Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

Mice with hepatocyte-specific deletion of ( mice) 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' when is 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 by -knockout (KO) hepatocytes may affect the behavior of -KO hepatoma in an autocrine manner. We, thus, crossed mice with systemic -KO ( ) mice to generate mice. The number and size of hepatoma of mice were significantly increased by additional KO. The proliferation of -KO hepatocyte was significantly increased by KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver of mice compared to mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver of mice compared to mice, which could explain the increased size of hepatoma in mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver of mice, which was further aggravated by additional KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma in mice compared to 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.