AUTHOR=Kim Jinyoung , Lee Soyeon , Lee Myung-Shik 

TITLE=Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.832804

DOI=10.3389/fonc.2022.832804

ISSN=2234-943X

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