44 94

Cited 0 times in

Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

Authors
 Jinyoung Kim  ;  Soyeon Lee  ;  Myung-Shik Lee 
Citation
 FRONTIERS IN ONCOLOGY, Vol.12 : 832804, 2022-03 
Journal Title
FRONTIERS IN ONCOLOGY
Issue Date
2022-03
Keywords
FGF21 (fibroblast growth factor 21) ; ROS (reactive oxygen species) ; YAP1/TAZ pathway ; autophagy ; hepatic tumor
Abstract
Mice with hepatocyte-specific deletion of autophagy-related 7 (Atg7 ΔHep 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 ΔHep mice with systemic Fgf21-KO (Fgf21 -/-) mice to generate Atg7 ΔHep Fgf21 -/- mice. The number and size of hepatoma of Atg7 ΔHep 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 ΔHep Fgf21 -/- mice compared to Atg7 ΔHep Fgf21 +/+ mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver of Atg7 ΔHep Fgf21 -/- mice compared to Atg7 ΔHep Fgf21 +/+ mice, which could explain the increased size of hepatoma in Atg7 ΔHep Fgf21 -/- mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver of Atg7 ΔHep 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 ΔHep Fgf21 -/- mice compared to Atg7 ΔHep 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.
Files in This Item:
T202201581.pdf Download
DOI
10.3389/fonc.2022.832804
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Jinyoung(김진영) ORCID logo https://orcid.org/0000-0002-3810-8549
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188819
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links