Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

초록

Mice with hepatocyte-specific deletion of autophagy-related 7 (Atg7(Delta Hep) 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 Atg7 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 Atg7-knockout (KO) hepatocytes may affect the behavior of Atg7-KO hepatoma in an autocrine manner. We, thus, crossed Atg7(Delta Hep) mice with systemic Fgf21-KO (Fgf21(-/-)) mice to generate Atg7(Delta Hep)Fgf21(-/-) mice. The number and size of hepatoma of Atg7(Delta Hep) mice were significantly increased by additional Fgf21 KO. The proliferation of Atg7-KO hepatocyte was significantly increased by Fgf21 KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver of Atg7(Delta Hep)Fgf21(-/-) mice compared to Atg7(Delta Hep)Fgf21(+/+) mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver of Atg7(Delta Hep)Fgf21(-/-) mice compared to Atg7(Delta Hep)Fgf21(+/+) mice, which could explain the increased size of hepatoma in Atg7(Delta Hep)Fgf21(-/-) mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver of Atg7(Delta Hep)Fgf21(+/+) mice, which was further aggravated by additional Fgf21 KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma in Atg7(Delta Hep)Fgf21(-/-) mice compared to Atg7(Delta Hep)Fgf21(+/+) 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.

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