hepatocyte was significantly increased byFgf21KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver ofAtg7ΔHepFgf21−/−mice compared toAtg7ΔHepFgf21+/+mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver ofAtg7ΔHepFgf21−/−mice compared toAtg7ΔHepFgf21+/+mice, which could explain the increased size of hepatoma inAtg7ΔHepFgf21−/−mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver ofAtg7ΔHepFgf21+/+mice, which was further aggravated by additionalFgf21KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma inAtg7ΔHepFgf21−/−mice compared toAtg7ΔHepFgf21+/+mice. These results show that FGF21 produced by autophagy-deficient hepatocytes could have autocrine or paracrine effects on the number and proliferation of autophagy-deficient hepatoma, suggesting that hormones or factors released from autophagy-deficient tumors can influence the behavior or prognosis of the tumor in addition to the effects on host metabolism.